The Role of Methylation in Chronic Lymphocytic Leukemia and Its Prognostic and Therapeutic Impacts in the Disease: A Systematic Review

Chatzidavid, Sevastianos; Kontandreopoulou, Christina-Nefeli; Giannakopoulou, Nefeli; Diamantopoulos, Panagiotis T.; Stafylidis, Christos; Kyrtsonis, Marie-Christine; Dimou, Maria; Panayiotidis, Panayiotis; Viniou, Nora-Athina

doi:https://doi.org/10.1155/2024/1370364

Advances in Hematology

On this page

Abstract Introduction Conclusion Data Availability Disclosure Conflicts of Interest Authors’ Contributions References Copyright Related Articles

Review Article | Open Access

Volume 2024 | Article ID 1370364 | https://doi.org/10.1155/2024/1370364

The Role of Methylation in Chronic Lymphocytic Leukemia and Its Prognostic and Therapeutic Impacts in the Disease: A Systematic Review

Sevastianos Chatzidavid,^1,2Christina-Nefeli Kontandreopoulou,¹Nefeli Giannakopoulou,³Panagiotis T. Diamantopoulos,¹Christos Stafylidis,¹Marie-Christine Kyrtsonis,⁴Maria Dimou,⁴Panayiotis Panayiotidis,⁵and Nora-Athina Viniou^1,6

Academic Editor: Manishekhar Kumar

Received22 Dec 2023

Revised04 Feb 2024

Accepted09 Feb 2024

Published23 Feb 2024

Abstract

Epigenetic regulation has been thoroughly investigated in recent years and has emerged as an important aspect of chronic lymphocytic leukemia (CLL) biology. Characteristic aberrant features such as methylation patterns and global DNA hypomethylation were the early findings of the research during the last decades. The investigation in this field led to the identification of a large number of genes where methylation features correlated with important clinical and laboratory parameters. Gene-specific analyses investigated methylation in the gene body enhancer regions as well as promoter regions. The findings included genes and proteins involved in key pathways that play central roles in the pathophysiology of the disease. Τhe application of these findings beyond the theoretical understanding can not only lead to the creation of prognostic and predictive models and scores but also to the design of novel therapeutic agents. The following is a review focusing on the present knowledge about single gene/gene promoter methylation or mRNA expression in CLL cases as well as records of older data that have been published in past papers.

1. Introduction

Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of clonal B cells in peripheral blood, bone marrow, and secondary lymphoid organs. It is the most common leukemia in adults of Western countries and accounts for approximately 2–35 percent of all leukemias in the United States [1]. CLL is more common in men with a male to female ratio ranging from 1.2 : 1 to 1.8 : 1 [1, 2] and is considered to be a disease of the elderly as the median age at diagnosis is 70 years and an incidence increasing rapidly with increasing age [3]. Despite characterized by a common morphology and immunophenotype pattern, CLL shows a variable clinical behavior spectrum. At one end, some CLL patients have a very indolent disease course and may not require treatment for many years, while at the other end, some patients present a very aggressive disease early from diagnosis and require prompt treatment with lower survival rates despite therapy [4].

In terms of genetic pathobiology, at least one of the four common chromosomal abnormalities (deletion 13q14, trisomy 12, deletion 11q22-23, and deletion 17p12) can be detected by interphase fluorescence in situ hybridization in most patients [5]. Most CLL tumors have myriads of somatic gene mutations. Of these, tumor protein 53 (TP53), ataxia telangiectasia mutated (ATM), neurogenic locus, notch homolog protein (NOTCH), and subunit 1 of the splicing factor 3b protein complex (SF3B1) genes are the most frequently mutated at diagnosis [6, 7]. Several other gene mutations seen in CLL tumors are involved in important cellular signaling pathways. NOTCH signaling, B-cell receptor (BCR) signaling, Toll-like receptor, mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK-Erk) pathway, nuclear factor kappa-light-chain enhancer of activated B cells (NF-kB) signaling, chromatin modifiers signaling, cell cycle signaling, DNA damage signaling, and RNA splicing are some of the many pathways investigated [6–10]. Moreover, it is well documented that the interaction between CLL tumor cells and antigens is regulated by the somatic hypermutation load of the immunoglobulin heavy chain variable region genes [11].

In the complex domain of the tumor microenvironment, CLL cells seem to influence the kind and arrangement of the cells surrounding them, and they are highly dependent on signals from these cells for their own survival and proliferation, encouraging a leukemia-supportive and immunosuppressive microenvironment [11].

Methylation of DNA is an enzyme-mediated modification of DNA structure without interfering in the specific sequence of the base pairs for the gene encoded. Although DNA methylation is important in normal biologic processes, aberrant patterns of methylation are observed in several malignancies. Specifically, two patterns have been mainly described, namely, large sites of global hypomethylation along the genome and localized areas of hypermethylation at CpG islands, within the gene promoter regions. Ιn more and more studies in neoplastic diseases in recent years, there has been an emergence of evidence that methylation of the promoter regions of hundreds of genes, including tumor suppressor genes, results in the failure to express their normal purpose. In other cases, DNA methylation may represent an early step in the pathway by which normal tissue cells undergo tumorigenesis. Some other possible mechanisms for mutational induction secondary to DNA methylation include failure to produce DNA repair proteins that normally protect from mutations and predisposition to increased oxidative DNA damage, resulting in increased mutation potential [12].

Abnormal DNA methylation has been documented in many solid neoplasms, including breast cancer, lung, prostate, colorectal cancer, and melanoma. As described above, hypermethylation of promoter regions inhibits the expression of tumor suppressor genes while hypomethylation activates an oncogene expression. Global hypomethylation is also of crucial role, leading to genomic and chromosomal instability. For instance, BRCA1/2 genes are two of the most studied genes in breast cancer. The hypermethylation of their promoter regions is reported to result in their inactivation and consequent increased risk of breast cancer [13].

As regards CLL, a global DNA methylation pattern was reported to be relatively stable during the disease course and similar both in resting and proliferative cell compartments, implying that aberrant methylation may present as an early leukemogenic event with early indications of specific gene epigenetic changes in CLL samples being described over 30 years ago [14]. Global DNA hypomethylation was reported few years later [15].

Except CLL, abnormal function of basic methylation‐related enzymes is widely reported in several hematological malignancies, such as in myelodysplastic syndromes, myeloproliferative neoplasms, acute myeloid leukemia, T-cell acute lymphoblastic leukemia, and diffuse large B‐cell lymphoma. The final DNA methylation patterns are suggested to be frequently lineage specific and accompanied by specific secondary mutations [16].

The research in this field led to the study and discovery of a large number of genes whose methylation plays an important role in their regulation, while certain correlations with clinical and laboratory parameters were also identified. The streptothricin acetyltransferase, alpha (SAT-α) gene, whose methylation levels were found to be an independent marker of poor treatment-free survival was an early example [17].

With the appearance and application of newer technics such as whole-genome bisulfite sequencing and DNA methylation arrays, global DNA hypomethylation was confirmed and it was reported that gene body and enhancer regions rather than promoter regions were primarily involved [18, 19] whereas hypermethylation was described to occur mainly in transcribed genomic regions [20] and regions affecting other regulatory mechanisms such as spliceosome [21]. After the CLL genome was discovered to be globally hypomethylated, research for aberrantly methylated oncogene targets revealed that hypomethylation of the B cell lymphoma 2 (BCL2) gene, an important antiapoptotic gene, correlated with higher protein expression in CLL [22]. In the following studies, multiple drug-resistance protein 1 (MDR1) and T-cell leukemia/lymphoma 1 (TCL1) genes were reported to be both hypomethylated and upregulated in CLL [23, 24]. Moreover, the nuclear factor of activated T-cell 1 (NFATc1) gene hypomethylation was also identified and was further shown to be associated with increased mRNA and protein expression, suggesting hypomethylation as a mechanism of constitutive activation of NFATc1 expression in CLL. Through subsequent findings, however, it was discovered that the activation of oncogenes through DNA hypomethylation was a rather infrequent lesion in CLL [25].

To date, several studies have reported gene promoter hypermethylation in CLL patients using both global and single gene approaches. The affected genes include tumor suppressors, transcription factors, genes involved in survival and proliferation, genes with prognostic impact, and microRNA genes. There are several methods that have been used to study gene methylation in chronic lymphocytic leukemia. Each approach has its own advantages and limitations, and the choice of the method depends on the specific research question being addressed. Bisulfite sequencing is considered the gold standard method for analyzing DNA methylation at single-nucleotide resolution. Bisulfite treatment of DNA converts unmethylated cytosine to uracil, while leaving methylated cytosine unchanged. After polymerisation chain reaction (PCR) amplification and sequencing, the pattern of cytosine-to-thymine conversion can be used to determine the methylation status of individual CpG sites. Methylation-specific PCR is a PCR-based method that uses primers specific for either methylated or unmethylated DNA to amplify a region of interest. By comparing the intensity of PCR products amplified using methylated-specific versus unmethylated-specific primers, the methylation status of a given region can be determined. Infinium methylation arrays are microarray-based platforms that can interrogate the DNA methylation status of thousands of CpG sites across the genome. Infinium arrays rely on bisulfite conversion of DNA, followed by hybridization with probes that distinguish between methylated and unmethylated DNA at each CpG site. Methylation-sensitive restriction enzyme digestion relies on the use of restriction enzymes that are sensitive to DNA methylation. By digesting genomic DNA with these enzymes and comparing the resulting fragment patterns with and without prior treatment with a DNA methyltransferase, the methylation status of specific regions can be inferred.

2. The CLL Methylome from a Gene-Specific Perspective

Early in 2004, using genome-wide screening for aberrant promoter methylation in CLL samples, 193 sequences were identified as novel targets for aberrant methylation in CLL. Among them, 173 were homologous to specific genes such as glutamate metabotropic receptor 7 (GRM7), cell division protein kinase 6 (CDK6), T-box transcription factor 3 (TBX3), paired box 5 (PAX5), and protein tyrosine phosphatase nonreceptor type 1 (PTPN1) genes [19]. In another study, where DNA methylation was compared within immunoglobulin heavy-chain gene variable region (IGVH) mutated/unmutated subgroups of CLL, it was reported that in IGVH-unmutated cells, tumor suppressor genes such as von Hippel–Lindau (VHL), Abelson interactor 3 (ABI3), and immunoglobulin superfamily member 4 (IGSF4) were found hypermethylated while genes associated with cell proliferation and migration such as adenosine A3 receptor (ADORA3) and perforin 1 (PRF1) were hypomethylated [26].

Regarding microRNAs, a genome-wide profiling in CLL patients led to the detection of 128 microRNAs carrying aberrantly methylated promoters. Hypermethylated loci included the promoter regions of miR-9-2, miR-124-2, miR-129-2, miR-551b, and miR-708, while miR-21, miR-29a/b-1, miR-34a, miR-155, miR-574, and miR-1204 gene promoters were found hypomethylated [27].

When DNA methylation was studied in paired diagnostic and follow-up samples from IGVH mutated and unmutated CLL patients, genes with prognostic significance including chronic lymphocytic leukemia upregulated 1 (CLLU1), lipoprotein lipase (LPL), zeta chain of T-cell receptor-associated protein kinase 70 (ZAP70) and NOTCH1, the epigenetic regulators histone deacetylases 9 and 4 (HDAC9/4), and DNA methyltransferase 3, beta (DNMT3B), were reported to be aberrantly methylated [14]. Another study used the methylation levels of five specific CpGs to track the cellular origin of CLL, where they seemed to act as enhancers. The varying methylation levels of these biomarkers did not translate into gene expression changes, suggesting that they may not have a functional impact but represented a stable molecular mark [28].

In the context of normal B-cell maturation, CLL DNA methylation was reported to be highly enriched in enhancer and promoter regions, especially in regions of transcriptional elongation and in genes involved in B cell- and lymphocyte-related processes and pathways. Regions targeted for hypomethylation during B cell maturation showed highly significant enrichment for the following six transcription factor families: activator protein 1 (AP-1), early B-cell factor (EBF), runt-related transcription factor (RUNX), octamer-binding transcription factor (OCT), interferon regulatory factor (IRF), and NF-kB [20].

In future, it will be crucial to further develop more efficient and accurate prognostic tools that incorporate clinical, cytogenetic, and molecular data. Therapeutic strategies and agent design are constantly reformed in order to pursue discoveries about the biology of the disease, the pathways involved, and the mechanisms of drug resistance.

To capture the latest discoveries, this review focuses on the present knowledge about single gene/gene promoter methylation in CLL biology while also recording older data that have been published in past papers. Through a review of 126 articles indexed in PubMed, we ended up recording data for 133 genes. Then, we classified them in the following tables according to their associated biological pathways and the related data on CLL studies. It is reasonable for several genes to be associated with more than one pathway. Α characteristic attempt to capture the correlations between most genes and pathways is presented in Figure 1.

In the following tables are presented the genes we identified in our search, with information on their function, as well as the findings of studies regarding CLL. In each table, we introduced in detail, data on the study of methylation or mRNA expression of single genes in CLL patients that showed interesting correlations with clinical and laboratory data.

2.1. Chromosome Maintenance and the Cell Cycle Process

2.1.1. SE Translocation and MYN Domain Containing 3 (SMYD3) and Human Telomerase Reverse Transcriptase (hTERT) Genes (Table 1)

SMYD3 is a chromatin modifier that is involved in the development and progression of several malignancies. Methylation levels in specific SMYD3 gene promoter CpG sites were reported to independently predict time to treatment [29].

Hypermethylation of the hTERT gene in CLL was one of the first to be described. TERT acts as a subunit of telomerase, preventing chromosomal degradation after DNA replication. It was reported that hTERT promoter hypermethylation led to decreased telomerase activity and was associated with superior overall survival [30].

2.2. DNA Repair Mechanisms and Purine Biosynthesis

2.2.1. Ribonucleotide Reductase Subunits 1 and 2 (RRM1 and RRM2) Genes (Table 2)

Ribonucleotide reductase is required for DNA replication and repair and consists of RRM1 and RRM2 proteins. In CLL patients, RRM1 mRNA expression was higher in patients without anemia, absence of lymphadenopathy, and 17p gene deletion. Moreover, abnormal lactate dehydrogenase (LDH) levels and higher Rai stage were associated with lower RRM1 mRNA levels. Higher expression of RRM2 mRNA was detected in patients without lymphadenopathy, Rai stage 0, and trisomy 12. The methylated status of RRM1 promoter significantly correlated with lymphadenopathy presence. The methylated status of RRM1 promoter correlated also with about 4 times lower levels of RRM1 mRNA and with about 10 times lower levels of RRM2 mRNA [39].

2.3. Gene Transcription

2.3.1. Cytotoxic T-Lymphocyte-Associated Protein 4 (CTLA-4) Gene (Table 3)

CTLA-4 protein is involved in gene transcription and acts as an immune checkpoint to regulate T-cell function. Mutations in its gene have been associated with insulin-dependent diabetes mellitus, Grave’s disease, Hashimoto thyroiditis, celiac disease, systemic lupus erythematosus, and other autoimmune diseases. In CLL cases, CTLA4 gene was hypomethylated in the first exon region and body region. Compared to healthy controls, CTLA4 gene had a 128-fold higher expression in CLL samples [37, 59].

2.4. RNA Polymerase I Promoter Opening

2.4.1. V-Maf Musculoaponeurotic Fibrosarcoma Oncogene Homolog B (MAFB) Gene (Table 4)

MAFB gene has been associated with survival parameters in CLL cohorts where differentially hypermethylated regions correlated with inferior post-treatment survival. The protein encoded by MAFB gene is a basic leucine zipper (bZIP) transcription factor with an important role in the regulation of hematopoiesis and nervous system development [66].

2.5. Programmed Cell Death/Cell Apoptosis and p53 Signaling

2.5.1. Integrin Subunit Alpha 4 (ITGA4) Gene (Table 5)

ITGA4 is capable of cell adhesion molecules and fibronectin binding and is involved in apoptotic and integrin pathways. It is reported to be deregulated in CLL with adverse clinical features, suggested as a negative prognostic factor related to a more aggressive course and shorter time to treatment. Protein expression is regulated at the mRNA level and in a methylation-regulated manner. Hypermethylation at specific ITGA4 CpG sites was a common phenomenon in the del13q14+ samples. Moreover, it was demonstrated that the methylation status of the ITGA4 gene at CpG site 1 may have a prognostic role [70].

2.6. Transforming Growth Factor-β (TGF-β) Pathway

2.6.1. Doublecortin-Like Kinase 2 (DCLK2) and Tumor Necrosis Factor Receptor Superfamily Member 1B (TNFRSF1B) Genes (Table 6)

Retrotransposons (also referred as class I transposable elements or transposons through RNA intermediates) are a type of genetic component that copy and paste themselves into different genomic locations (transposons) by retroconverting RNA into DNA via the reverse transcription process using RNA transposition intermediate. In solid neoplasms, universal hypomethylation of these elements has been described. In CLL, locus-specific hypomethylation was detected with differential expression of proximal genes, including DCLK2 and TNFRSF1B genes. Moreover, higher levels of DCLK2 and TNFRSF1B expression were associated with inferior survival. DCLK2 protein is characterized by transferase and protein tyrosine kinase activity, whereas TNFRSF1B protein by ubiquitin protein ligase binding and tumor necrosis factor (TNF) receptor activity. Both proteins are involved in TGF-β and TNF pathways [88].

2.7. Wingless-Related Integration Site (WNT) and Hedgehog Pathways

2.7.1. WNT Family Member 5A (WNT5A) Gene (Table 7)

WNT5A gene encodes a receptor tyrosine kinase-like orphan receptor (ROR1) ligand with DNA-binding transcription factor activity and is involved in the regulation of p21 activated kinase 2 (PAK-2), WNT signaling, and developmental pathways during embryogenesis. It is known that its expression differs in CLL patients with worse prognosis in the IGVH-mutated subgroup. Methylation levels of all CpG sites in the WNT5A gene promoter were lower in the group of the intermediate genome methylation profile. In the memory-like and intermediate genome methylation profile groups, promoter methylation and subsequent undetectable WNT5A expression correlated with longer treatment-free survival [95].

2.8. NFAT and T-Cell Receptor (TCR) Signaling

2.8.1. NFATC1 Gene (Table 8)

NFATC1 is part of the NFAT transcription complex. It is primarily involved in gene transcription during the immune response and acts as a downstream regulator of the BCR signaling pathway. As with many other proteins, alternative splicing leads to multiple transcription variants, which in turn may induce the expression of different cytokine genes. Moreover, NFATC1 protein is a central target for immunosuppressive agents. Regarding CLL, when the genome-wide DNA methylation study was performed, NFATC1 gene was reported to be hypomethylated and upregulated. Moreover, NFATC1 gene promoter DNA hypomethylation correlated inversely with RNA levels and was associated with Binet disease staging and thymidine kinase levels, suggesting a potential central role of NFATC1 in CLL pathobiology [105].

2.9. NF-kB Pathway

2.9.1. Leucine Zipper Was Downregulated in Cancer 1 (LDOC1) Gene (Table 9)

LDOC1 gene encodes a leucine zipper protein and is suggested to regulate the NF-κB pathway through the plasma membrane ATPase or TNF-mediated pathway of apoptosis. Its expression has been studied in oral squamous cell carcinoma and pancreatic cancer cells. Regarding CLL, unmethylated status was found in IGVH-unmutated cases [26, 111, 112].

2.10. MAPK/Erk Pathway

2.10.1. Angiopoietin 2 (ANGPT2) Gene (Table 10)

ANGPT2 is a glycoprotein involved in angiogenesis. Conflicting data regarding the involvement of Erkand phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathways in the regulation of ANGPT2 suggest a possible cell-type specific control for this gene in solid tumors. As regards CLL, higher levels of ANGPT2 methylation in the IGHV-mutated population showed a possible epigenetic regulation of this gene. Furthermore, it was reported that ANGPT2 expression is highly dependent on the DNA methylation status, where a lower degree of methylation was associated with a particularly poor prognosis in CLL. Importantly, the percentages of methylation showed negative correlations with ANGPT2 mRNA expression, suggesting that methylation of the ANGPT2 promoter leads to this gene silencing. CLL cases with highly methylated gene status had a more favorable prognosis. Considering that normal B cells showed high levels of ANGPT2 methylation, the apparently aberrant low ANGPT2 methylation levels found in aggressive CLL patients indicate that these latter cases lose normal epigenetic control [14, 119–121].

2.11. NOTCH Signaling

2.11.1. CREBBP (cAMP Response Element-Binding Protein Binding Protein) Gene (Table 11)

In a small Korean cohort, genome-wide methylation profiling identified the CREBBP gene with no known relevance to CLL to be differentially methylated among other genes previously known to be affected in CLL. CREBBP gene encodes chromatin-modifying enzymes and has been described in diffuse large B cell lymphoma, acute lymphoblastic leukemia, and lung cancer [130].

2.12. JAK-STAT Pathway

2.12.1. SOCS-1 (Suppressor of Cytokine Signaling 1) Gene (Table 12)

SOCS-1 is an inhibitor of cytokine signal transduction. Its gene expression can be positively affected by interleukins 2 and 3, erythropoietin, granulocyte macrophage colony-stimulating factor, and interferon-gamma. Gene polymorphisms of SOCS1 and its expression have been studied in several malignancies including diffuse large B-cell lymphoma and acute lymphoblastic leukemia, where, particularly, the expression level of SOCS1 was lower compared to the control group. In CLL, the SOCS1 gene body was hypermethylated in no case [135].

2.13. Phosphatidylinositol-3 Kinase/Protein Kinase B (PI3K/Akt) Signaling

2.13.1. T-Cell Leukemia/Lymphoma 1 Oncogene (TCL1A) Gene (Table 13)

Abnormal expression of TCL1A gene in mouse B-cells led to a leukemia phenotype similar to aggressive human CLL. It is demonstrated that TCL1A physically interacts with DNA methylthansferases 3A and 3B. TCL1A is suggested to act as a coactivator of Akt, activator protein 1 (AP1), and NF-κB pathways with a potential involvement in CLL cells resistance to apoptotic mechanisms. TCL1A expression seems to be strongly associated with the expression levels of ataxia-telangiesctasia mutated (ATM) gene in malignant and nonmalignant B cells. TCL1A gene promoter was hypomethylated in CLL cells and significantly correlated with TCL1A transcription enhancement [139].

2.14. Rho GTPases/Rhodopsin-Like Receptors

2.14.1. Endothelin-1 (ET-1) Gene (Table 14)

This gene is responsible for the creation of a peptide that belongs to the endothelin/sarafotoxin family. This peptide acts as a potent vasoconstrictor and its receptors have been well studied as therapeutic targets in the treatment of pulmonary arterial hypertension. Regarding ET-1 gene expression, alternative splicing leads to several transcript variants and abnormal expression is thought to promote tumorigenic activity, with ET-1 expression being under the constant control of the NF-kB signaling pathway. In CLL, ET-1 is reported to be involved in survival, drug resistance, and growth signaling of leukemic cells. Moreover, it is reported that basal expression levels of ET-1 are affected when high methylation in the region of ET-1 gene first intron is detected [141].

2.15. Class I Major Histocompatibility Complex (MHC)-Mediated Antigen Processing

2.15.1. Ubiquitin Conjugating Enzyme E2 R2 (UBE2R2) Gene (Table 15)

UBE2R2 is involved in Class I MHC-mediated pathways as well as in the metabolism of certain proteins. To develop a tool useful in stratifying CLL patients on a specific methylation signature basis and focusing on time to treatment, it was demonstrated that UBE2R gene methylation levels independently predicted time to treatment [29].

2.16. Estrogen Receptor (ESR)-Mediated Signaling

2.16.1. Estrogen Receptor 1 (ESR1) Gene (Table 16)

ESR1 gene encodes a ligand-dependent transcription factor. ESR1 acts through direct binding to specific estrogen response elements and is associated with other transcription factors. ESR-mediated signaling has been studied in several solid tumors and hematological malignancies. When studied in CLL samples, ESR1 gene was amplified in 15% of the samples examined with a copy number loss frequency ranging between 1 and 10%. The ESR1 gene promoter region was methylated in one out of ten CLL samples controlled, and in normal B cell, the gene promoter was completely unmethylated [51].

2.17. Angiogenesis/Erythropoiesis

2.17.1. Thrombospondin-1 (THBS1) Gene (Table 17)

THBS1 acts as an adhesion-specific glycoprotein. THBS1 is able to bind fibrinogen, fibronectin, laminin, and type V collagen and is involved in platelet aggregation, angiogenesis, and tumorigenesis. In CLL studies, THBS1 gene promoter methylation was detected in 50% of the samples, while in normal samples, the gene promoters were unmethylated [51].

2.18. Slit Glycoprotein/Roundabout Receptor (SLIT/ROBO) Signaling and Nervous System Development

2.18.1. Protein Tyrosine Phosphatase Type O (PTPRO) Gene (Table 18)

The methylation levels of the PTPRO gene have been studied in the pathobiology of several neoplasms including hepatocellular cancer and various lung tumors, with indications of potential tumor suppressor features. Regarding CLL, PTPRO gene promoter was also methylated and gene expression was suppressed compared to normal B cells, with the overall expression of PTPRO being lower in CLL lymphocytes than in normal samples [51].

2.19. Drug Uptake and Sensitivity Mechanisms

2.19.1. Solute Carrier Family 22 Member 18 (SLCO3A1) Gene (Table 19)

Methylation of the SLCO3A1 gene has been associated with survival features in CLL cohorts where specific differentially hypermethylated regions were linked to inferior post-treatment survival. SLCO3A1 gene encodes an anion transporter that is suggested to be involved in transport of inorganic cations/anions and amino acids/oligopeptides, transport of vitamins, nucleosides, and related molecules, as well as drug uptake mechanisms [66].

2.20. Various Other Genes Investigated

2.20.1. GATA-Binding Protein 5 (GATA5) Gene (Table 20)

GATA5 contains two GATA-type zinc fingers and is related to hepatocyte nuclear factor-1alpha. Promoter methylation of the GATA5 gene has been involved in gastric cancer biology. When studied in CLL, GATA 5 gene hypermethylation was detected in 35.1% of the cases. Another study reported that genomic regions which became hypomethylated prior to specific CLL treatment initiation but also after disease relapse were enriched for binding sites of several transcription factors related to CLL pathogenesis, including GATA5. Compared to normal B-cells, these hypomethylated regions were also enriched for the GATA 5 transcription factor [51, 167].

2.20.2. SH3 and Multiple Ankyrin Repeat Domain 1 (SHANK1) Genes (Table 20)

SHANK1 gene encodes a protein acting as a scaffold molecule required for the development and function of neuronal synapses. In CLL samples, a specific CpG region of the SHANK1 gene body (hg19) was reported to be hypermethylated when compared to control samples. Moreover, without yet being strongly supported, it was reported that methylation in the same CpG was detectable in blood samples collected years before CLL diagnosis [170].

2.20.3. RalA-Binding Protein-Associated Eps Domain Containing 1 (REPS1), Interleukin 1B (IL1B), and ATPase Phospholipid Transporting 9B (ATP9B) Genes (Tables 21 and 22)

Specific CpG sites at which the methylation levels independently predicted time to treatment were detected and some of them located in the gene bodies of REPS1, IL1B, and ATP9B. REPS1 protein has calcium ion and SH3 domain-binding activity with involvement in vesicle transport and endocytosis. IL1B protein has interleukin-1 receptor-binding activity and is involved in MIF-mediated glucocorticoid regulation. ATP9B protein is capable of nucleotide binding and ATPase-coupled monoatomic cation transmembrane transporting and is involved in ion channel transport and cardiac conduction mechanisms [29].

2.21. Noncoding RNAs

2.21.1. Colorectal Neoplasia Differentially Expressed (CRNDE) Gene (Table 23)

The expression of the CRNDE gene is increased in proliferating tissues and is involved in the expression of genes associated with metabolism and in neoplasms such as colorectal adenomas and adenocarcinomas. Its related transcription is inversely regulated by insulin and insulin-like growth factors. When studied in CLL cell lines, CRNDE was downregulated and the methylation level of CRNDE promoter was higher than in normal B cells. After exposure to demethylating agents, an increase of CRNDE expression levels was reported [183].

3. Conclusion

Some studies have focused on the potential clinical impact of DNA methylation in CLL phenotypes. Based on the findings abovementioned, time to treatment, an essential feature of CLL management, was reported to be predicted by the methylation status of SMYD3 gene promoter and UBE2R gene methylation levels [29]. Methylation levels in specific CpG sites located in the gene bodies of REPS1, IL1B, and ATP9B genes also correlated with the time to treatment [29].

Regarding overall survival, hTERT gene promoter hypermethylation was associated with superior overall survival [30], and specific hypermethylated MAFB gene loci correlated with inferior post-treatment survival [66]. Moreover, locus-specific hypomethylation of retrotransposons proximal to DCLK2 and TNFRSF1B was related with higher levels of DCLK2 and TNFRSF1B expression and subsequent inferior survival [88]. When CLL patients were classified upon specific IGVH mutation patterns, promoter methylation of the WNT5A gene showed longer treatment-free survival in a subgroup of the patients [95]. Lower levels of DNA methylation of the ANGPT2 gene were related to a particularly poor prognosis in CLL patients [14, 121].

Findings that could be useful in staging and correlating methylation with pre-existing prognostic factors in CLL include RRM1/2 expression, the promoter methylation status that correlated with lymphadenopathy, 17p gene deletion, Rai stage, and trisomy 12 [39], and the documentation of hypermethylation at specific ITGA4 CpG sites in del13q14+ samples [70]. NFATC1 gene promoter hypomethylation was associated with Binet disease staging [105].

Drug sensitivity and mechanisms of resistance development are another important area of study in CLL. Hypermethylation of specific SLCO3A1 gene loci, a gene which among others is involved in drug uptake mechanisms, has also been associated with inferior post-treatment survival [66]. Another gene, ET-1, is related with drug-resistance potential and its expression is affected upon high methylation levels in its first intron region in patients with CLL [141].

Α last finding that could theoretically have a clinical application in CLL cases is about the SHANK1 gene. A specific CpG locus of its body (hg19) was hypermethylated when compared to control samples. Also, it was even weakly supported that methylation in the same CpG was detectable in blood samples collected years before CLL diagnosis [170]. It is a finding that, if confirmed, is very interesting and could be used in panels for early diagnosis of the disease, certainly in combination with other markers in the context of a population screening program or the surveillance of high-risk patients. Certainly, such methods of investigation have their peculiarities and must be applied after appropriate research and discussion in order to be necessary or beneficial for the patients.

Our findings suggested that certain methylation patterns have been associated with disease progression and survival features and may be used as prognostic markers. In addition, some studies have investigated the use of hypomethylating agents as a part of a therapeutic strategy in CLL.

Regarding findings from previous studies that focused on studying large numbers of genes, data are generally limited but quite intriguing. Kanduri et al. applied high-resolution methylation microarrays (27 578 CpG sites) to CLL samples, which were classified in IGHV-mutated (favorable) and IGHV-unmutated/IGHV3-21 (poor-prognostic) subsets. Results demonstrated significant differences in methylation patterns between these subgroups. In IGHV-unmutated cases, they reported methylation of known or potent tumor suppressor genes (for example, VHL, ABI3, and IGSF4) as well as unmethylated genes involved in cell growth and tumor progression (ADORA3 and PRF1). In contrast, these latter genes were silenced by methylation in IGHV-mutated patients. Moreover, they reported the reinducing of four methylated tumor suppressor genes (including VHL and ABI3) in IGHV-unmutated samples using the methyl inhibitor 5-aza-2′-deoxycytidine [26]. Pei et al. reported a genome-wide DNA methylation analysis with 1,764 gene promoters being identified as differentially methylated in at least one sample when compared with normal B cell samples. Aberrant hypermethylation was discovered in all HOX gene clusters and a significant number of WNT signaling pathway genes. The NFATc1p2 promoter and first intron hypomethylated status correlated with the upregulation of both NFAT protein expressions [25]. Kulis et al. performed a wide analysis of the DNA methylome in normal B cells and CLL samples. They identified widespread hypomethylation targeting mainly the gene body and enhancer regions, suggesting that DNA methylation may be functionally relevant beyond promoter regions. Moreover, they reported that distinct patterns in DNA methylation were recorded between different CLL subtypes [18]. Cahill et al. used high-resolution 450 K arrays to analyze samples from IGHV-mutated or untreated and IGHV-unmutated or treated patients. They identified 2239 differentially methylated CpG regions between IGHV-mutated and -unmutated patients, where the majority of the regions were placed outside annotated CpG islands. Known CLL prognostic genes (i.e., LPL, ZAP70, and NOTCH1), epigenetic regulators (HDAC9/4 and DNMT3B), B-cell signaling, and numerous TGF-β and NF-κB/TNF pathway genes were differentially methylated between the subgroups [14]. Barrow et al. reported 490 differentially methylated regions after exposure to therapy. Among them, 31 were CLL related. Seventeen genes were classified as differentially expressed, following treatment in an independent cohort. Methylation of the HOXA4, MAFB, and SLCO3A1 differentially methylated regions associated with post-treatment patient survival and HOXA4 displayed the strongest association. Reinducing of HOXA4 expression in cell lines and primary CLL cells increased apoptosis following treatment with fludarabine, ibrutinib, and idelalisib [66]. Lastly, Zhang et al. identified 34,797 differentially methylated positions related to CLL. Most of them were hypomethylated and located in gene body sites. They combined these positions with existing DNA methylation and RNA sequencing data and identified regions associated with 1,130 genes whose expression was significantly different in CLL samples [37].

The limitations of this study include possible evidence selection bias because data from statistically significant studies are more likely to be published than those that are not statistically significant. Moreover, in some limited reports, it was not stated whether the methylation study included the gene body, the promoter region, or some other related loci. Lastly, some papers did not reported correlations with patients’ clinical data such as sampling time, staging, or prognostic and treatment features.

To summarize, there are still many mechanisms that need to be investigated in order to define the extent of global aberrant DNA methylation in different prognostic groups, the fundamental role of DNA methylation in sites other than CpG islands, and the interaction of DNA methylation with other regulatory processes in the pathogenesis of CLL. Moreover, with the prospect that there is and will continue to be increasing data on gene methylation, it should be noted that a large number of findings will concern passenger DNA methylation events that need to be identified accordingly.

In conclusion, at some points, the research raises even more questions than answers. Further research is still needed to fully understand the complex interplay between DNA methylation and other epigenetic and genetic alterations in CLL and to develop more effective targeted therapies and prognostic stratification tools for this disease.

Data Availability

The datasets used to support the findings of this study are available from the corresponding author on reasonable request.

Disclosure

Citations are included in the reference list.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Authors’ Contributions

SC and N-AV had the idea for the article. SC performed the literature search and wrote the first draft of the manuscript. N-AV critically revised the work. All the authors have discussed the results, drafted further work, and approved the version to be published. All the authors have agreed to be responsible for the accuracy and integrity of any part of the manuscript.

References

R. L. Siegel, K. D. Miller, N. S. Wagle, and AL Jemal, “Cancer statistics,” CA: A Cancer Journal for Clinicians, vol. 73, no. 1, pp. 17–48, 2023.
View at: Publisher Site | Google Scholar
J. A. Hernández, K. J. Land, and R. W. McKenna, “Leukemia, myeloma, and other lymphoreticular neoplasms,” Cancer, vol. 75, pp. 1–381, 1995.
View at: Publisher Site | Google Scholar
A. Smith, D. Howell, R. Patmore, A. Jack, and E. Roman, “Incidence of haematological malignancy by subtype: a report from the haematological malignancy research network,” British Journal of Cancer, vol. 105, no. 11, pp. 1684–1692, 2011.
View at: Publisher Site | Google Scholar
M. Hallek, B. D. Cheson, D. Catovsky et al., “IwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL,” Blood, vol. 131, no. 25, pp. 2745–2760, 2018.
View at: Publisher Site | Google Scholar
V. Grubor, A. Krasnitz, J. E. Troge et al., “Novel genomic alterations and clonal evolution in chronic lymphocytic leukemia revealed by representational oligonucleotide microarray analysis (ROMA),” Blood, vol. 113, no. 6, pp. 1294–1303, 2009.
View at: Publisher Site | Google Scholar
D. A. Landau, E. Tausch, A. N. Taylor-Weiner et al., “Mutations driving CLL and their evolution in progression and relapse,” Nature, vol. 526, no. 7574, pp. 525–530, 2015.
View at: Publisher Site | Google Scholar
F. Nadeu, J. Delgado, C. Royo et al., “Clinical impact of clonal and subclonal TP53, SF3B1BIRC3, NOTCH1, and ATM mutations in chronic lymphocytic leukemia,” Blood, vol. 127, no. 17, pp. 2122–2130, 2016.
View at: Publisher Site | Google Scholar
C. J. Wu, “CLL clonal heterogeneity: an ecology of competing subpopulations,” Blood, vol. 120, no. 20, pp. 4117-4118, 2012.
View at: Publisher Site | Google Scholar
M. D. V Minden, R. Übelhart, D. Schneider et al., “Chronic lymphocytic leukaemia is driven by antigen-independent cell-autonomous signalling,” Nature, vol. 489, no. 7415, pp. 309–312, 2012.
View at: Publisher Site | Google Scholar
J. A. Woyach, A. J. Johnson, and J. C. Byrd, “The B-cell receptor signaling pathway as a therapeutic target in CLL,” Blood, vol. 120, no. 6, pp. 1175–1184, 2012.
View at: Publisher Site | Google Scholar
A. Vardi, A. Agathangelidis, L. A. Sutton, P. Ghia, R. Rosenquist, and K. Stamatopoulos, “Immunogenetic studies of chronic lymphocytic leukemia: revelations and speculations about ontogeny and clinical evolution,” Cancer Research, vol. 74, no. 16, pp. 4211–4216, 2014.
View at: Publisher Site | Google Scholar
S. A. Wajed, P. W. Laird, and T. R. DeMeester, “DNA methylation: an alternative pathway to cancer,” Annals of Surgery, vol. 234, no. 1, pp. 10–20, 2001.
View at: Publisher Site | Google Scholar
C. Zhang, H. Zhao, J. Li et al., “The identification of specific methylation patterns across different cancers,” PLoS One, vol. 10, no. 3, Article ID e0120361, 2015.
View at: Publisher Site | Google Scholar
N. Cahill, A. C. Bergh, M. Kanduri et al., “450K-array analysis of chronic lymphocytic leukemia cells reveals global DNA methylation to be relatively stable over time and similar in resting and proliferative compartments,” Leukemia, vol. 27, no. 1, pp. 150–158, 2013.
View at: Publisher Site | Google Scholar
J. Wahlfors, H. Hiltunen, K. Heinonen, E. Hämäläinen, L. Alhonen, and J. Jänne, “Genomic hypomethylation in human chronic lymphocytic leukemia,” Blood, vol. 80, no. 8, pp. 2074–2080, 1992.
View at: Publisher Site | Google Scholar
P. Blecua, L. Martinez-Verbo, and M. Esteller, “The DNA methylation landscape of hematological malignancies: an update,” Molecular Oncology, vol. 14, no. 8, pp. 1616–1639, 2020.
View at: Publisher Site | Google Scholar
S. Fabris, V. Bollati, L. Agnelli et al., “Biological and clinical relevance of quantitative global methylation of repetitive DNA sequences in chronic lymphocytic leukemia,” Epigenetics, vol. 6, no. 2, pp. 188–194, 2011.
View at: Publisher Site | Google Scholar
M. Kulis, S. Heath, M. Bibikova et al., “Epigenomic analysis detects widespread gene-body DNA hypomethylation in chronic lymphocytic leukemia,” Nature Genetics, vol. 44, no. 11, pp. 1236–1242, 2012.
View at: Publisher Site | Google Scholar
L. J. Rush, A. Raval, P. Funchain et al., “Epigenetic profiling in chronic lymphocytic leukemia reveals novel methylation targets,” Cancer Research, vol. 64, no. 7, pp. 2424–2433, 2004.
View at: Publisher Site | Google Scholar
C. C. Oakes, M. Seifert, Y. Assenov et al., “DNA methylation dynamics during B cell maturation underlie a continuum of disease phenotypes in chronic lymphocytic leukemia,” Nature Genetics, vol. 48, no. 3, pp. 253–264, 2016.
View at: Publisher Site | Google Scholar
U. Rozovski, M. Keating, and Z. Estrov, “The significance of spliceosome mutations in chronic lymphocytic leukemia,” Leukemia and Lymphoma, vol. 54, no. 7, pp. 1364–1366, 2013.
View at: Publisher Site | Google Scholar
M. Hanada, D. Delia, A. Aiello, E. Stadtmauer, and J. C. Reed, “bcl-2 gene hypomethylation and high-level expression in B-cell chronic lymphocytic leukemia,” Blood, vol. 82, no. 6, pp. 1820–1828, 1993.
View at: Publisher Site | Google Scholar
P. Kantharidis, A. El-Osta, M. deSilva et al., “Altered methylation of the human MDR1 promoter is associated with acquired multidrug resistance,” Clinical Cancer Research, vol. 3, no. 11, pp. 2025–2032, 1997.
View at: Google Scholar
M. R. Yuille, A. Condie, E. M. Stone et al., “TCL1 is activated by chromosomal rearrangement or by hypomethylation,” Genes, Chromosomes and Cancer, vol. 30, no. 4, pp. 336–341, 2001.
View at: Publisher Site | Google Scholar
L. Pei, J. H. Choi, J. Liu et al., “Genome-wide DNA methylation analysis reveals novel epigenetic changes in chronic lymphocytic leukemia,” Epigenetics, vol. 7, no. 6, pp. 567–578, 2012.
View at: Publisher Site | Google Scholar
M. Kanduri, N. Cahill, H. Göransson et al., “Differential genome-wide array-based methylation profiles in prognostic subsets of chronic lymphocytic leukemia,” Blood, vol. 115, no. 2, pp. 296–305, 2010.
View at: Publisher Site | Google Scholar
C. Baer, R. Claus, L. P. Frenzel et al., “Extensive promoter DNA hypermethylation and hypomethylation is associated with aberrant microRNA expression in chronic lymphocytic leukemia,” Cancer Research, vol. 72, no. 15, pp. 3775–3785, 2012.
View at: Publisher Site | Google Scholar
A. C. Queirós, N. Villamor, G. Clot et al., “A B-cell epigenetic signature defines three biologic subgroups of chronic lymphocytic leukemia with clinical impact,” Leukemia, vol. 29, no. 3, pp. 598–605, 2015.
View at: Publisher Site | Google Scholar
D. Hussmann, A. Starnawska, L. Kristensen et al., “IGHV-associated methylation signatures more accurately predict clinical outcomes of chronic lymphocytic leukemia patients than IGHV mutation load,” Haematologica, vol. 107, no. 4, pp. 877–886, 2021.
View at: Publisher Site | Google Scholar
O. E. Bechter, W. Eisterer, M. Dlaska, T. Kühr, and J. Thaler, “CpG island methylation of the hTERT promoter is associated with lower telomerase activity in B-cell lymphocytic leukemia,” Experimental Hematology, vol. 30, no. 1, pp. 26–33, 2002.
View at: Publisher Site | Google Scholar
V. Martel, A. Guerci, J. C. Humbert et al., “De novo methylation of tumour suppressor genes CDKN2A and CDKN2B is a rare finding in B-cell chronic lymphocytic leukaemia,” British Journal of Haematology, vol. 99, no. 2, pp. 320–324, 1997.
View at: Publisher Site | Google Scholar
B. Seeliger, S. Wilop, R. Osieka, O. Galm, and E. Jost, “CpG island methylation patterns in chronic lymphocytic leukemia,” Leukemia and Lymphoma, vol. 50, no. 3, pp. 419–426, 2009.
View at: Publisher Site | Google Scholar
S. G. Papageorgiou, S. Lambropoulos, V. Pappa et al., “Hypermethylation of the p15^INK4B gene promoter in B‐chronic lymphocytic leukemia,” American Journal of Hematology, vol. 82, no. 9, pp. 824-825, 2007.
View at: Publisher Site | Google Scholar
J. G. Herman, C. I. Civin, J. P. Issa, M. I. Collector, S. J. Sharkis, and S. B. Baylin, “Distinct patterns of inactivation of p15INK4B and p16INK4A characterize the major types of hematological malignancies,” Cancer Research, vol. 57, no. 5, pp. 837–841, 1997.
View at: Google Scholar
K. Filarsky, A. Garding, N. Becker et al., “Krüppel-like factor 4 (KLF4) inactivation in chronic lymphocytic leukemia correlates with promoter DNA-methylation and can be reversed by inhibition of NOTCH signaling,” Haematologica, vol. 101, no. 6, pp. e249–e253, 2016.
View at: Publisher Site | Google Scholar
K. Forsterová, H. Votavová, J. Schwarz, J. Karban, C. Stuka, and M. Trněný, “Advanced rai stage in patients with chronic lymphocytic leukaemia correlates with simultaneous hypermethylation of plural tumour suppressor genes,” Folia Biologica, vol. 56, no. 4, pp. 158–164, 2010.
View at: Google Scholar
Q. Zhang, Y. Gao, S. Lin et al., “Genome-wide DNA methylation profiling in chronic lymphocytic leukaemia,” Frontiers in Genetics, vol. 13, Article ID 1056043, 2022.
View at: Publisher Site | Google Scholar
K. Rogowski, J. van Dijk, M. M. Magiera et al., “A family of protein-deglutamylating enzymes associated with neurodegeneration,” Cell, vol. 143, no. 4, pp. 564–578, 2010.
View at: Publisher Site | Google Scholar
S. Chatzidavid, C. N. Kontandreopoulou, P. Diamantopoulos et al., “The clinical and prognostic significance of ribonucleotide reductase subunits RRM1 and RRM2 mRNA levels in patients with chronic lymphocytic leukemia,” Clinical Hematology International, vol. 5, no. 2-3, pp. 92–100, 2023.
View at: Publisher Site | Google Scholar
S. Rankin, “Complex elaboration: making sense of meiotic cohesin dynamics,” FEBS Journal, vol. 282, no. 13, pp. 2426–2443, 2015.
View at: Publisher Site | Google Scholar
C. Gelot, J. Guirouilh-Barbat, T. Le Guen et al., “The cohesin complex prevents the end joining of distant DNA double-strand ends,” Molecular Cell, vol. 61, no. 1, pp. 15–26, 2016.
View at: Publisher Site | Google Scholar
D. A. Solomon, J. S. Kim, and T. Waldman, “Cohesin gene mutations in tumorigenesis: from discovery to clinical significance,” BMB Reports, vol. 47, no. 6, pp. 299–310, 2014.
View at: Publisher Site | Google Scholar
S. Thota, A. D. Viny, H. Makishima et al., “Genetic alterations of the cohesin complex genes in myeloid malignancies,” Blood, vol. 124, no. 11, pp. 1790–1798, 2014.
View at: Publisher Site | Google Scholar
J. Mullenders, B. Aranda-Orgilles, P. Lhoumaud et al., “Cohesin loss alters adult hematopoietic stem cell homeostasis, leading to myeloproliferative neoplasms,” Journal of Experimental Medicine, vol. 212, no. 11, pp. 1833–1850, 2015.
View at: Publisher Site | Google Scholar
A. Ioannidou, S. Zachaki, M. Karakosta, A. Daraki, P. Roussou, and K. N. Manola, “Cohesin RAD21 Gene Promoter Methylation in Patients with Chronic Lymphocytic Leukemia,” Cytogenetic and Genome Research, vol. 154, no. 3, pp. 126–131, 2018.
View at: Publisher Site | Google Scholar
M. Esteller, S. R. Hamilton, P. C. Burger, S. B. Baylin, and J. G. Herman, “Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia,” Cancer Research, vol. 59, no. 4, pp. 793–797, 1999.
View at: Google Scholar
G. Lenz, G. Hutter, W. Hiddemann, and M. Dreyling, “Promoter methylation and expression of DNA repair genes hMLH1 and MGMT in acute myeloid leukemia,” Annals of Hematology, vol. 83, no. 10, pp. 628–633, 2004.
View at: Publisher Site | Google Scholar
D. Rossi, D. Capello, A. Gloghini et al., “Aberrant promoter methylation of multiple genes throughout the clinico-pathologic spectrum of B-cell neoplasia,” Haematologica, vol. 89, no. 2, pp. 154–164, 2004.
View at: Google Scholar
D. Sobieszkoda, J. Czech, N. Gablo et al., “MGMT promoter methylation as a potential prognostic marker for acute leukemia,” Archives of Medical Science, vol. 6, pp. 1433–1441, 2017.
View at: Publisher Site | Google Scholar
Z. Fülöp, B. Csernus, B. Tímár, Á Szepesi, and A. Matolcsy, “Microsatellite instability and hMLH1 promoter hypermethylation in Richter's transformation of chronic lymphocytic leukemia,” Leukemia, vol. 17, no. 2, pp. 411–415, 2003.
View at: Publisher Site | Google Scholar
A. M. Cosialls, A. F. Santidrián, L. Coll-Mulet et al., “Epigenetic profile in chronic lymphocytic leukemia using methylation-specific multiplex ligation-dependent probe amplification,” Epigenomics, vol. 4, no. 5, pp. 491–501, 2012.
View at: Publisher Site | Google Scholar
G. Bahari, M. Hashemi, M. Naderi, S. Sadeghi-Bojd, and M. Taheri, “FHIT promoter DNA methylation and expression analysis in childhood acute lymphoblastic leukemia,” Oncology Letters, vol. 14, no. 4, pp. 5034–5038, 2017.
View at: Publisher Site | Google Scholar
S. Takeuchi, M. Matsushita, M. Zimmermann et al., “Clinical significance of aberrant DNA methylation in childhood acute lymphoblastic leukemia,” Leukemia Research, vol. 35, no. 10, pp. 1345–1349, 2011.
View at: Publisher Site | Google Scholar
J. Cui, G. Li, J. Yin et al., “GSTP1 and cancer: expression, methylation, polymorphisms and signaling (Review),” International Journal of Oncology, vol. 56, no. 4, pp. 867–878, 2020.
View at: Publisher Site | Google Scholar
V. A. Paixão, D. O. Vidal, O. L. Caballero et al., “Hypermethylation of CpG island in the promoter region of CALCA in acute lymphoblastic leukemia with central nervous system (CNS) infiltration correlates with poorer prognosis,” Leukemia Research, vol. 30, no. 7, pp. 891–894, 2006.
View at: Publisher Site | Google Scholar
M. Yuille, A. Condie, C. Hudson et al., “Relationship between glutathione S-transferase M1, T1, and P1 polymorphisms and chronic lymphocytic leukemia,” Blood, vol. 99, no. 11, pp. 4216–4218, 2002.
View at: Publisher Site | Google Scholar
F. Rosenthal, K. L. H. Feijs, E. Frugier et al., “Macrodomain-containing proteins are new mono-ADP-ribosylhydrolases,” Nature Structural & Molecular Biology, vol. 20, no. 4, pp. 502–507, 2013.
View at: Publisher Site | Google Scholar
S. Bar-Yehuda, S. M. Stemmer, L. Madi et al., “The A3 adenosine receptor agonist CF102 induces apoptosis of hepatocellular carcinoma via de-regulation of the Wnt and NF-kappaB signal transduction pathways,” International Journal of Oncology, vol. 33, no. 2, pp. 287–295, 2008.
View at: Publisher Site | Google Scholar
M. Palma, G. Gentilcore, K. Heimersson et al., “T cells in chronic lymphocytic leukemia display dysregulated expression of immune checkpoints and activation markers,” Haematologica, vol. 102, no. 3, pp. 562–572, 2017.
View at: Publisher Site | Google Scholar
P. Van Vlierberghe, H. B. Beverloo, J. Buijs-Gladdines et al., “Monoallelic or biallelic LMO2 expression in relation to the LMO2 rearrangement status in pediatric T-cell acute lymphoblastic leukemia,” Leukemia, vol. 22, no. 7, pp. 1434–1437, 2008.
View at: Publisher Site | Google Scholar
M. Zhang and P. C. Swanson, “Swanson PC: V(D)J recombinase binding and cleavage of cryptic recombination signal sequences identified from lymphoid malignancies,” Journal of Biological Chemistry, vol. 283, no. 11, pp. 6717–6727, 2008.
View at: Publisher Site | Google Scholar
Y. Natkunam, S. Zhao, D. Y. Mason et al., “The oncoprotein LMO2 is expressed in normal germinal center B cells and in human B-cell lymphomas,” Blood, vol. 109, no. 4, pp. 1636–1642, 2007.
View at: Publisher Site | Google Scholar
O. di Martino and J. S. Welch, “Retinoic acid receptors in acute myeloid leukemia therapy,” Cancers, vol. 11, no. 12, p. 1915, 2019.
View at: Publisher Site | Google Scholar
G. P. Maiti, S. Sinha, H. Mahmud et al., “SIRT3 overexpression and epigenetic silencing of catalase regulate ROS accumulation in CLL cells activating AXL signaling axis,” Blood Cancer Journal, vol. 11, no. 5, p. 93, 2021.
View at: Publisher Site | Google Scholar
Z. Xiang, W. Yuan, N. Luo et al., “A novel human zinc finger protein ZNF540 interacts with MVP and inhibits transcriptional activities of the ERK signal pathway,” Biochemical and Biophysical Research Communications, vol. 347, no. 1, pp. 288–296, 2006.
View at: Publisher Site | Google Scholar
T. M. Barrow, S. Nakjang, F. Lafta et al., “Epigenome-wide analysis reveals functional modulators of drug sensitivity and posttreatment survival in chronic lymphocytic leukaemia,” British Journal of Cancer, vol. 124, no. 2, pp. 474–483, 2021.
View at: Publisher Site | Google Scholar
G. Strathdee, A. Sim, A. Parker, D. Oscier, and R. Brown, “Promoter hypermethylation silences expression of the HoxA4 gene and correlates with IgVh mutational status in CLL,” Leukemia, vol. 20, no. 7, pp. 1326–1329, 2006.
View at: Publisher Site | Google Scholar
L. Irving, T. Mainou-Fowler, A. Parker, R. E. Ibbotson, D. G. Oscier, and G. Strathdee, “Methylation markers identify high risk patients inIGHVmutated chronic lymphocytic leukemia,” Epigenetics, vol. 6, no. 3, pp. 300–306, 2011.
View at: Publisher Site | Google Scholar
P. K. Kopparapu, M. Abdelrazak Morsy, C. Kanduri, and M. Kanduri, “Gene-body hypermethylation controlled cryptic promoter and miR26A1-dependent EZH2 regulation of TET1 gene activity in chronic lymphocytic leukemia,” Oncotarget, vol. 8, no. 44, pp. 77595–77608, 2017.
View at: Publisher Site | Google Scholar
H. R. Attia, M. H. Ibrahim, S. H. A. El-Aziz et al., “ITGA4 gene methylation status in chronic lymphocytic leukemia,” Future Science OA, vol. 6, no. 7, p. 583, 2020.
View at: Publisher Site | Google Scholar
Q. Jin, H. Chen, A. Luo, F. Ding, and Z. Liu, “S100A14 stimulates cell proliferation and induces cell apoptosis at different concentrations via the receptor for advanced glycation end products (RAGE),” PLoS One, vol. 11, no. 1, Article ID e0147881, 2016.
View at: Publisher Site | Google Scholar
H. Chen, D. Yu, A. Luo et al., “Functional role of S100A14 genetic variants and their association with esophageal squamous cell carcinoma,” Cancer Research, vol. 69, no. 8, pp. 3451–3457, 2009.
View at: Publisher Site | Google Scholar
A. Contente, A. Dittmer, M. C. Koch, J. Roth, and M. Dobbelstein, “A polymorphic microsatellite that mediates induction of PIG3 by p53,” Nature Genetics, vol. 30, no. 3, pp. 315–320, 2002.
View at: Publisher Site | Google Scholar
R. Voltan, P. Secchiero, F. Corallini, and G. Zauli, “Selective induction of TP53I3/p53-inducible gene 3 (PIG3) in myeloid leukemic cells, but not in normal cells by Nutlin-3,” Molecular Carcinogenesis, vol. 53, no. 6, pp. 498–504, 2014.
View at: Publisher Site | Google Scholar
W. H. Saeed, A. A. Eissa, and A. A. Al-Doski, “Impact of TP53 gene promoter methylation on chronic lymphocytic leukemia pathogenesis and progression,” Journal of Blood Medicine, vol. 10, pp. 399–404, 2019.
View at: Publisher Site | Google Scholar
P. M. Flatt, K. Polyak, L. J. Tang et al., “p53-dependent expression of PIG3 during proliferation, genotoxic stress, and reversible growth arrest,” Cancer Letters, vol. 156, no. 1, pp. 63–72, 2000.
View at: Publisher Site | Google Scholar
L. Boominathan, “Some facts and thoughts: p73 as a tumor suppressor gene in the network of tumor suppressors,” Molecular Cancer, vol. 6, no. 1, p. 27, 2007.
View at: Publisher Site | Google Scholar
U. Novak, T. J. Grob, G. Baskaynak et al., “Overexpression of the p73 gene is a novel finding in high-risk B-cell chronic lymphocytic leukemia,” Annals of Oncology, vol. 12, no. 7, pp. 981–986, 2001.
View at: Publisher Site | Google Scholar
P. G. Corn, S. J. Kuerbitz, M. M. van Noesel et al., “Transcriptional silencing of the p73 gene in acute lymphoblastic leukemia and Burkitt's lymphoma is associated with 5' CpG island methylation,” Cancer Research, vol. 59, no. 14, pp. 3352–3356, 1999.
View at: Google Scholar
N. Papakonstantinou, S. Ntoufa, M. Tsagiopoulou et al., “Integrated epigenomic and transcriptomic analysis reveals TP63 as a novel player in clinically aggressive chronic lymphocytic leukemia,” International Journal of Cancer, vol. 144, no. 11, pp. 2695–2706, 2019.
View at: Publisher Site | Google Scholar
A. B. Raneros, A. Minguela, R. M. Rodriguez et al., “Increasing TIMP3 expression by hypomethylating agents diminishes soluble MICA, MICB, and ULBP2 shedding in acute myeloid leukemia, facilitating NK cell-mediated immune recognition,” Oncotarget, vol. 8, no. 19, pp. 31959–31976, 2017.
View at: Publisher Site | Google Scholar
D. D. Wang, W. X. Xu, W. Q. Chen et al., “Identification of TIMP2 as a prognostic biomarker and its correlation with yumor immune microenvironment: a comprehensive pan-cancer analysis,” JAMA Oncology, vol. 59, no. 14, pp. 3352–3356, 2022.
View at: Publisher Site | Google Scholar
A. Troeger, S. Gudowius, G. Escherich et al., “High nerve growth factor receptor (p75NTR) expression is a favourable prognostic factor in paediatric B cell precursor acute lymphoblastic leukaemia,” British Journal of Haematology, vol. 139, no. 3, pp. 450–457, 2007.
View at: Publisher Site | Google Scholar
E. Hutterer, D. Asslaber, C. Caldana et al., “CD18 (ITGB2) expression in chronic lymphocytic leukaemia is regulated by DNA methylation-dependent and independent mechanisms,” British Journal of Haematology, vol. 169, no. 2, pp. 286–289, 2015.
View at: Publisher Site | Google Scholar
A. Rinaldi, A. A. Mensah, I. Kwee et al., “Promoter methylation patterns in Richter syndrome affect stem cell maintenance and cell cycle regulation and differ from de novo diffuse large B-cell lymphoma,” British Journal of Haematology, vol. 163, no. 2, pp. 194–204, 2013.
View at: Publisher Site | Google Scholar
S. Rivas, A. Marín, S. Samtani, E. González-Feliú, and R. Armisén, “MET signaling pathways, resistance mechanisms, and opportunities for target therapies,” International Journal of Molecular Sciences, vol. 23, no. 22, Article ID 13898, 2022.
View at: Publisher Site | Google Scholar
A. Raval, D. M. Lucas, J. J. Matkovic et al., “TWIST2 demonstrates differential methylation in immunoglobulin variable heavy chain mutated and unmutated chronic lymphocytic leukemia,” Journal of Clinical Oncology, vol. 23, no. 17, pp. 3877–3885, 2005.
View at: Publisher Site | Google Scholar
T. M. Barrow, N. Wong Doo, R. L. Milne et al., “Analysis of retrotransposon subfamily DNA methylation reveals novel early epigenetic changes in chronic lymphocytic leukemia,” Haematologica, vol. 106, no. 1, pp. 98–110, 2020.
View at: Publisher Site | Google Scholar
A. G. S. Buggins and C. J. Pepper, “The role of Bcl-2 family proteins in chronic lymphocytic leukaemia,” Leukemia Research, vol. 34, no. 7, pp. 837–842, 2010.
View at: Publisher Site | Google Scholar
D. R. Haudenschild, S. B. Curtiss, T. A. Moseley, and A. H. Reddi, “Generation of interleukin-17 receptor-like protein (IL-17RL) in prostate by alternative splicing of RNA,” The Prostate, vol. 66, no. 12, pp. 1268–1274, 2006.
View at: Publisher Site | Google Scholar
K. Giannopoulos, L. Li, A. Bojarska-Junak et al., “Expression of RHAMM/CD168 and other tumor-associated antigens in patients with B-cell chronic lymphocytic leukemia,” International Journal of Oncology, vol. 29, no. 1, pp. 95–103, 2006.
View at: Publisher Site | Google Scholar
C. Rosenfeld, M. Cheever, and A. Gaiger, “WT1 in acute leukemia, chronic myelogenous leukemia, and myelodysplastic syndrome: therapeutic potential of WT1 targeted therapies,” Leukemia, vol. 17, no. 7, pp. 1301–1312, 2003.
View at: Publisher Site | Google Scholar
R. Sztrolovics, X.-N. Chen, J. Grover, P. J. Roughley, and J. R. Korenberg, “Localization of the human fibromodulin gene (FMOD) to chromosome 1q32 and completion of the cDNA sequence,” Genomics, vol. 23, no. 3, pp. 715–717, 1994.
View at: Publisher Site | Google Scholar
R. J. M. Bashford-Rogers, A. L. Palser, C. Hodkinson et al., “Dynamic variation of CD5 surface expression levels within individual chronic lymphocytic leukemia clones,” Experimental Hematology, vol. 46, pp. 31–37.e10, 2017.
View at: Publisher Site | Google Scholar
L. Poppova, S. Pavlova, B. Gonzalez et al., “Memory B-cell like chronic lymphocytic leukaemia is associated with specific methylation profile of WNT5A promoter and undetectable expression of WNT5A gene,” Epigenetics, vol. 17, no. 12, pp. 1628–1635, 2022.
View at: Publisher Site | Google Scholar
C. G. Kleer, Y. Zhang, Q. Pan et al., “WISP3 is a novel tumor suppressor gene of inflammatory breast cancer,” Oncogene, vol. 21, no. 20, pp. 3172–3180, 2002.
View at: Publisher Site | Google Scholar
A. Gutierrez Jr, R. C. Tschumper, X. Wu et al., “LEF-1 is a prosurvival factor in chronic lymphocytic leukemia and is expressed in the preleukemic state of monoclonal B-cell lymphocytosis,” Blood, vol. 116, no. 16, pp. 2975–2983, 2010.
View at: Publisher Site | Google Scholar
L. Rani, N. Mathur, R. Gupta et al., “Genome-wide DNA methylation profiling integrated with gene expression profiling identifies PAX9 as a novel prognostic marker in chronic lymphocytic leukemia,” Clinical Epigenetics, vol. 9, no. 1, p. 57, 2017.
View at: Publisher Site | Google Scholar
T. H. Liu, A. Raval, S. S. Chen, J. J. Matkovic, J. C. Byrd, and C. Plass, “CpG island methylation and expression of the secreted frizzled-related protein gene family in chronic lymphocytic leukemia,” Cancer Research, vol. 66, no. 2, pp. 653–658, 2006.
View at: Publisher Site | Google Scholar
C. S. Chim, R. Pang, and R. Liang, “Epigenetic dysregulation of the Wnt signalling pathway in chronic lymphocytic leukaemia,” Journal of Clinical Pathology, vol. 61, no. 11, pp. 1214–1219, 2008.
View at: Publisher Site | Google Scholar
E. A. Moskalev, K. Luckert, I. A. Vorobjev et al., “Concurrent epigenetic silencing of wnt/β-catenin pathway inhibitor genes in B cell chronic lymphocytic leukaemia,” BMC Cancer, vol. 12, no. 1, p. 213, 2012.
View at: Publisher Site | Google Scholar
J. R. Melki, P. C. Vincent, R. D. Brown, and S. J. Clark, “Hypermethylation of E-cadherin in leukemia,” Blood, vol. 95, no. 10, pp. 3208–3213, 2000.
View at: Publisher Site | Google Scholar
G. Berx, A. M. Cleton‐Jansen, F. Nollet et al., “E-cadherin is a tumour/invasion suppressor gene mutated in human lobular breast cancers,” The EMBO Journal, vol. 14, no. 24, pp. 6107–6115, 1995.
View at: Publisher Site | Google Scholar
I. G. H. Schmidt-Wolf, C. Plass, J. C. Byrd, K. Frevel, T. Pietsch, and A. Waha, “Assessment of promoter methylation identifies PTCH as a putative tumor suppressor gene in human CLL,” Anticancer Research, vol. 36, no. 9, pp. 4515–4519, 2016.
View at: Publisher Site | Google Scholar
C. Wolf, A. Garding, K. Filarsky et al., “NFATC1 activation by DNA hypomethylation in chronic lymphocytic leukemia correlates with clinical staging and can be inhibited by ibrutinib,” International Journal of Cancer, vol. 142, no. 2, pp. 322–333, 2018.
View at: Publisher Site | Google Scholar
K. Zarnack, H. Eichhorn, R. Kahmann, and M. Feldbrügge, “Pheromone-regulated target genes respond differentially to MAPK phosphorylation of transcription factor Prf1,” Molecular Microbiology, vol. 69, no. 4, pp. 1041–1053, 2008.
View at: Publisher Site | Google Scholar
D. Grimwade, M. Q. Du, S. Langabeer, J. Rogers, and E. Solomon, “Screening for mutations of Bcl10 in leukaemia,” British Journal of Haematology, vol. 109, no. 3, pp. 611–615, 2000.
View at: Publisher Site | Google Scholar
N. Kanazawa, I. Okafuji, N. Kambe et al., “Early-onset sarcoidosis and CARD15 mutations with constitutive nuclear factor- B activation: common genetic etiology with Blau syndrome,” Blood, vol. 105, no. 3, pp. 1195–1197, 2004.
View at: Publisher Site | Google Scholar
H. Ishikawa and G. N. Barber, “STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling,” Nature, vol. 455, no. 7213, pp. 674–678, 2008.
View at: Publisher Site | Google Scholar
J. Zhang, L. G. Xu, K. J. Han, and H. B. Shu, “Identification of a ZU5 and death domain-containing inhibitor of NF-κB,” Journal of Biological Chemistry, vol. 279, no. 17, pp. 17819–17825, 2004.
View at: Publisher Site | Google Scholar
C. H. Lee, T. S. Wong, J. Y. W. Chan et al., “Epigenetic regulation of the X‐linked tumour suppressors <scp>BEX1</scp> and <scp>LDOC1</scp> in oral squamous cell carcinoma,” The Journal of Pathology, vol. 230, no. 3, pp. 298–309, 2013.
View at: Publisher Site | Google Scholar
K. Nagasaki, C. Schem, C. von Kaisenberg et al., “Leucine-zipper protein, LDOC1 inhibits NF-κB activation and sensitizes pancreatic cancer cells to apoptosis,” International Journal of Cancer, vol. 105, no. 4, pp. 454–458, 2003.
View at: Publisher Site | Google Scholar
L. Wang, W. Deng, T. Shi, and D. Ma, “URP2SF, a FERM and PH domain containing protein, regulates NF-κB and apoptosis,” Biochemical and Biophysical Research Communications, vol. 368, no. 4, pp. 899–906, 2008.
View at: Publisher Site | Google Scholar
L. Chen, G. Widhopf, L. Huynh et al., “Expression of ZAP-70 is associated with increased B-cell receptor signaling in chronic lymphocytic leukemia,” Blood, vol. 100, no. 13, pp. 4609–4614, 2002.
View at: Publisher Site | Google Scholar
A. Wiestner, A. Rosenwald, T. S. Barry et al., “ZAP-70 expression identifies a chronic lymphocytic leukemia subtype with unmutated immunoglobulin genes, inferior clinical outcome, and distinct gene expression profile,” Blood, vol. 101, no. >12, pp. 4944–4951, 2003.
View at: Publisher Site | Google Scholar
M. Corcoran, A. Parker, J. Orchard et al., “ZAP-70 methylation status is associated with ZAP-70 expression status in chronic lymphocytic leukemia,” Haematologica, vol. 90, no. 8, pp. 1078–1088, 2005.
View at: Google Scholar
S. P. Chantepie, D. Vaur, C. Grunau et al., “ZAP-70 intron1 DNA methylation status: determination by pyrosequencing in B chronic lymphocytic leukemia,” Leukemia Research, vol. 34, no. 6, pp. 800–808, 2010.
View at: Publisher Site | Google Scholar
R. Claus, D. M. Lucas, S. Stilgenbauer et al., “Quantitative DNA methylation analysis identifies a single CpG dinucleotide important for ZAP-70 expression and predictive of prognosis in chronic lymphocytic leukemia,” Journal of Clinical Oncology, vol. 30, no. 20, pp. 2483–2491, 2012.
View at: Publisher Site | Google Scholar
P. C. Maisonpierre, C. Suri, P. F. Jones et al., “Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis,” Science, vol. 277, no. 5322, pp. 55–60, 1997.
View at: Publisher Site | Google Scholar
S. Krug, J. Huth, F. Göke et al., “Knock-down of Pdcd4 stimulates angiogenesis via upregulation of angiopoietin-2,” Biochimica et Biophysica Acta (BBA) Molecular Cell Research, vol. 1823, no. 4, pp. 789–799, 2012.
View at: Publisher Site | Google Scholar
S. Martinelli, M. Kanduri, R. Maffei et al., “ANGPT2promoter methylation is strongly associated with gene expression and prognosis in chronic lymphocytic leukemia,” Epigenetics, vol. 8, no. 7, pp. 720–729, 2013.
View at: Publisher Site | Google Scholar
M. Hojjat-Farsangi, M. Jeddi-Tehrani, A. H. Daneshmanesh et al., “Spontaneous immunity against the receptor tyrosine kinase ROR1 in patients with chronic lymphocytic leukemia,” PLoS One, vol. 10, no. 11, Article ID e0142310, 2015.
View at: Publisher Site | Google Scholar
A. Raval, S. M. Tanner, J. C. Byrd et al., “Downregulation of death-associated protein kinase 1 (DAPK1) in chronic lymphocytic leukemia,” Cell, vol. 129, no. 5, pp. 879–890, 2007.
View at: Publisher Site | Google Scholar
A. Mohamad, R. Hassan, A. Husin, M. F. Johan, and S. Sulong, “Aberrant methylation of tumour suppressor gene ADAM12 in chronic lympocytic leukemia patients: application of methylation specific PCr technique,” Asian Pacific Journal of Cancer Prevention, vol. 22, no. 1, pp. 85–91, 2021.
View at: Publisher Site | Google Scholar
S. Nagafuchi, H. Katsuta, R. Koyanagi-Katsuta et al., “Autoimmune regulator (AIRE) gene is expressed in human activated CD4+ T-cells and regulated by mitogen-activated protein kinase pathway,” Microbiology and Immunology, vol. 50, no. 12, pp. 979–987, 2006.
View at: Publisher Site | Google Scholar
S. M. Okamura, C. E. Oki-Idouchi, and P. S. Lorenzo, “The exchange factor and diacylglycerol receptor RasGRP3 interacts with dynein light chain 1 through its C-terminal domain,” Journal of Biological Chemistry, vol. 281, no. 47, pp. 36132–36139, 2006.
View at: Publisher Site | Google Scholar
Y. Zheng, H. Liu, J. Coughlin, J. Zheng, L. Li, and J. C. Stone, “Phosphorylation of RasGRP3 on threonine 133 provides a mechanistic link between PKC and Ras signaling systems in B cells,” Blood, vol. 105, no. 9, pp. 3648–3654, 2005.
View at: Publisher Site | Google Scholar
J. J. Coughlin, S. L. Stang, N. A. Dower, and J. C. Stone, “RasGRP1 and RasGRP3 regulate B cell proliferation by facilitating B cell receptor Ras signaling,” The Journal of Immunology, vol. 175, no. 11, pp. 7179–7184, 2005.
View at: Publisher Site | Google Scholar
Y. Hayashida, T. Goi, Y. Hirono, K. Katayama, T. Urano, and A. Yamaguchi, “PPP1R3 gene (protein phosphatase 1) alterations in colorectal cancer and its relationship to metastasis,” Oncology Reports, vol. 13, no. 6, pp. 1223–1227, 2005.
View at: Publisher Site | Google Scholar
M. Kim, E. Lee, D. Y. Zang et al., “Novel genes exhibiting DNA methylation alterations in Korean patients with chronic lymphocytic leukaemia: a methyl-CpG-binding domain sequencing study,” Scientific Reports, vol. 10, no. 1, p. 1085, 2020.
View at: Publisher Site | Google Scholar
D. A. Moreno, C. A. Scrideli, M. A. A. Cortez et al., “Research paper: differential expression of HDAC3, HDAC7 and HDAC9 is associated with prognosis and survival in childhood acute lymphoblastic leukaemia,” British Journal of Haematology, vol. 150, no. 6, pp. 665–673, 2010.
View at: Publisher Site | Google Scholar
T. Shinawi, V. Hill, A. Dagklis et al., “KIBRA gene methylation is associated with unfavorable biological prognostic parameters in chronic lymphocytic leukemia,” Epigenetics, vol. 7, no. 3, pp. 211–215, 2012.
View at: Publisher Site | Google Scholar
A. Slipicevic, K. Jørgensen, M. Skrede et al., “Fatty acid binding protein 7 (FABP7) is involved in the proliferation and invasion of melanoma cells,” BMC Cancer, vol. 8, pp. 1–13, 2008.
View at: Publisher Site | Google Scholar
G. Fabbri, S. Rasi, D. Rossi et al., “Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation,” Journal of Experimental Medicine, vol. 208, no. 7, pp. 1389–1401, 2011.
View at: Publisher Site | Google Scholar
T. T. Dristy, A. R. Noor, P. Dey, and A. Saha, “Structural analysis and conformational dynamics of SOCS1 gene mutations involved in diffuse large B-cell lymphoma,” Gene, vol. 864, Article ID 147293, 2023.
View at: Publisher Site | Google Scholar
L. Dumoutier, C. Leemans, D. Lejeune, S. V. Kotenko, and J. C. Renauld, “Cutting edge: STAT activation by IL-19, IL-20 and mda-7 through IL-20 receptor complexes of two types,” The Journal of Immunology, vol. 167, no. 7, pp. 3545–3549, 2001.
View at: Publisher Site | Google Scholar
D. T. Francois, I. M. Katona, C. H. June, L. M. Wahl, and J. J. Mond, “Examination of the inhibitory and stimulatory effects of IFN-α, β, and γ on human B-cell proliferation induced by various B-cell mitogens,” Clinical Immunology and Immunopathology, vol. 48, no. 3, pp. 297–306, 1988.
View at: Publisher Site | Google Scholar
F. Arruga, B. Gizdic, C. Bologna et al., “Mutations in NOTCH1 PEST domain orchestrate CCL19-driven homing of chronic lymphocytic leukemia cells by modulating the tumor suppressor gene DUSP22,” Leukemia, vol. 31, no. 9, pp. 1882–1893, 2017.
View at: Publisher Site | Google Scholar
A. Garding, N. Bhattacharya, S. Haebe et al., “TCL1A and ATM are co-expressed in chronic lymphocytic leukemia cells without deletion of 11q,” Haematologica, vol. 98, no. 2, pp. 269–273, 2013.
View at: Publisher Site | Google Scholar
M. O'Hayre, M. Niederst, J. F. Fecteau et al., “Mechanisms and consequences of the loss of PHLPP1 phosphatase in chronic lymphocytic leukemia (CLL),” Leukemia, vol. 26, no. 7, pp. 1689–1692, 2012.
View at: Publisher Site | Google Scholar
S. Martinelli, R. Maffei, S. Fiorcari et al., “The expression of endothelin-1 in chronic lymphocytic leukemia is controlled by epigenetic mechanisms and extracellular stimuli,” Leukemia Research, vol. 54, pp. 17–24, 2017.
View at: Publisher Site | Google Scholar
Y. H. Jang, S. Namkoong, Y. M. Kim, S. J. Lee, B. J. Park, and D. S. Min, “Cleavage of phospholipase D1 by caspase promotes apoptosis via modulation of the p53-dependent cell death pathway,” Cell Death & Differentiation, vol. 15, no. 11, pp. 1782–1793, 2008.
View at: Publisher Site | Google Scholar
E. A. Moskalev, P. Jandaghi, M. Fallah et al., “GHSR DNA hypermethylation is a common epigenetic alteration of high diagnostic value in a broad spectrum of cancers,” Oncotarget, vol. 6, no. 6, pp. 4418–4427, 2015.
View at: Publisher Site | Google Scholar
F. Latif, K. Tory, J. Gnarra et al., “Identification of the von Hippel-Lindau disease tumor suppressor gene,” Science, vol. 260, no. 5112, pp. 1317–1320, 1993.
View at: Publisher Site | Google Scholar
K. Vargova, N. Curik, P. Burda et al., “MYB transcriptionally regulates the miR-155 host gene in chronic lymphocytic leukemia,” Blood, vol. 117, no. 14, pp. 3816–3825, 2011.
View at: Publisher Site | Google Scholar
M. K. Bos, T. Deger, S. Sleijfer, J. W. M. Martens, and S. M. Wilting, “ESR1 methylation measured in cell-free DNA to evaluate endocrine resistance in metastatic breast cancer patients,” International Journal of Molecular Sciences, vol. 23, no. 10, p. 5631, 2022.
View at: Publisher Site | Google Scholar
A. Roma and P. A. Spagnuolo, “Estrogen receptors alpha and beta in acute myeloid leukemia,” Cancers, vol. 12, no. 4, p. 907, 2020.
View at: Publisher Site | Google Scholar
M. P. Navarrete-Meneses and P. Pérez-Vera, “Epigenetic alterations in acute lymphoblastic leukemia,” Boletín Médico del Hospital Infantil de México, vol. 74, no. 4, pp. 243–264, 2017.
View at: Publisher Site | Google Scholar
N. Maass, T. Hojo, M. Zhang, R. Sager, W. Jonat, and K. Nagasaki, “Maspin-A novel protease inhibitor with tumor-suppressing activity in breast cancer,” Acta Oncologica, vol. 39, no. 8, pp. 931–934, 2000.
View at: Publisher Site | Google Scholar
R. Maffei, S. Fiorcari, J. Bulgarelli et al., “Endothelium-mediated survival of leukemic cells and angiogenesis-related factors are affected by lenalidomide treatment in chronic lymphocytic leukemia,” Experimental Hematology, vol. 42, no. 2, pp. 126–136.e1, 2014.
View at: Publisher Site | Google Scholar
E. Pramil, L. Herbi Bastian, T. Denèfle et al., “Targeting chronic lymphocytic leukemia with N-methylated thrombospondin-1–derived peptides overcomes drug resistance,” Blood Advances, vol. 3, no. 20, pp. 2920–2933, 2019.
View at: Publisher Site | Google Scholar
J. Pu, T. Ai, W. Weng et al., “TJP1, a membrane-expressed protein, is a potential therapeutic and prognostic target for lung cancer,” Technology in Cancer Research and Treatment, vol. 21, 2022.
View at: Publisher Site | Google Scholar
M. Hanoun, L. Eisele, M. Suzuki et al., “Epigenetic silencing of the circadian clock gene CRY1 is associated with an indolent clinical course in chronic lymphocytic leukemia,” PLoS One, vol. 7, no. 3, Article ID e34347, 2012.
View at: Publisher Site | Google Scholar
T. L. Dunwell, R. E. Dickinson, T. Stankovic et al., “Frequent epigenetic inactivation of the SLIT2 gene in chronic and acute lymphocytic leukemia,” Epigenetics, vol. 4, pp. 265–269, 2009.
View at: Publisher Site | Google Scholar
A. J. Appe, A. Aggerholm, M. C. Hansen et al., “Differential expression levels and methylation status of ROBO1 in mantle cell lymphoma and chronic lymphocytic leukaemia,” The International Journal of Literary Humanities, vol. 39, no. 3, pp. 70–73, 2017.
View at: Publisher Site | Google Scholar
S. S. Chen, A. J. Johnson, R. Claus, F. Sablitzky, C. Plass, and J. C. L. Byrd, “Loss of Id4 accelerates CLL progression in TCL1 mice,” Blood, vol. 112, no. 11, p. 3153, 2008.
View at: Publisher Site | Google Scholar
S. Weiler, J. A. Ademokun, and J. D. Norton, “ID helix-loop-helix proteins as determinants of cell survival in B-cell chronic lymphocytic leukemia cells in vitro,” Molecular Cancer, vol. 14, no. 1, p. 30, 2015.
View at: Publisher Site | Google Scholar
S. S. Chen, R. Claus, D. M. Lucas et al., “Silencing of the inhibitor of DNA binding protein 4 (ID4) contributes to the pathogenesis of mouse and human CLL,” Blood, vol. 117, no. 3, pp. 862–871, 2011.
View at: Publisher Site | Google Scholar
J. R. Slupsky, “Does B cell receptor signaling in chronic lymphocytic leukaemia cells differ from that in other B cell types?” Scientific, vol. 2014, Article ID 208928, 14 pages, 2014.
View at: Publisher Site | Google Scholar
T. Motiwala, S. Majumder, H. Kutay et al., “Methylation and silencing of protein tyrosine phosphatase receptor type O in chronic lymphocytic leukemia,” Clinical Cancer Research, vol. 13, no. 11, pp. 3174–3181, 2007.
View at: Publisher Site | Google Scholar
J. Wakim, E. Arman, S. Becker-Herman et al., “The PTPROt tyrosine phosphatase functions as an obligate haploinsufficient tumor suppressor in vivo in B-cell chronic lymphocytic leukemia,” Oncogene, vol. 36, no. 26, pp. 3686–3694, 2017.
View at: Publisher Site | Google Scholar
H. Y. Yamada and G. J. Gorbsky, “Tumor suppressor candidate TSSC5 is regulated by UbcH6 and a novel ubiquitin ligase RING105,” Oncogene, vol. 25, no. 9, pp. 1330–1339, 2006.
View at: Publisher Site | Google Scholar
M. A. Kaderi, M. Kanduri, A. M. Buhl et al., “LPL is the strongest prognostic factor in a comparative analysis of RNA-based markers in early chronic lymphocytic leukemia,” Haematologica, vol. 96, no. 8, pp. 1153–1160, 2011.
View at: Publisher Site | Google Scholar
I. Daugaard, D. Hussmann, L. Kristensen et al., “Chronic lymphocytic leukemia patients with heterogeneously or fully methylated LPL promotor display longer time to treatment,” Epigenomics, vol. 10, no. 9, pp. 1155–1166, 2018.
View at: Publisher Site | Google Scholar
F. R. M. Latini, J. P. Hemerly, B. C. G. Freitas, G. Oler, G. J. Riggins, and J. M. Cerutti, “ABI3 ectopic expression reduces in vitro and in vivocell growth properties while inducing senescence,” BMC Cancer, vol. 11, no. 1, p. 11, 2011.
View at: Publisher Site | Google Scholar
A. Sjödin, D. Guo, S. Sørhaug, L. Bjermer, R. Henriksson, and H. Hedman, “Dysregulated secretoglobin expression in human lung cancers,” Lung Cancer, vol. 41, no. 1, pp. 49–56, 2003.
View at: Publisher Site | Google Scholar
M. Tsagiopoulou, N. Papakonstantinou, T. Moysiadis et al., “DNA methylation profiles in chronic lymphocytic leukemia patients treated with chemoimmunotherapy,” Clinical Epigenetics, vol. 11, no. 1, p. 177, 2019.
View at: Publisher Site | Google Scholar
S.-E. Tzorakoleftheraki, A. Iliadis, I. Kostopoulos, and T. Koletsa, “TdT expression in normal and neoplastic sebaceous cells,” Histopathology, vol. 71, no. 6, pp. 985–988, 2017.
View at: Publisher Site | Google Scholar
T. P. McGraw, J. D. Folds, F. J. Bollum, and S. A. Stass, “Terminal deoxynucleotidyl transferase-positive acute myeloblastic leukemia,” American Journal of Hematology, vol. 10, no. 3, pp. 251–258, 1981.
View at: Publisher Site | Google Scholar
E. Loi, L. Moi, A. Fadda et al., “Methylation alteration of SHANK1 as a predictive, diagnostic and prognostic biomarker for chronic lymphocytic leukemia,” Oncotarget, vol. 10, no. 48, pp. 4987–5002, 2019.
View at: Publisher Site | Google Scholar
E. D. Apel, R. M. Lewis, R. M. Grady, and J. R. Sanes, “Syne-1, A dystrophin- and klarsicht-related protein associated with synaptic nuclei at the neuromuscular junction,” Journal of Biological Chemistry, vol. 275, no. 41, pp. 31986–31995, 2000.
View at: Publisher Site | Google Scholar
D. Jiang, X. Wu, X. Sun et al., “Bone mesenchymal stem cell-derived exosomal microRNA-7-5p inhibits progression of acute myeloid leukemia by targeting OSBPL11,” Journal of Nanobiotechnology, vol. 20, no. 1, p. 29, 2022.
View at: Publisher Site | Google Scholar
Y. Murakami, “Involvement of a cell adhesion molecule, TSLC1/IGSF4, in human oncogenesis,” Cancer Science, vol. 96, no. 9, pp. 543–552, 2005.
View at: Publisher Site | Google Scholar
S. Nakahata, Y. Saito, K. Marutsuka et al., “Clinical significance of CADM1/TSLC1/IgSF4 expression in adult T-cell leukemia/lymphoma,” Leukemia, vol. 26, no. 6, pp. 1238–1246, 2012.
View at: Publisher Site | Google Scholar
K. Ando, M. Ohira, T. Ozaki et al., “Expression of TSLC1, a candidate tumor suppressor gene mapped to chromosome 11q23, is downregulated in unfavorable neuroblastoma without promoter hypermethylation,” International Journal of Cancer, vol. 123, no. 9, pp. 2087–2094, 2008.
View at: Publisher Site | Google Scholar
Y. P. Yu, G. Yu, G. Tseng et al., “Glutathione peroxidase 3, deleted or methylated in prostate cancer, suppresses prostate cancer growth and metastasis,” Cancer Research, vol. 67, no. 17, pp. 8043–8050, 2007.
View at: Publisher Site | Google Scholar
K. Takahashi, C. Matsumoto, and C. Ra, “FHL3 negatively regulates human high-affinity IgE receptor β-chain gene expression by acting as a transcriptional co-repressor of MZF-1,” Biochemical Journal, vol. 386, no. 1, pp. 191–200, 2005.
View at: Publisher Site | Google Scholar
Y. Yang, H. Hou, E. M. Haller, S. V. Nicosia, and W. Bai, “Suppression of FOXO1 activity by FHL2 through SIRT1-mediated deacetylation,” The EMBO Journal, vol. 24, no. 5, pp. 1021–1032, 2005.
View at: Publisher Site | Google Scholar
M. Hammarsund, M. M. Corcoran, W. Wilson et al., “Characterization of a novel B-CLL candidate gene DLEU7, located in the 13q14 tumor suppressor locus,” FEBS Letters, vol. 556, no. 1-3, pp. 75–80, 2004.
View at: Publisher Site | Google Scholar
Z. Jia, S. Gao, N. M'Rabet, C. De Geyter, and H. Zhang, “Sp1 is necessary for gene activation of Adamts17 by estrogen,” Journal of Cellular Biochemistry, vol. 115, no. 10, pp. 1829–1839, 2014.
View at: Publisher Site | Google Scholar
G. A. Gutman, K. G. Chandy, S. Grissmer et al., “International Union of Pharmacology. LIII. Nomenclature and molecular relationships of voltage-gated potassium channels,” Pharmacological Reviews, vol. 57, no. 4, pp. 473–508, 2005.
View at: Publisher Site | Google Scholar
G. Loeber, I. Maurer-Fogy, and R. Schwendenwein, “Purification, cDNA cloning, and heterologous expression of the human mitochondrial NADP(+)-dependent malic enzyme,” Biochemical Journal, vol. 304, no. 3, pp. 687–692, 1994.
View at: Publisher Site | Google Scholar
J. Ni, J. Hong, Q. Li, Q. Zeng, and R. Xia, “Long non-coding RNA CRNDE suppressing cell proliferation is regulated by DNA methylation in chronic lymphocytic leukemia,” Leukemia Research, vol. 105, Article ID 106564, 2021.
View at: Publisher Site | Google Scholar
A. S. Chan, P. S. Thorner, J. A. Squire, and M. Zielenska, “Identification of a novel gene NCRMS on chromosome 12q21 with differential expression between rhabdomyosarcoma subtypes,” Oncogene, vol. 21, no. 19, pp. 3029–3037, 2002.
View at: Publisher Site | Google Scholar
L. Q. Wang, K. Y. Wong, Z. H. Li, and C. S. Chim, “Sang Chim C: epigenetic silencing of tumor suppressor long non-coding RNA BM742401 in chronic lymphocytic leukemia,” Oncotarget, vol. 7, no. 50, pp. 82400–82410, 2016.
View at: Publisher Site | Google Scholar
A. M. Buhl, J. Jurlander, C. H. Geisler et al., “CLLU1 expression levels predict time to initiation of therapy and overall survival in chronic lymphocytic leukemia,” European Journal of Haematology, vol. 76, no. 6, pp. 455–464, 2006.
View at: Publisher Site | Google Scholar
S. Subhash, P. O. Andersson, S. T. Kosalai, C. Kanduri, and M. Kanduri, “Global DNA methylation profiling reveals new insights into epigenetically deregulated protein coding and long noncoding RNAs in CLL,” Clinical Epigenetics, vol. 8, no. 1, p. 106, 2016.
View at: Publisher Site | Google Scholar

Copyright

Copyright © 2024 Sevastianos Chatzidavid et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PDF Download Citation

Download other formats

Order printed copies

Views

185

Downloads

189

Citations