| | Gene name | Related pathway | Findings in CLL | Ref. |
| | ITGA4 | Apoptotic pathways and integrin pathway | Protein levels are related to 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 shown to be a common phenomenon in the del13q14+ samples, and the methylation status of ITGA4 at CpG site 1 was demonstrated to be have a prognostic role | [70] | | S100A14 | Modulates TP53 protein levels MAPK-Erk NF-kB | Unmethylated gene body status was found in IGVH-unmutated samples | [26, 71, 72] | | TP53I3 | Gene expression (transcription), TP53-mediated transcription of cell death genes | Gene methylated gene body status was reported in IGVH-mutated cases, patients showed the unmethylated TP53 gene promoter status, and TP53 promoter methylation significantly correlated to reduced platelet counts and advanced stage at diagnosis | [26, 73–76] | | p73 | TP53-mediated transcription of cell death genes; gene expression (transcription) | Protein expression correlated positively with higher risk of CLL stages; regarding p73 hypermethylation, there are conflicting results from different studies showing that pathways other than isolated regulation of p73 activity are responsible for CLL pathogenesis | [32, 77–79] | | TP63 | TP53-mediated transcription of cell death genes; gene expression (transcription) | TP63 gene was primarily hypomethylated in the promoter region and overexpressed in a subset of IGVH-unmutated samples with the highest risk for Richter’s transformation. BCR stimulation in that group of CLL cases led to protein induction and increased cell survival | [80] | | TIMP-2/3 | GPCR signaling | TIMP-2 and TIMP-3 generally lack hypermethylation | [32, 81, 82] | | NGFR | Antiproliferative signals transmission, p75 NTR receptor-mediated signaling | NGFR gene body was reported to be unmethylated in IGVH-mutated cases | [26, 83] | | ITGB2 | Apoptotic pathways integrin pathway | The grade of methylation was negatively associated with CD18 surface expression; high grade of ITGB2 promoter methylation was found in CLL samples with low CD18 expression, whereas high CD18 expressing CLL cells; in the trisomy 12 subgroup, they were mainly unmethylated at the same region; when proliferating and nonproliferating cells were compared, the ITGB2 promoter methylation was similar among these groups | [84] | | OSM | MIF-mediated glucocorticoid regulation, Erk signaling | In a study where cells from CLL, Richter’s transformed CLL, and normal B cells were analyzed, OSM displayed significantly higher promoter methylation levels in Richter’s syndrome compared to the other groups | [85] | | MET | Apoptotic pathways, GPCR signaling | MET expression was reduced in patients with hypermethylated promoter regions and hypomethylated body regions | [37, 86] | | TWIST2 | Gene expression (transcription), regulation of activated PAK-2 negative regulator of p53 | Promoter methylation was reported in IGVH-mutated cases | [87] |
|
|
CLL: chronic lymphocytic leukemia, Ref.: reference, NGFR: nerve growth factor receptor, S100A14: S100 calcium binding protein A14, TP53I3: tumor protein P53 inducible protein 3, p73: a, TP63: tumor protein 63, TIMP-2/3: tissue inhibitors of metalloproteinase 2 and 3, ITGA4: integrin subunit alpha 4, ITGB2: integrin subunit beta 2, OSM: oncostatin M, MET: mesenchymal epithelial transition receptor tyrosine kinase, TWIST2: twist family basic helix-loop-helix transcription factor 2, p75: p75 neurotrophin receptor, NTR: neurotrophin receptor, TP53: tumor protein 53, MAPK-Erk: mitogen-activated protein kinase—extracellular signal-regulated kinases, NF-kB: nuclear factor kappa-beta, GPCR: G protein-coupled receptor, PAK-2: P21 activated kinase 2, BCR: B cell receptor gene, del: deletion, CD18: cluster of differentiation 18, IGVH: immunoglobulin variable heavy chain gene.
|
