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

Table 2

DNA repair mechanisms and purine biosynthesis.

Gene names	Related pathway	Findings in CLL	Ref.
RRM1 and RRM2	Pyrimidine deoxyribonucleotides biosynthesis and purine nucleotides de novo biosynthesis	RRM1 mRNA expression was higher in patients without anemia, absence of lymphadenopathy and 17p gene deletion, abnormal LDH and higher Rai stage were reported to be associated with lower RRM1 mRNA levels, and higher expression of RRM2 mRNA was detected in patients without lymphadenopathy, Rai stage 0, and trisomy 12	[29, 39]
RAD21	Separation of sister chromatids and cell cycle DNA repair mechanisms	There are differences in RAD21 promoter methylation proportion among patients, RAD21 inactivation via methylation may affect DNA repair mechanisms and amplify self-renewal potential of CLL cells	[40–45]
MGMT and hMLH1	DNA damage reversal homology-directed repair	MGMT promoter region was rarely identified to be hypermethylated, and hMLH1 promoter was reported to be hypermethylated in a small case series of indolent CLL with later Richter’s transformation	[32, 46–50]
FHIT	Loss of its activity results in replication stress and DNA damage	In a limited series of CLL cases studied, FHIT promoter was reported to be hypermethylated	[51–53]
GSTP1	Important regulatory features in detoxification, antioxidative damage innate immune system	GSTP1 promoter hypermethylation was reported in 2.7% of the samples controlled	[51, 54–56]
MACROD2	DNA damage response purine nucleoside metabolic process	MACROD2 expression was demonstrated to be lower in cases with hypermethylated promoter regions and hypomethylated body regions	[37, 57]
ADORA3	Activation of the NF-kB pathway, purinergic signaling, GPCR signaling	Methylated gene body is reported in IGVH-mutated cases	[26, 58]

CLL: chronic lymphocytic leukemia, Ref.: reference, RRM1: ribonucleotide reductase subunit 1, RRM2: ribonucleotide reductase subunit 2, RAD21: double-strand-break repair protein rad21, MGMT: methylguanine methyltransferase, hMLH1: human mutL homolog 1, FHIT: fragile histidine triad, GSTP1: glutathione S-transferase p1 gene, MACROD2: mono-ADP ribosylhydrolase 2, ADORA3: adenosine A3 receptor, NF-kB: Nuclear factor kappa B, GPCR: G protein-coupled receptor, LDH: lactic dehydrogenase, IGVH: immunoglobulin variable heavy chain gene.