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

Table 1

Chromosome maintenance and cell cycle process.

Gene names	Related pathways	Findings in CLL	Ref.
SMYD3	Chromatin organization	Methylation levels in specific CpG sites independently predicted time to treatment	[29]
hTERT	Chromosome maintenance signaling by WNT	Promoter hypermethylation was associated with superior overall survival	[30]
CDKN2A/2B	Capable of inducing cell cycle arrest in G1 and G2 phases and regulation of activated PAK-2 gene expression (transcription)	Both genes’ promoters have been found variously hypermethylated in CLL cases among different studies; common point of these studies was that hypermethylation of CDKN2A and CDKN2B was mutually exclusive in CLL cases	[31–34]
KLF4	G1-to-S transition of the cell cycle after DNA damage through p53 gene expression (transcription), NOTCH	Aberrant methylation of the KLF4 promoter was significantly associated with gene expression levels compared to normal samples after B cell activation, KLF4 expression was reported to be downregulated	[35]
PTPN6	Cell growth, differentiation, mitotic cycle, and oncogenic transformation	In advanced Rai stage cases, aberrant methylation of PTPN6 promoter reached 70% in the samples examined	[36]
AGBL4	Metabolism of proteins actin and tubulin folding	AGBL4 expression was reported to be reduced in patients with hypermethylated promoter regions and hypomethylated body regions	[37, 38]

CLL: chronic lymphocytic leukemia, Ref.: reference, SMYD3: SE translocation and MYN-domain containing 3 protein, hTERT: human telomerase reverse transcriptase, CDKN2A/2B: cyclin-dependent kinase inhibitors 2A and 2B, KLF4: Krüppel-like factor 4, PTPN6: tyrosine-protein phosphatase nonreceptor type 6, AGBL4: ATP/GTP binding protein like 4, WNT: wingless-related integration site, PAK-2: P21 activated kinase 2, NOTCH: neurogenic locus notch homolog protein.