Methylated Epigenetic biomarker Clinical Impact Details Supporting literature Follicular lymphoma IRF-4 Pathogenesis Overexpression of BCL-6 Choi et al. [45] SHP-1 Pathogenesis Proliferation of B-cells Hayslip et al. [47] Androgen receptor gene Pathogenesis Release of immature B-cells Hayslip et al. [47] DAPK Pathogenesis Protection from apoptosis Hayslip et al[47] p16INK4A Grade Progression to high grade lymphoma Villuendas et al[49] Genome-wide methylation profiling Prognosis and Biology 263 genes differentially methylated between ABC and GCB-DLBCL Shaknovich et al. [52] Diffuse Large BCell Lymphoma p16INK4A Grade Correlated with high grade histology, more aggressive phenotype Herman et al. [48] p16INK4A Prognosis Poor outcomes after RCHOP chemotherapy Jardin et al. [50] p16INK4A Prognosis Marker for relapse risk following therapy Martinez-elgado et al. [51] MGMT Prognosis Hypermethylation associated with improved OS and PFS, Improved responses to alkylator therapy Esteller et al[60] Mantle Cell Lymphoma Genome-wide methylation profiling Biology Differential methylation of several genes including CDKN2B, MLF-1, PCDH8 and HOXD8 Leshchenko et al. [56] CD-37 Therapy Hypomethylated and overexpressed in 13/14 patients. Targeting cytotoxic in cell lines. Leshchenko et al. [56] Myelodysplastic Syndromes DAPK Pathogenesis Protection from apoptosis Voso et al[70] p15INK4B Prognosis Associated with high risk MDS and progression to AML Tien et al[73] p15INK4B, CDH1, HIC1, and ER Prognosis Hypermethylation more frequent in advanced stages and associated with shorter survival Aggerholm et al. [74] Multi-gene score Prognosis Combined methylation score predicts OS and PFS Shen at al. [76] SOCS1 Prognosis Methylated in 54/114 (47.4%) MDS. Associated with higher grade MDS. Correlated with remission/relapse. Wu et al. [75] Acute Myeloid Leukemia Genome-wide methylation profiling Prognosis/Classification/Biology Can differentiate prognostic groups. May shed more light on biology of AML. Figueroa et al[79] Chronic Lymphocytic Leukemia Genome-wide methylation profiling Prognosis Several tumor suppressor genes including ABI3, VHL and IGSF4 were hypermethylated in poor prognostic unmutated IgHV CLL Kanduri et al. [92] DAPK1 Biology Hypermethylated and poorly expressed in sporadic and familial CLL Raval et al. [95] ZAP-70 Prognosis Hypomethylated and expressed in IgHV CLL Corcoran et al. [94] CD38, BTG4, HOXA4 Prognosis Combined methylation score predicts prognosis independent of other factors. Irving et al. [98] Multiple Myeloma Genome-wide methylation profiling Prognosis/Classification Differential methylation between normal plasma cells/MGUS –Myeloma – Plasma cell leukemia Walker at al. [102] p16INK4A Prognosis Methylation associated with poorer OS Guillerm et al. [103]

MRD – Minimal residual disease OS – Overall survival PFS – Progression free survival DAPK – Death associated protein kinase MGMT – O6-methylguanine DNA methyltransferase

Table 2: Aberrant methylation and impact in various hematological malignancies.