Targeting DNA Methylation in Leukemia, Myelodysplastic Syndrome, and Lymphoma: A Potential Diagnostic, Prognostic, and Therapeutic Tool

Abstract

DNA methylation represents a crucial mechanism of epigenetic regulation in hematologic malignancies. The methylation process is controlled by specific DNA methyl transferases and other regulators, which are often affected by genetic alterations. Global hypomethylation and hypermethylation of tumor suppressor genes are associated with hematologic cancer development and progression. Several epi-drugs have been successfully implicated in the treatment of hematologic malignancies, including the hypomethylating agents (HMAs) decitabine and azacytidine. However, combinations with other treatment modalities and the discovery of new molecules are still the subject of research to increase sensitivity to anti-cancer therapies and improve patient outcomes. In this review, we summarized the main functions of DNA methylation regulators and genetic events leading to changes in methylation landscapes. We provide current knowledge about target genes with aberrant methylation levels in leukemias, myelodysplastic syndromes, and malignant lymphomas. Moreover, we provide an overview of the clinical trials, focused mainly on the combined therapy of HMAs with other treatments and its impact on adverse events, treatment efficacy, and survival rates among hematologic cancer patients. In the era of precision medicine, a transition from genes to their regulation opens up the possibility of an epigenetic-based approach as a diagnostic, prognostic, and therapeutic tool.

The Clinical and Prognostic Significance of Ribonucleotide Reductase Subunits RRM1 and RRM2 mRNA Levels in Patients with Chronic Lymphocytic Leukemia

“…Other investigators reported that the hypomethylation status of the neoangiogenic factor ANGPT2 was correlated with shorter overall survival and poor prognosis in CLL patients [43]. Τhe above findings and a series of others described in several studies demonstrate the importance of DNA methylation in CLL diagnosis, prognosis and potential therapeutic targeting [44]. Previous attempts to incorporate a hypomethylating agent as monotherapy in the treatment of refractory CLL were not so successful [45].…”

Epigenetic Modulation of DDIT3 and MGMT Expression Acts Synergistically with Resistance to Imatinib towards CML Disease Progression: A Hospital based Study

“…DNA Methylation in CpG islands is a robust phenomenon of gene silencing that may drive malignancy by inactivating crucial tumour -suppressor mechanisms (Jelinek et al, 2011). Hyper-methylation of DNA is a familiar witness in myelogenous leukemia (Kalinkova et al, 2022). Failure of the gene regulation may be accompanied with leukemogenesis and the development of CML.…”

Phospholipase C delta 1 inhibits WNT/β‐catenin and EGFR-FAK-ERK signaling and is disrupted by promoter CpG methylation in renal cell carcinoma

“…PLCD1 encodes an enzyme involved in calcium homeostasis, energy metabolism, intracellular transport and signal transduction. Silence of PLCD1 by promoter CpG methylation has been described in a few epithelial and hematological malignancies, including gastric cancer (GsCa), ESCC, colorectal cancer (CRC), breast cancer (BrCa), pancreatic cancer (PAAD), chronic myeloid leukemia (CML) and non-small cell lung cancer (NSCLC) [ 10 – 14 ]. However, its relevance to RCC pathogenesis is unclear.…”