Distinct Mechanisms of Alterations in DNA Methylation/Demethylation Leading to Myelodysplastic Syndromes/Acute Myeloid Leukemia and Chronic Lymphocytic Leukemia

Abstract

Epigenetic dysregulation is present in both myeloid and lymphoid disorders, with important differences reported between myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML), on one hand, and chronic lymphocytic leukemia (CLL), on the other. Qualitative differences are reported in MDS/AML with gene fusions (e.g. TET1/LCX) and somatic mutations in epigenetic regulators (e.g. DNMT3A, TET2, IDH1/2), while differences in CLL are predominantly quantitative (e.g. DNMT3A, TET2). Indeed, and as supported by studies in animal models, a defective DNA methylation/demethylation process represents a competitive advantage to the myeloid lineage and an early event in MDS/AML, while in the case of CLL, epigenetic events appear later and are associated with disease progression. Finally, in both MDS/AML and CLL, the focal or global DNA methylation/demethylation process is altered and contributes to disease progression and activity. In conclusion, a better understanding of the epigenetic regulators involved in myeloid/lymphoid differentiation, their localization and the co-recruitment of other proteins at specific DNA target sites, could offer us the possibility to modulate hematopoiesis, and control disease initiation and/or progression.