Insights into novel emerging epigenetic drugs in myeloid malignancies

Abstract

Epigenetics has been defined as ‘a stably heritable phenotype resulting from changes in a chromosome without alterations in the DNA sequence’ and several epigenetic regulators are recurrently mutated in hematological malignancies. Epigenetic modifications include changes such as DNA methylation, histone modifications and RNA associated gene silencing. Transcriptional regulation, chromosome stability, DNA replication and DNA repair are all controlled by these modifications. Mutations in genes encoding epigenetic modifiers are a frequent occurrence in hematologic malignancies and important in both the initiation and progression of cancer. Epigenetic modifications are also frequently reversible, allowing excellent opportunities for therapeutic intervention. The goal of epigenetic therapies is to reverse epigenetic dysregulation, restore the epigenetic balance, and revert malignant cells to a more normal condition. The role of epigenetic therapies thus far is most established in hematologic malignancies, with several agents already approved by the US Food and Drug Administration. In this review, we discuss pharmacological agents targeting epigenetic regulators.

Epigenetics in a Spectrum of Myeloid Diseases and Its Exploitation for Therapy

“…HDAC1 and HDAC2 behave as tumor suppressors during the initiation of acute promyelocytic leukemia, while they act as oncogenes in established leukemia cells [ 144 ]. HDAC inhibitors are approved for lymphoma and multiple myeloma, and clinical trials, both as monotherapy and in combination, are ongoing for MDS and AML [ 145 ]. Early combinatorial trials with azacitidine show promising clinical activity and safety for MDS [ 146 ].…”

DNA Methylation and Intra-Clonal Heterogeneity: The Chronic Myeloid Leukemia Model

“…However, the myelosuppression induced by these drugs and the constraints related to injectable forms remain an ethical obstacle to the implementation of a clinical research protocol in patients with CP-CML because of the benefit/risk balance and the difficulty to formally identify patients with CML that will be resistant or less sensitive to TKIs. New drugs or dosage forms, especially oral ones, which have already proven their efficacy in AML and myelodysplastic syndromes [ 118 , 119 , 120 ] could be an interesting alternative.…”

Obesity and Related Type 2 Diabetes: A Failure of the Autonomic Nervous System Controlling Gastrointestinal Function?

“…Pharmaceutical-epigenetics is an area of research that refers to the study of chemotherapeutic agents that can reverse the epigenome alterations [151]. Since a crucial characteristic of epigenetic modification is that it is reversible and modifiable, the opportunity exists for preventive and therapeutic interventions on obesity and type 2 diabetes using specific drugs, as already effectively applied to other pathologies [152].…”