[Epigenetic therapy for hematologic malignancies].

Abstract

Cumulative evidence suggests that at least some hematologic malignancies are derived from alterations of epigenetic machinery. Next generation sequencing has revealed recurrent mutations of genes related to DNA methylation and histone modification in myelodysplastic syndromes (MDS), acute myeloid leukemia, malignant lymphoma, and multiple myeloma. Both these pathways are targetable and specific inhibitors of their related proteins are currently in development. Among these novel therapies, hypomethylating agents have been approved for MDS, and recently, histone deacetylase inhibitors became available for T-cell lymphoma and multiple myeloma. Agents currently undergoing clinical trials include inhibitors of IDH2 targeting DNA methylation, and EZH2, Dot1L, and BRD4 inhibitors designed to target either writers or readers of post-translational modifications (PTMs) of histones. In a phase I setting, where the maximum tolerated dose has not been reached, efficacy was reported with these agents. Furthermore, Dot1bL and IDH2 inhibitors have been shown to induce differentiation of leukemic blasts in patients with MLL gene rearrangements and IDH2 mutations, respectively, thus providing functional evidence supporting the use of inhibitors of epigenetic mechanisms as a means of differentiation therapy for hematologic malignancies.

• Authors: Yukio Kobayashi
• Journal: [Rinsho ketsueki] The Japanese journal of clinical hematology (Rinsho Ketsueki) Vol. 56 Issue 10 Pg. 2015-23 (Oct 2015) ISSN: 0485-1439 [Print] Japan
• PMID: 26458440 (Publication Type: English Abstract, Journal Article)

Chemical References

• Antineoplastic Agents
• Histones

Topics

• Antineoplastic Agents (chemistry, therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• DNA Methylation
• Drug Design
• Epigenesis, Genetic
• Hematologic Neoplasms (drug therapy, genetics)
• Histones (metabolism)
• Humans