How Epigenetic Therapy Beats Adverse Genetics in Monosomy Karyotype AML
- 15 February 2021
- journal article
- editorial
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 81 (4), 813-815
- https://doi.org/10.1158/0008-5472.can-20-4108
Abstract
The study by Greve and colleagues, in this issue of Cancer Research, provides new molecular insights into the intriguing clinical activity of DNA hypomethylating agents (HMA) in patients with acute myeloid leukemia (AML) with monosomal karyotypes. Patients with AML with adverse monosomal karyotypes are known to benefit from HMAs, but not cytarabine, a cytidine analog without HMA activity, but the specific molecular mechanisms remain poorly understood. The authors investigated the mechanistic effects of HMAs on gene reactivation in AML in the context of the most common monosomal karyotypes, genetic deletion of chromosome 7q and 5q. They identified genes with tumor-suppressive properties, an endogenous retrovirus cooperatively repressed by DNA hypermethylation, and increased genetic losses on hemizygous chromosomal regions versus normal biallelic regions in AML cell models. Treatment with HMAs preferentially induced expression of these hemizygous genes to levels similar to those of genes in a biallelic state. In addition to CpG hypomethylation, decitabine treatment resulted in histone acetylation and an open chromatin configuration specifically at hemizygous loci. By using primary blood blasts isolated from patients with AML receiving decitabine and AML patient-derived xenograft models established from patients with either monosomal karyotypes or normal cytogenetics, Greve and colleagues both validated their findings in primary patient samples and demonstrated superior antileukemic activity of decitabine compared with chemotherapy with cytarabine. These mechanistic insights into how epigenetic therapy beats adverse genetics in monosomy karyotype AML will open new therapeutic opportunities for a difficult-to-treat patient group. See related article by Greve et al., p. 834Funding Information
- Stand Up To Cancer (P30 CA82709-20)
This publication has 10 references indexed in Scilit:
- Decitabine Induces Gene Derepression on Monosomic Chromosomes: In Vitro and In Vivo Effects in Adverse-Risk Cytogenetics AMLCancer Research, 2021
- Pharmacologic induction of innate immune signaling directly drives homologous recombination deficiencyProceedings of the National Academy of Sciences of the United States of America, 2020
- Activation of a Subset of Evolutionarily Young Transposable Elements and Innate Immunity Are Linked to Clinical Responses to 5-AzacytidineCancer Research, 2020
- Exploiting epigenetically mediated changes: Acute myeloid leukemia, leukemia stem cells and the bone marrow microenvironmentPublished by Elsevier BV ,2019
- Decitabine improves response rate and prolongs progression-free survival in older patients with newly diagnosed acute myeloid leukemia and with monosomal karyotype: A subgroup analysis of the DACO-016 trialAmerican Journal of Hematology, 2018
- Epigenetic Therapy Ties MYC Depletion to Reversing Immune Evasion and Treating Lung CancerCell, 2017
- Decitabine improves progression-free survival in older high-risk MDS patients with multiple autosomal monosomies: results of a subgroup analysis of the randomized phase III study 06011 of the EORTC Leukemia Cooperative Group and German MDS Study GroupAnnals of Hematology, 2015
- Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous RetrovirusesCell, 2015
- DNA-Demethylating Agents Target Colorectal Cancer Cells by Inducing Viral Mimicry by Endogenous TranscriptsCell, 2015
- Phase 1 study of low-dose prolonged exposure schedules of the hypomethylating agent 5-aza-2′-deoxycytidine (decitabine) in hematopoietic malignanciesBlood, 2004