ISSN 2997-1036
International Journal of Hematology | Vol. 6, No. 3, March 2015 | pp. 17–24
DOI: 10.46882/2015/IJH/000063
Review Article
Title: Evolving mechanisms of drug resistance to hypomethylating agents in myelodysplastic syndromes management
Names of Authors: M. A. Bello¹, O. R. Eze²
Authors’ Affiliations: ¹Department of Haematology, Aminu Kano Teaching Hospital, Kano, Nigeria; ²Department of Pathology, University of Benin, Benin City, Nigeria
Abstract: Hypomethylating agents like azacitidine and decitabine have changed the therapeutic management of high-risk myelodysplastic syndromes, yet primary or secondary drug resistance eventually develops in most patients. This review synthesizes current insights into the cellular and molecular mechanisms driving this resistance, focusing on altered drug transport kinetics, down-regulated cytidine deaminase activation pathways, and mutations in DNA methyltransferase enzymes (DNMT3A). Clonal evolution studies demonstrate that under therapeutic selection, myelodysplastic subclones harboring mutations in TP53, ASXL1, or RUNX1 expand rapidly, promoting resistance and accelerated transformation to acute myeloid leukemia. Additionally, the bone marrow microenvironment protects malignant cells via cytokine signaling cascades and immune checkpoint upregulation (PD-L1). Managing hypomethylating agent failure is a major clinical challenge due to limited second-line choices. Evolving combination regimens that pair hypomethylating backbones with histone deacetylase inhibitors, BCL-2 inhibitors (venetoclax), or targeted immunotherapies offer a promising way to overcome epigenetic resistance mechanisms and improve clinical survival.
Keywords: Myelodysplastic syndromes, hypomethylating agents, azacitidine, drug resistance, clonal evolution
Manuscript Timeline: Received: December 11, 2014; Revised: January 20, 2015; Accepted: February 12, 2015; Published: March 19, 2015.