Transcriptomic Signatures of Hypomethylating Agent Failure in Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia

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1 Scopus citations

Abstract

Hypomethylating agents (HMAs) are the standard of care for myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). HMA treatment failure is a major clinical problem and its mechanisms are poorly characterized. We performed RNA sequencing in CD34+ bone marrow stem hematopoietic stem and progenitor cells (BM-HSPCs) from 51 patients with CMML and MDS before HMA treatment and compared transcriptomic signatures between responders and nonresponders. We observed very few genes with significant differential expression in HMA non-responders versus responders, and the commonly altered genes in non-responders to both azacitidine (AZA) and decitabine (DAC) treatments were immunoglobulin genes. Gene set analysis identified 78 biological pathways commonly altered in non-responders to both treatments. Among these, we determined that the γ-aminobutyric acid (GABA) receptor signaling significantly affected hematopoiesis in both human BM-HSPCs and mice, indicating that the transcriptomic signatures identified here could serve as candidate biomarkers and therapeutic targets for HMA failure in MDS and CMML.

Original languageEnglish (US)
Pages (from-to)44-53
Number of pages10
JournalExperimental Hematology
Volume115
DOIs
StatePublished - Nov 2022

ASJC Scopus subject areas

  • Molecular Biology
  • Hematology
  • Genetics
  • Cell Biology
  • Cancer Research

MD Anderson CCSG core facilities

  • Research Animal Support Facility
  • Biostatistics Resource Group
  • Advanced Technology Genomics Core
  • Epigenomics Profiling Core Facility

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