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

Autor: Darbaniyan F; Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX., Zheng H; Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX., Kanagal-Shamanna R; Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, TX., Lockyer P; Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX., Montalban-Bravo G; Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX., Estecio M; Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, X., Lu Y; Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, X., Soltysiak KA; Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX., Chien KS; Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX., Yang H; Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX., Sasaki K; Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX., Class C; Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX; Department of Pharmaceutical Sciences, Butler University, Indianapolis, IN., Ganan-Gomez I; Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX., Do KA; Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX., Garcia-Manero G; Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX., Wei Y; Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX. Electronic address: ywei@mdanderson.org.
Jazyk: angličtina
Zdroj: Experimental hematology [Exp Hematol] 2022 Nov; Vol. 115, pp. 44-53. Date of Electronic Publication: 2022 Sep 21.
DOI: 10.1016/j.exphem.2022.09.002
Abstrakt: 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.
Competing Interests: Conflict of Interest Disclosure The authors declare no competing interests.
(Published by Elsevier Inc.)
Databáze: MEDLINE
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