TY - JOUR
T1 - Transcriptomic Signatures of Hypomethylating Agent Failure in Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia
AU - Darbaniyan, Faezeh
AU - Zheng, Hong
AU - Kanagal-Shamanna, Rashmi
AU - Lockyer, Pamela
AU - Montalban-Bravo, Guillermo
AU - Estecio, Marcos
AU - Lu, Yue
AU - Soltysiak, Kelly A.
AU - Chien, Kelly S.
AU - Yang, Hui
AU - Sasaki, Koji
AU - Class, Caleb
AU - Ganan-Gomez, Irene
AU - Do, Kim Anh
AU - Garcia-Manero, Guillermo
AU - Wei, Yue
N1 - Publisher Copyright:
© 2022
PY - 2022/11
Y1 - 2022/11
N2 - 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.
AB - 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.
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U2 - 10.1016/j.exphem.2022.09.002
DO - 10.1016/j.exphem.2022.09.002
M3 - Article
C2 - 36150563
AN - SCOPUS:85139059802
SN - 0301-472X
VL - 115
SP - 44
EP - 53
JO - Experimental Hematology
JF - Experimental Hematology
ER -