Scientific publications

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

Nov 15, 2022 | Magazine: Experimental Hematology

Faezeh Darbaniyan 1, Hong Zheng 2, Rashmi Kanagal-Shamanna 3, Pamela Lockyer 2, Guillermo Montalban-Bravo 2, Marcos Estecio 4, Yue Lu 4, Kelly A Soltysiak 2, Kelly S Chien 2, Hui Yang 2, Koji Sasaki 2, Caleb Class 5, Irene Ganan-Gomez 2, Kim-Anh Do 1, Guillermo Garcia-Manero 2, Yue Wei 6     


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.

CITATION Exp Hematol. 2022 Nov:115:44-53. doi: 10.1016/j.exphem.2022.09.002. Epub 2022 Sep 21.