3149 – THE EPIGENETIC STATE OF THE CELL OF ORIGIN DEFINES MECHANISMS OF LEUKEMOGENESIS

• Published in: Experimental hematology 2024-08, Vol.137, p.104470, Article 104470
• Main Authors: Li, Zhiheng, Fierstein, Sara, Yano, Mayuri, Frenis, Katie, Chen, Chun-Chin, Wang, Dahai, Falchetti, Marcelo, Cote, Parker, Liu, Tianxin, Orkin, Stuart, Li, Hojun, da Rocha, Edroaldo Lummertz, Hu, Shaoyan, Zhu, Qian, Rowe, Grant
• Format: Article
• Language: English
• ISSN: 0301-472X
• DOI: 10.1016/j.exphem.2024.104470

Despite advances in risk-stratified therapy, acute myeloid leukemia (AML) continues to show variable clinical outcomes, with a subset of patients presenting with refractory disease or experiencing relapse. Expression of stem cell programs is an adverse prognostic factor in AML. Studies in model systems have demonstrated that the normal hematopoietic cell of origin impacts the clinical behavior and stem cell biology of AML, with AML engineered from hematopoietic stem cells (HSCs) or multipotent progenitors (MPPs) prone to chemotherapy resistance compared to AML from lineage-restricted progenitors. However, the mechanisms by which stem cell programs are transmitted from the hematopoietic cell of origin to AML are not fully understood. Here, we engineer the leukemogenic MLL-AF9 chromosomal translocation into defined human hematopoietic populations using gene editing for expression under endogenous promoter regulation. We find that AML from HSCs is enriched for self-renewing leukemia stem cells (LSCs) compared to AML from MPPs or lineage-restricted progenitors. By performing epigenomic profiling, we observe two distinct mechanisms by which the epigenetic state of the HSC/progenitor of origin impacts the biology of the resultant AML: 1) by defining target loci accessible to the MLL-AF9 fusion, and 2) by epigenetic transmission of loci bound by endogenous, full-length MLL1/KMT2A independently of the MLL-AF9 fusion. Within latter mechanism, we identify an inherited HSC epigenetic program that confers dependency on RNA polymerase II recruitment via TFIID that can be readily exploited therapeutically. Together, these findings demonstrate how attributes of the cell of origin are epigenetically transferred to AML to impart LSC programs and impact heterogeneity in clinical behavior, and how this approach can be utilized to define a basis for therapeutic development.