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- Title
MLL-AF9- and HOXA9-mediated acute myeloid leukemia stem cell self-renewal requires JMJD1C.
- Authors
Nan Zhu; Mo Chen; Rowena Eng; DeJong, Joshua; Sinha, Amit U.; Rahnamay, Noushin F.; Koche, Richard; Al-Shahrour, Fatima; Minehart, Janna C.; Chun-Wei Chen; Deshpande, Aniruddha J.; Haiming Xu; Chu, S. Haihua; Ebert, Benjamin L.; Roeder, Robert G.; Armstrong, Scott A.; Zhu, Nan; Chen, Mo; Eng, Rowena; Chen, Chun-Wei
- Abstract
Self-renewal is a hallmark of both hematopoietic stem cells (HSCs) and leukemia stem cells (LSCs); therefore, the identification of mechanisms that are required for LSC, but not HSC, function could provide therapeutic opportunities that are more effective and less toxic than current treatments. Here, we employed an in vivo shRNA screen and identified jumonji domain-containing protein JMJD1C as an important driver of MLL-AF9 leukemia. Using a conditional mouse model, we showed that loss of JMJD1C substantially decreased LSC frequency and caused differentiation of MLL-AF9- and homeobox A9-driven (HOXA9-driven) leukemias. We determined that JMJD1C directly interacts with HOXA9 and modulates a HOXA9-controlled gene-expression program. In contrast, loss of JMJD1C led to only minor defects in blood homeostasis and modest effects on HSC self-renewal. Together, these data establish JMJD1C as an important mediator of MLL-AF9- and HOXA9-driven LSC function that is largely dispensable for HSC function.
- Subjects
MYELOID leukemia; HEMATOPOIETIC stem cells; STEM cell culture; LABORATORY mice; CELL differentiation; GENE expression; REGULATION of blood circulation; PHYSIOLOGY; STEM cells; ANIMAL experimentation; ANIMALS; MICE; OXIDOREDUCTASES; PROTEINS; RESEARCH funding; ACUTE myeloid leukemia; CANCER cell culture
- Publication
Journal of Clinical Investigation, 2016, Vol 126, Issue 3, p997
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI82978