Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 126, Issue 3, Pages 997-1011Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI82978
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Funding
- American Cancer Society
- Leukemia and Lymphoma Society
- Gabrielle's Angel Foundation
- National Cancer Institute [U01CA105423, R01CA140575, P01CA66996, K99/R00 CA168996]
- NIH [P30CA008748]
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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 JMJU1C 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.
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