MLL-AF9– and HOXA9-mediated acute myeloid leukemia stem cell self-renewal requires JMJD1C
Nan Zhu, Mo Chen, Rowena Eng, Joshua DeJong, Amit U. Sinha, Noushin F. Rahnamay, Richard Koche, Fatima Al-Shahrour, Janna C. Minehart, Chun-Wei Chen, Aniruddha J. Deshpande, Haiming Xu, S. Haihua Chu, Benjamin L. Ebert, Robert G. Roeder, Scott A. Armstrong
Nan Zhu, Mo Chen, Rowena Eng, Joshua DeJong, Amit U. Sinha, Noushin F. Rahnamay, Richard Koche, Fatima Al-Shahrour, Janna C. Minehart, Chun-Wei Chen, Aniruddha J. Deshpande, Haiming Xu, S. Haihua Chu, Benjamin L. Ebert, Robert G. Roeder, Scott A. Armstrong
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Research Article Oncology

MLL-AF9– and HOXA9-mediated acute myeloid leukemia stem cell self-renewal requires JMJD1C

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.

Authors

Nan Zhu, Mo Chen, Rowena Eng, Joshua DeJong, Amit U. Sinha, Noushin F. Rahnamay, Richard Koche, Fatima Al-Shahrour, Janna C. Minehart, Chun-Wei Chen, Aniruddha J. Deshpande, Haiming Xu, S. Haihua Chu, Benjamin L. Ebert, Robert G. Roeder, Scott A. Armstrong

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Figure 4

Loss of JMJD1C impairs leukemic transformation by HOXA9/MEIS1.

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Loss of JMJD1C impairs leukemic transformation by HOXA9/MEIS1. (A) Colon...
(A) Colony counts of HOXA9/MEIS1 transformed LSKs from Jmjd1cf/f BM after transduction of CRE or MIT control viruses in methylcellulose. (B) Colony counts of AML-ETO9a transformed LIN– Jmjd1cf/f BM cells after transduction of CRE or MIT control viruses in methylcellulose. Results from 2 to 3 independent experiments for A and B. (C) Morphologic changes (left, colony in methylcellulose; right, Wright-Giemsa stain) in HOXA9/MEIS1 preleukemia cells 10 days after transduction with CRE. Scale bars: 100 μm (left panels). Original magnification, ×400 (right panels). (D–F) Flow cytometry analysis of c-Kit expression (D), cell-cycle analysis by BrdU and sytox blue (E), apoptosis analysis (F) in HOXA9/MEIS1 leukemic cells day 5 after transduction with CRE. Results from 3 independent leukemias. (G) Survival curves of secondary recipient mice that received 100,000; 20,000 or 5,000 double-sorted GFP+Tomato+ HOXA9/MEIS1 leukemia cells 2 days after transduction with CRE or MIT control viruses (n = 5 per group). Right panel: genotyping result of BM at the time of sacrifice. Data are represented as mean ± SEM in A, B, and D–F. *P < 0.05; **P < 0.01 Student’s t test.