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MLL-AF9– and HOXA9-mediated acute myeloid leukemia stem cell self-renewal requires JMJD1C
Nan Zhu, … , Robert G. Roeder, Scott A. Armstrong
Nan Zhu, … , Robert G. Roeder, Scott A. Armstrong
Published February 15, 2016
Citation Information: J Clin Invest. 2016;126(3):997-1011. https://doi.org/10.1172/JCI82978.
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Research Article Oncology Article has an altmetric score of 1

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

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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 7

Effect of loss of JMJD1C on regenerative function of HSC.

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Effect of loss of JMJD1C on regenerative function of HSC.
(A–F) Flow cyt...
(A–F) Flow cytometry analysis shows results of chimerism of recipient mice from serial transplantation experiments. (A–C) One million BM cells from Vav1-Cre or Jmjd1cf/f Vav1-Cre mice were mixed 1:1 with CD45.1 BM and transplanted into lethally irradiated CD45.1 recipients. (n = 10). (D–F) Two million BM cells from primary competitive transplantation were serially transplanted into secondary CD45.1 recipients (n = 5). Chimerism in PB (A) and (D); BM and SPL (B) and (E); stem and progenitor populations in BM (C) and (F). (G) Heat map of differentially expressed genes in Vav1-Cre and Jmjd1cf/f Vav1-Cre LSK cells. (H) GSEA analysis result showing enrichment of E2F1, Myc, and cyclin D1 signature. (I) Percentage of cells in S/G2/M phase of cell cycle determined by Sytox blue staining (n = 3 per genotype). (J) Time course of wbc counts after 5-Fu administrations (indicated by arrows, n = 5 per genotype). (K) Percentage of apoptotic cells determined by annexin V staining (n = 3 per genotype). (L) HSPC numbers 2 weeks after 5-Fu treatment (n = 3–4 per genotype). Data are represented as mean ± SEM in A–F and I–L. *P < 0.05. See also Supplemental Figures 5 and 6 and Supplemental Table 6.

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