The histone demethylase KDM6B (JMJD3) is upregulated in blood disorders, suggesting that it may have important pathogenic functions. Here we examined the function of Kdm6b in hematopoietic stem cells (HSC) to evaluate its potential as a therapeutic target. Loss of Kdm6b lead to depletion of phenotypic and functional HSCs in adult mice, and Kdm6b is necessary for HSC self-renewal in response to inflammatory and proliferative stress. Loss of Kdm6b leads to a pro-differentiation poised state in HSCs due to the increased expression of the AP-1 transcription factor complex (Fos and Jun) and immediate early response (IER) genes. These gene expression changes occurred independently of chromatin modifications. Targeting AP-1 restored function of Kdm6b-deficient HSCs, suggesting that Kdm6b regulates this complex during HSC stress response. We also show Kdm6b supports developmental context-dependent leukemogenesis for T-cell acute lymphoblastic leukemia (T-ALL) and M5 acute myeloid leukemia (AML). Kdm6b is required for effective fetal-derived T-ALL and adult-derived AML, but not vice versa. These studies identify a crucial role for Kdm6b in regulating HSC self-renewal in different contexts, and highlight the potential of KDM6B as a therapeutic target in different hematopoietic malignancies.
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We thank Dr. Martin Matzuk (Baylor College of Medicine) for providing Kdm6bfl/fl mice, Dr. Lukas Wartman (Washington University) for providing Utx1fl/fl mice, and Dr. Jeff Magee (Washington University) for providing MLL-AF9 retroviral plasmid. We thank the Alvin J. Siteman Cancer Center at Washington University for use of the Siteman Flow Cytometry Core, supported in part by NCI Grant CA91842. We thank the Genome Technology Access Center at Washington University for genomic analysis, partially supported by NCI Grant CA91842 and by ICTS/CTSA Grant UL1TR000448 NIH. This work was supported by the National Institutes of Health (R01DK102428), the Edward Mallinckrodt Jr. Foundation, the American Society of Hematology, the V Foundation, Gabrielle’s Angel Foundation, and the Sidney Kimmel Foundation (all to GAC). Bioinformatics analysis was supported by the Washington University Center for Regenerative Medicine. CM was supported by NIH T32HL007088, and NIH DK111058-01. ELO was supported by NIH 5T32CA113275-10 and NIH F31DK114951. HC was supported by a post-doctoral scholar award from the American Society of Hematology and an Edward P. Evans Foundation Young Investigator Award. GAC is a Leukemia and Lymphoma Society scholar.
Project conceptualization and experimental design: GAC. Performed experiments: CM, ELO, HC, ACK, AM, AK, WKK, EH, GAC. Provided critical reagents: NI. Data analysis: CM, ELO, PG, BZ, GAC. Writing—original draft preparation: CM. Writing—review and editing: GAC. Project administration and funding acquisition: GAC.
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Mallaney, C., Ostrander, E.L., Celik, H. et al. Kdm6b regulates context-dependent hematopoietic stem cell self-renewal and leukemogenesis. Leukemia 33, 2506–2521 (2019). https://doi.org/10.1038/s41375-019-0462-4
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