Kdm6b regulates context-dependent hematopoietic stem cell self-renewal and leukemogenesis

Cates Mallaney, Elizabeth L. Ostrander, Hamza Celik, Ashley C. Kramer, Andrew Martens, Alok Kothari, Won Kyun Koh, Emily Haussler, Naoki Iwamori, Paul Gontarz, Bo Zhang, Grant A. Challen

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)2506-2521
Number of pages16
JournalLeukemia
Volume33
Issue number10
DOIs
Publication statusPublished - Oct 1 2019

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Hematopoietic Stem Cells
Transcription Factor AP-1
Acute Myeloid Leukemia
Histone Demethylases
T-Lymphocytes
Immediate-Early Genes
Hematologic Neoplasms
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Chromatin
Gene Expression
Cell Self Renewal
Therapeutics

All Science Journal Classification (ASJC) codes

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Mallaney, C., Ostrander, E. L., Celik, H., Kramer, A. C., Martens, A., Kothari, A., ... Challen, G. A. (2019). Kdm6b regulates context-dependent hematopoietic stem cell self-renewal and leukemogenesis. Leukemia, 33(10), 2506-2521. https://doi.org/10.1038/s41375-019-0462-4

Kdm6b regulates context-dependent hematopoietic stem cell self-renewal and leukemogenesis. / Mallaney, Cates; Ostrander, Elizabeth L.; Celik, Hamza; Kramer, Ashley C.; Martens, Andrew; Kothari, Alok; Koh, Won Kyun; Haussler, Emily; Iwamori, Naoki; Gontarz, Paul; Zhang, Bo; Challen, Grant A.

In: Leukemia, Vol. 33, No. 10, 01.10.2019, p. 2506-2521.

Research output: Contribution to journalArticle

Mallaney, C, Ostrander, EL, Celik, H, Kramer, AC, Martens, A, Kothari, A, Koh, WK, Haussler, E, Iwamori, N, Gontarz, P, Zhang, B & Challen, GA 2019, 'Kdm6b regulates context-dependent hematopoietic stem cell self-renewal and leukemogenesis', Leukemia, vol. 33, no. 10, pp. 2506-2521. https://doi.org/10.1038/s41375-019-0462-4
Mallaney C, Ostrander EL, Celik H, Kramer AC, Martens A, Kothari A et al. Kdm6b regulates context-dependent hematopoietic stem cell self-renewal and leukemogenesis. Leukemia. 2019 Oct 1;33(10):2506-2521. https://doi.org/10.1038/s41375-019-0462-4
Mallaney, Cates ; Ostrander, Elizabeth L. ; Celik, Hamza ; Kramer, Ashley C. ; Martens, Andrew ; Kothari, Alok ; Koh, Won Kyun ; Haussler, Emily ; Iwamori, Naoki ; Gontarz, Paul ; Zhang, Bo ; Challen, Grant A. / Kdm6b regulates context-dependent hematopoietic stem cell self-renewal and leukemogenesis. In: Leukemia. 2019 ; Vol. 33, No. 10. pp. 2506-2521.
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