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Cited by 63Hematopoietic Stem Cell TransplantationAcute Myeloid Leukemia ResearchEpigenetics and DNA Methylation

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

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Mallaney, Cates, Ostrander, Elizabeth L., Celik, Hamza, Kramer, Ashley C., Martens, Andrew, Kothari, Alok, Koh, Won Kyun, Haussler, Emily +4 more·2019·Leukemia
DOI 10.1038/s41375-019-0462-4PMC PMC6773521
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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.

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  • Loss of the histone demethylase Kdm6b leads to opposite effects on Fos and Jun.

    “Strikingly, loss of the histone demethylase Kdm6b leads to opposite effects on Fos and Jun”

    From Chronic infection drives Dnmt3a-loss-of-function clonal hematopoiesis via IFNγ signaling (2021) · cites this paper as Mallaney et al., 2019

    The Results section (page not supplied) says that both Fos and Jun were overexpressed in Kdm6b-deficient hematopoietic stem cells, at baseline and more strongly under stress. It therefore reports effects in the same direction, not opposite effects. (LLM, conf=0.90)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • Loss of Kdm6b and Dnmt3a loss have an interrelated regulatory mechanism affecting Fos and Jun.

    “suggesting an interrelated regulatory mechanism (Mallaney et al., 2019).”

    From Chronic infection drives Dnmt3a-loss-of-function clonal hematopoiesis via IFNγ signaling (2021) · cites this paper as Mallaney et al., 2019

    The Results and Discussion report that Kdm6b loss dysregulates Fos and Jun in hematopoietic stem cells, and that reducing their expression improves engraftment. They do not establish an interrelated regulatory mechanism involving Dnmt3a loss; searches for Dnmt3a and the proposed mechanism found no supporting passage. The Discussion also says the mechanism linking Kdm6b and AP-1 remains unclear. Page numbers were not available in our copy. (LLM, conf=0.86)

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Authors
Mallaney, C., Ostrander, E. L., Celik, H., Kramer, A. C., Martens, A., Kothari, A., Koh, W. K., Haussler, E., Iwamori, N., Gontarz, P., Zhang, B., & Challen, G. A.
Affiliations
  • Washington University in St. Louis (US)
  • Kyushu University (JP)
Corresponding author
Challen, Grant A.
ORCID
Venue
Leukemia
Publisher
Springer Science and Business Media LLC
Published
2019-04-01
Volume
33
Issue
10
Pages
2506-2521
ISSN
  • 0887-6924 (ISSN-L)
  • 1476-5551
DOI
10.1038/s41375-019-0462-4
PMC
PMC6773521
OpenAlex
W2933260868
Cited by
63
References
4
Citations by year
2026: 4 · 2025: 6 · 2024: 6 · 2023: 11 · 2022: 15 · 2021: 12 · 2020: 8 · 2019: 1
FWCI
6.36
Type
journal article
Language
en
Open access
Licence
Locations
  • Leukemia (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • U.S. Department of Health & Human Services | National Institutes of Health (HL007088, DK111058, CA113275, DK114951, R01DK102428)
  • American Society of Hematology
  • Edward P. Evans Foundation
  • Edward Mallinckrodt, Jr. Foundation
  • V Foundation for Cancer Research
  • Gabrielle's Angel Foundation for Cancer Research
  • Sidney Kimmel Foundation
Topics
  • Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Keywords
KDM6B, JMJD3, histone demethylase, hematopoietic stem cells, HSC self-renewal, leukemogenesis, T-cell acute lymphoblastic leukemia, acute myeloid leukemia, AP-1 transcription factor, immediate early genes, HSC differentiation, inflammatory stress response, therapeutic target
MeSH terms
Cell Self Renewal, Animals, Cell Differentiation, Hematopoietic Stem Cells, Mice, Inbred C57BL, T-Lymphocytes, Transcription Factors, Leukemia, Myeloid, Acute, Up-Regulation, Mice, Jumonji Domain-Containing Histone Demethylases, Carcinogenesis

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