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

Leukemia. 2019 Oct;33(10):2506-2521. doi: 10.1038/s41375-019-0462-4. Epub 2019 Apr 1.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinogenesis / metabolism*
  • Carcinogenesis / pathology*
  • Cell Differentiation / genetics
  • Cell Self Renewal / genetics
  • Cell Self Renewal / physiology*
  • Hematopoietic Stem Cells / metabolism*
  • Hematopoietic Stem Cells / pathology*
  • Jumonji Domain-Containing Histone Demethylases / metabolism*
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / pathology
  • Mice
  • Mice, Inbred C57BL
  • T-Lymphocytes / pathology
  • Transcription Factors / genetics
  • Up-Regulation / genetics


  • Transcription Factors
  • Jumonji Domain-Containing Histone Demethylases
  • Kdm6b protein, mouse