Targeting lysine demethylase 6B ameliorates ASXL1 truncation–mediated myeloid malignancies in preclinical models Journal Article


Authors: Ge, G.; Zhang, P.; Sui, P.; Chen, S.; Yang, H.; Guo, Y.; Rubalcava, I. P.; Noor, A.; Delma, C. R.; Agosto-Peña, J.; Geng, H.; Medina, E. A.; Liang, Y.; Nimer, S. D.; Mesa, R.; Abdel-Wahab, O.; Xu, M.; Yang, F. C.
Article Title: Targeting lysine demethylase 6B ameliorates ASXL1 truncation–mediated myeloid malignancies in preclinical models
Abstract: ASXL1 mutation frequently occurs in all forms of myeloid malignancies and is associated with aggressive disease and poor prognosis. ASXL1 recruits Polycomb repressive complex 2 (PRC2) to specific gene loci to repress transcription through trimethylation of histone H3 on lysine 27 (H3K27me3). ASXL1 alterations reduce H3K27me3 levels, which results in leukemogenic gene expression and the development of myeloid malignancies. Standard therapies for myeloid malignancies have limited efficacy when mutated ASXL1 is present. We discovered upregulation of lysine demethylase 6B (KDM6B), a demethylase for H3K27me3, in ASXL1-mutant leukemic cells, which further reduces H3K27me3 levels and facilitates myeloid transformation. Here, we demonstrated that heterozygous deletion of Kdm6b restored H3K27me3 levels and normalized dysregulated gene expression in Asxl1Y588XTg hematopoietic stem/progenitor cells (HSPCs). Furthermore, heterozygous deletion of Kdm6b decreased the HSPC pool, restored their self-renewal capacity, prevented biased myeloid differentiation, and abrogated progression to myeloid malignancies in Asxl1Y588XTg mice. Importantly, administration of GSK-J4, a KDM6B inhibitor, not only restored H3K27me3 levels but also reduced the disease burden in NSG mice xenografted with human ASXL1-mutant leukemic cells in vivo. This preclinical finding provides compelling evidence that targeting KDM6B may be a therapeutic strategy for myeloid malignancies with ASXL1 mutations. Copyright: © 2024, Ge et al.
Keywords: genetics; neoplasm; neoplasms; mouse; animal; metabolism; animals; mice; transcription factor; transcription factors; histone; repressor protein; repressor proteins; histones; lysine; histone demethylase; jumonji domain-containing histone demethylases; asxl1 protein, human; humans; human; kdm6b protein, human
Journal Title: Journal of Clinical Investigation
Volume: 134
Issue: 1
ISSN: 0021-9738
Publisher: American Society for Clinical Investigation  
Date Published: 2024-01-02
Start Page: e163964
Language: English
DOI: 10.1172/jci163964
PUBMED: 37917239
PROVIDER: scopus
PMCID: PMC10760961
DOI/URL:
Notes: Article -- Source: Scopus
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