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Lysine demethylase 6A (KDM6A), a H3K27 demethylase and key component of the COMPASS complex, is frequently mutated in hematologic malignancies, but its roles in embryonic hematopoiesis and tumor suppression in CMML remain unclear. Using zebrafish models with kdm6a mutants and integrative multi\u2010omics analysis (ATAC\u2010seq, RNA\u2010seq, ChIP), we find that Kdm6a is a critical positive regulator of hematopoietic stem and progenitor cell (HSPC) emergence via Syk\u2010related inflammatory signaling in a H3K27me3\u2010dependent manner. We further find that Kdm6a haploinsufficiency in zebrafish leads to myeloid\u2010biased hematopoiesis and a CMML\u2010like disease, similar to CMML patients with reduced KDM6A expression. This KDM6A haploinsufficiency also significantly alters the chromatin landscape of genes associated with aging and cellular homeostasis in HSPCs. Mechanistically, KAM6A haploinsufficiency represses SOCS3 expression, thereby activating JAK\/STAT3 signaling in HSPCs. Importantly, inhibitors targeting JAK or STAT3 phosphorylation alleviate myeloid expansion, providing a rationale for JAK\/STAT pathway inhibition in CMML therapy. These findings enhance our understanding of CMML pathogenesis and propose new therapeutic avenues.<\/jats:p>","DOI":"10.1002\/advs.202413091","type":"journal-article","created":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T06:18:34Z","timestamp":1747203514000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["KDM6A Deficiency Induces Myeloid Bias and Promotes CMML\u2010Like Disease Through JAK\/STAT3 Activation by Repressing SOCS3"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2440-6908","authenticated-orcid":false,"given":"Huiqiao","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Hematology and Cell Therapy Sir Run Run Shaw Hospital Zhejiang University School of Medicine  Hangzhou Zhejiang Province 310016 P. R. 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