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We report that mice with germ line monoallelic deletion or induced biallelic deletion of the 9p21-syntenic locus (9p21s) developed a fatal myelodysplastic syndrome\/myeloproliferative neoplasm (MDS\/MPN)-like disease associated with aberrant trabecular bone formation and\/or fibrosis in the bone marrow (BM). Reciprocal BM transfers and conditional targeting of 9p21s suggested that the disease originates in the BM stroma. Single-cell analysis of 9p21s-deficient BM stroma revealed the expansion of chondrocyte and osteogenic precursors, reflected in increased osteogenic differentiation in\u00a0vitro. It also showed reduced expression of factors maintaining hematopoietic stem\/progenitor cells, including Cxcl12. Accordingly, 9p21s-deficient mice showed reduced levels of circulating Cxcl12 and concomitant upregulation of the profibrotic chemokine Cxcl13 and the osteogenesis- and fibrosis-related multifunctional glycoprotein osteopontin\/Spp1. Our study highlights the potential of mutations in the BM microenvironment to drive MDS\/MPN\u2013like disease.<\/jats:p>","DOI":"10.1182\/blood.2022018512","type":"journal-article","created":{"date-parts":[[2023,6,2]],"date-time":"2023-06-02T19:54:37Z","timestamp":1685735677000},"page":"460-476","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":7,"title":["Haplodeficiency of the 9p21 tumor suppressor locus causes myeloid disorders driven by the bone marrow microenvironment"],"prefix":"10.1182","volume":"142","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2506-1294","authenticated-orcid":false,"given":"Jue","family":"Feng","sequence":"first","affiliation":[{"name":"1Department of Pathology, New York University Grossman School of Medicine, New York, NY"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9749-7591","authenticated-orcid":false,"given":"Pei-Feng","family":"Hsu","sequence":"additional","affiliation":[{"name":"1Department of Pathology, New York University Grossman School of Medicine, New York, NY"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7223-6632","authenticated-orcid":false,"given":"Eduardo","family":"Esteva","sequence":"additional","affiliation":[{"name":"1Department of Pathology, New York University Grossman School of Medicine, New York, NY"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3768-9273","authenticated-orcid":false,"given":"Rossella","family":"Labella","sequence":"additional","affiliation":[{"name":"2Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY"},{"name":"3Edward P. 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