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Haplodeficiency of the 9p21 Tumor Suppressor Locus Causes Myeloid Disorders Driven by Bone Marrow Microenvironment

ABSTRACT: The chromosome 9p21 locus comprises several tumor suppressor genes including MTAP, CDKN2A and CDKN2B, and its homo- or heterozygous deletions are associated with reduced survival in multiple cancer types. We report that mice with germline monoallelic deletion or induced biallelic deletion of the 9p21-syntenic locus (9p21s) developed 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 vitro. 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 a concomitant upregulation of the pro-fibrotic chemokine Cxcl13. Our study highlights the potential of mutations in the BM microenvironment to drive MDS/MPN-like disease. We then performed gene expression profiling analysis using data obtained from RNA-seq of 4 different cells at two time points.

ORGANISM(S): Mus musculus

PROVIDER: GSE211779 | GEO | 2023/06/06

REPOSITORIES: GEO

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