2030 – STEPWISE INFLAMMATORY REMODELING OF THE HUMAN BONE MARROW NICHE IN CHIP AND MDS

Abstract

Clonal hematopoiesis of indeterminate potential (CHIP) is a premalignant state that increases the risk of myelodysplastic syndromes (MDSs), yet whether mutant hematopoietic stem and progenitor cells (HSPCs) reprogram the bone marrow (BM) niche before overt disease remains unresolved.

We analyzed matched BM aspirates and biopsies from 84 individuals in the BoHemE study (NCT02867085), including healthy donors, CHIP carriers, and individuals with MDSs. By integrating single-cell transcriptomics, spatial imaging, mutational profiling, and proteomics, we delineated progressive rewiring of the BM HSPC niche across myeloid evolution and validated key findings in primary BM cocultures and a DNMT3A-driven CHIP mouse model.

We identify stepwise inflammatory remodeling of the BM niche as an early feature of CHIP that intensifies in MDS. This transition is marked by loss of supportive CXCL12-abundant adipogenic stromal cells and emergence of inflammatory mesenchymal stromal cells (iMSCs), already detectable in CHIP and expanded in MDS. Although iMSCs retain partial HSPC-supporting activity, they acquire inflammatory and pro-angiogenic programs, consistent with vascular remodeling in MDS. In parallel, we define IFN-responsive cytotoxic T cell states enriched across CHIP and MDS that preferentially interact with iMSCs, supporting a feed-forward immune–stromal circuit that amplifies niche inflammation. Functionally, aged and CHIP HSPCs preserve the capacity to activate stromal MSC support, whereas MDS HSPCs fail to do so, and MDS blasts further suppress HSPC support.

Together, these findings show that disruption of the BM HSPC niche begins at the CHIP stage and advances through coordinated stromal and immune rewiring. They position iMSCs and IFN-responsive T cells as mediators of niche dysfunction and candidate biomarkers and therapeutic entry points for intercepting premalignant myeloid evolution.

Clonal hematopoiesis of indeterminate potential (CHIP) is a premalignant state that increases the risk of myelodysplastic syndromes (MDSs), yet whether mutant hematopoietic stem and progenitor cells (HSPCs) reprogram the bone marrow (BM) niche before overt disease remains unresolved.

We analyzed matched BM aspirates and biopsies from 84 individuals in the BoHemE study (NCT02867085), including healthy donors, CHIP carriers, and individuals with MDSs. By integrating single-cell transcriptomics, spatial imaging, mutational profiling, and proteomics, we delineated progressive rewiring of the BM HSPC niche across myeloid evolution and validated key findings in primary BM cocultures and a DNMT3A-driven CHIP mouse model.

We identify stepwise inflammatory remodeling of the BM niche as an early feature of CHIP that intensifies in MDS. This transition is marked by loss of supportive CXCL12-abundant adipogenic stromal cells and emergence of inflammatory mesenchymal stromal cells (iMSCs), already detectable in CHIP and expanded in MDS. Although iMSCs retain partial HSPC-supporting activity, they acquire inflammatory and pro-angiogenic programs, consistent with vascular remodeling in MDS. In parallel, we define IFN-responsive cytotoxic T cell states enriched across CHIP and MDS that preferentially interact with iMSCs, supporting a feed-forward immune–stromal circuit that amplifies niche inflammation. Functionally, aged and CHIP HSPCs preserve the capacity to activate stromal MSC support, whereas MDS HSPCs fail to do so, and MDS blasts further suppress HSPC support.

Together, these findings show that disruption of the BM HSPC niche begins at the CHIP stage and advances through coordinated stromal and immune rewiring. They position iMSCs and IFN-responsive T cells as mediators of niche dysfunction and candidate biomarkers and therapeutic entry points for intercepting premalignant myeloid evolution.