Mutations of signal-induced proliferation-associated gene 1 (), a RAP1 GTPase-activating protein, were reported in patients with juvenile myelomonocytic leukemia, a childhood myelodysplastic/myeloproliferative neoplasm (MDS/MPN). deficiency in mice leads to the development of age-dependent MPN. However, expression in bone marrow (BM) microenvironment and its effect on the pathogenesis of MPN remain unclear. We here report that is expressed in human and mouse BM stromal cells and downregulated in these cells from patients with MPN or MDS/MPN at diagnosis. By using the MPN mouse model, we find that deletion causes phenotypic and functional alterations of BM mesenchymal stem and progenitor cells prior to the initiation of the MPN. Importantly, the altered BM niche is required for the development of MDS/MPN following transplantation of normal hematopoietic cells. RNA sequencing reveals an enhanced inflammatory cytokine signaling and dysregulated , , , , and in the BM cellular niches. Our data suggest that expression in the BM niche is critical for maintaining BM niche homeostasis. Moreover, loss-induced BM niche alterations likely enable evolution of clonal hematopoiesis to the hematological malignancies. Therefore, restoring expression or modulating the altered signaling pathways involved might offer therapeutic potential for MPN.