(A) HSCs reside in specialized niches in the BM comprised of many specialized cell types, including endothelial cells, perivascular multipotent stromal cells (MSCs) which differentiate into osteoblast-lineage cells (OBC), and hematopoietic populations including CD169+ macrophages and T-lymphocytes. Collectively, these cell populations produce a variety of soluble and membrane-bound factors, which contribute to HSC maintenance and regulate their activity and output. (B) During the development of blood disease such as MPNs, LSCs aberrantly overproduce granulocytes. These MPN myeloid cells in turn produce high levels of IL-6, which reprogram MPPs to overproduce myeloid cells at the expense of the lymphoid lineage, hence promoting disease progression. In addition, MPN myeloid cells drive aberrant MSC differentiation into OBCs via elevated production of CCL3, TPO, and additional contact-dependent signals. These overproduced OBCs display features of remodeled fibrotic cells, and produce elevated levels of inflammatory factors at the expense of HSC maintenance factors such as SCF and CXCL12. Collectively, this leads to impaired maintenance of normal HSCs, whereas LSCs are insensitive to these alterations, leading to the establishment of a self-reinforcing leukemic niche that favors the expansion of LSCs and hence disease progression.