Microenvironmental changes during leukemogenesis. In the BM niche, HSC function is tightly controlled by a specialized microenvironment comprising sympathetic neurons, BMSCs, OBs, and ECs. (A) During early stages of myeloid malignancies, HSPCs acquire genetic alterations that transform them into LSCs. These mutations also create a proinflammatory environment that damages sensitive elements of the microenvironment, such as Schwann cells and their associated nerve terminals. (B) During intermediate stages of the disease, the environment remodels into a self-reinforcing niche that interferes with normal hematopoiesis. LSCs become independent of niche signals and localize more centrally in the BM. MSCs acquire an abnormal phenotype, and angiogenesis increases as a result of high VEGF and cytokine levels. (C) Late stages of the disease are characterized by a proinflammatory environment and myelofibrosis, high blood vessel density, and central LSC localization. Rarγ, retinoic acid receptor γ; Rb, retinoblastoma protein; TPO, thrombopoeitin.