Conceptual models of MME–HSC interactions are illustrated. (A) Normally, the HSC is supported by various niche cells, including endothelial cells (EC), macrophages (Mø), and osteolineage cells (OL). (B) In hematologic malignancies, clonal neoplastic cells (NC) alter the MME so that it becomes supportive of leukemic stem cells (LSC) and becomes less supportive of normal HSCs, ultimately leading to decreased normal hematopoiesis. (C) There is a strong rationale for therapeutic targeting of the MME in hematologic malignancies to push the MME into becoming less supportive of LSCs and more supportive of HSCs in an effort to restore normal hematopoiesis.