The inflammatory BM microenvironment. Disease-related chronic inflammation and/or physiological aging leads to the presence of continuous production of proinflammatory signals (systemically and locally in the BM). In turn, this leads to an inflammatory BM microenvironment as MSCs of the BM, for example, nestin⁺ (Nes⁺), Gli1⁺, leptin-receptor (LepR⁺) cells, acquire an inflammatory, secretory phenotype as well and also release proinflammatory signals that affect both the HSC niche and also the erythroblastic islands. This leads to significant alterations in HSC function and output. Myeloid cells expand and innate immune cells/MDSCs are recruited. High numbers of platelets are released by megakaryocytes whereas lymphoid cells decrease. The erythroid differentiation is significantly impaired leading to anemia (anemia of chronic inflammation or anemia in the elderly). The central macrophage of the erythroblastic island can also acquire an inflammatory phenotype and further contributes to inflammation in the BM microenvironment. Adipocytes are increased in the aged BM and can also release inflammatory signals. Chronic inflammation leads to loss of support of normal hematopoiesis and can lead to decreased self-renewal of HSCs and skewed lineage output. The continuous exposure to this stress situation leads to dysfunction of the BM microenvironment and increased reactive oxygen levels (ROS), inducing genotoxic stress for HSCs, potentially promoting genomic instability. Normal hematopoiesis may thus also be impaired in a manner such that preexisting HSC clones carrying potentially leukemic mutations have increased potential to expand and evolve. Thus, chronic inflammation in the BM microenvironment may function as an initiator or even driver of hematological malignancies. Yellow geometrical forms highlight inflammatory cytokines that are further specified in Table 1.