recently identified IL-1 in a functional screen as one of the factors that promoted the growth of patient AML cells prolonged survival in a murine model of AML driven by AML1-ETO9a and NrasG12D. the acquisition of genetic and epigenetic changes in HSCs. This can occur through the initiation of clonal hematopoiesis, followed by the emergence preleukemic stem cells (pre-LSCs). In this review, we describe the functions of multiple inflammatory signaling pathways in the generation of pre-LSCs and in progression to myelodysplastic syndrome (MDS), myeloproliferative neoplasms, and acute myeloid leukemia (AML). In AML, activation of some inflammatory signaling pathways can promote the cycling and differentiation of LSCs, and this can be exploited therapeutically. We also discuss the therapeutic potential of modulating inflammatory signaling for the treatment of myeloid malignancies. in hematopoietic cells could promote atherosclerosis in the LDL-receptor knockout mouse model due to activation of macrophages (13). They found that macrophages from bone marrow secreted increased levels of several chemokines, including CXCL1, CXCL2, CXCL3, PF4, and PBBP, some of which are known to promote atherogenesis. In patients with CHIP with TET2 mutations, ADOS they also found serum elevations of the inflammatory chemokine interleukin 8 (IL-8) (13). Another recent study also recognized increased interleukin 1 beta (IL-1) and inflammasome activation in mice with deficiency (14). Furthermore, Cull et al. found constitutive activation of the lipopolysaccharide (LPS)-related inflammatory pathway in peritoneal ADOS fluid in a knockdown mouse model, and increased IL-1 and interleukin 6 (IL-6) levels from bone marrow-derived macrophages knockout mast cells were more responsive to stimuli than wild-type mast cells, and secreted higher levels of inflammatory cytokines, such as IL-6, tumor necrosis factor alpha (TNF-), and IL-13, leading to increased acute and chronic inflammatory responses or studies showing inhibition of CML growth with IFN treatment. Subsequent clinical trial data showed up to a 60% total cytogenetic response and improved overall survival compared to traditional chemotherapy. Rare total long-term remissions post-IFN treatment were reported in a subset of patients who were treated without allogeneic stem cell transplantation (SCT), making this the standard of care for the treatment of CML prior to the era of tyrosine kinase inhibitors (TKIs) (18). IFN has also been used clinically in the treatment of Philadelphia chromosome (Ph)-unfavorable MPNs, including polycythemia vera (PV), essential thrombocythemia (ET), and main myelofibrosis (MF) (19, 20). While successful as the first biologic treatment in malignancy, the mechanism of action of IFN- in the treatment of MPN, or its effects on hematopoiesis in general, remained elusive. Open in a separate window Physique 1 Inflammatory signaling pathways in hematopoietic cells and potential therapeutic targets for myeloid malignancies. Interleukin (IL)-1 activates the IL-1 receptor (IL-1R), which causes dimerization and intracellular downstream signaling MYD88 and IRAK. This activates multiple downstream pathways, including NF-B and p38 MAPK. Two interleukin 6 (IL-6) molecules form a hexamer with two IL-6 receptors (IL-6R) and two GP-130 molecules, which transmission the JAK1CSTAT3 pathway. The binding of IFN-/ to IFNAR receptors activates TYK2 and JAK1, which phosphorylate STAT1 and STAT2. The association of IRF9 and phosphorylated STAT1 and STAT2 activates transcription by binding to IFN-stimulated response elements (ISREs). IFN- binding to IFNGR receptors promotes STAT1 phosphorylation by JAK. ADOS The STAT1 homodimer translocates to the nucleus and activates IFN–activated site (GAS) sequences. IL-8 binds to its receptor, either CXCR1 or CXCR2, which can ADOS activate numerous downstream signaling pathways, including PI3K/AKT, JAK/STAT, and MAPK. There is considerable crosstalk between tumor necrosis factor alpha (TNF-) and Toll-like receptor (TLR) signaling pathways. TNF- binds to its receptor TNFR and activates TCF1 IKK RIP and TRAF2 recruitment by TRADD. IKK activation promotes IKB phosphorylation and release of NF-B, which can then translocate to the nucleus. TNF-.