The role of inflammation in myeloid malignancies. (A) Intrinsic leukemic stem cell (LSC) signaling as well as interactions with the microenvironment result in inflammation and a permissive environment for further clonal expansion. Cytokines secreted from the LSC or their progeny may promote clonal expansion and/or suppress normal HSCs. Immune and stromal cells can also respond to the LSC by secreting cytokines, which can have differential effect on the HSC and LSC. (B) Activation of inflammatory pathways in LSCs can be divided into cell-intrinsic and cell-extrinsic. Cell-intrinsic alterations can drive increased intracellular signalling through activated intracellular pathways, causing proliferative signalling and cytokine secretion. Cell-extrinsic factors refer to cytokines or other factors secreted by LSCs, immune cells, or the stroma which can (i) suppress normal HSCs, (ii) suppress the LSCs, or (iii) activate the LSCs to different degrees after interacting with their cellular receptors. MDSC, myeloid-derived stromal cell; MSC, mesenchymal stromal cell. Illustration by Vicky Earle.