Figure 2.
IL-1 signaling pathway as a driver of CH and myeloid malignancy. The left panel depicts the proposed effects of IL-1 on normal and mutant HSCs: the top scheme depicts how WT HSCs respond to IL-1 stimulation. IL-1 exposure levels determine different cellular outcomes. Higher IL-1 exposure results in increased PU.1 levels, decreased proliferation, increased myelopoiesis, and decreased self-renewal. The lower scheme depicts the effects of high IL-1 exposure on Tet2-, Jak2-, and Cepba-mutant HSCs, compared with the effect observed in WT HSCs. “+” indicates a stronger effect in mutant compared with WT. “–” indicates a weaker effect in mutant compared with WT. The central panel depicts how the IL-1 signaling pathway drives CH progression via a self-sustaining feedback loop. Increased IL-1 levels, derived from aged CH-mutant mature myeloid cells, act directly on HSPCs favoring CH-mutant HSPC expansion (circular arrows) and multilineage differentiation (linear arrows) over WT HSPCs. The right upper panel depicts the IL-1 pathway alterations in myeloid malignancies: HSPCs from patients with MDS show increased expression of IL-1β, IL-1R3, and IRAK1. Patients with MPNs have increased levels of IL-1α, IL-1β, and IL-1RN and surface expression of IL-1R1/3 on HSCPs. Patients with CML show increased levels of IL-1β and surface expression of IL-1R3 on HSCPs. Increased levels of IL-1β and IL-1R3 surface expression in blasts associates with poorer survival in patients with AML. Increased IL-1 signaling leads to increased proliferation and survival in HSPCs/blasts from these myeloid malignancies. The right lower panel depicts the nonhematological effects of IL-1 production by CH-mutant myeloid cells: increased IL-1 levels in individuals with CH associate with cardiovascular disease, gout, and potentially with lung and other cancer incidence. FLT3, fms-like tyrosine kinase 3; SCF, stem cell factor.

IL-1 signaling pathway as a driver of CH and myeloid malignancy. The left panel depicts the proposed effects of IL-1 on normal and mutant HSCs: the top scheme depicts how WT HSCs respond to IL-1 stimulation. IL-1 exposure levels determine different cellular outcomes. Higher IL-1 exposure results in increased PU.1 levels, decreased proliferation, increased myelopoiesis, and decreased self-renewal. The lower scheme depicts the effects of high IL-1 exposure on Tet2-, Jak2-, and Cepba-mutant HSCs, compared with the effect observed in WT HSCs. “+” indicates a stronger effect in mutant compared with WT. “–” indicates a weaker effect in mutant compared with WT. The central panel depicts how the IL-1 signaling pathway drives CH progression via a self-sustaining feedback loop. Increased IL-1 levels, derived from aged CH-mutant mature myeloid cells, act directly on HSPCs favoring CH-mutant HSPC expansion (circular arrows) and multilineage differentiation (linear arrows) over WT HSPCs. The right upper panel depicts the IL-1 pathway alterations in myeloid malignancies: HSPCs from patients with MDS show increased expression of IL-1β, IL-1R3, and IRAK1. Patients with MPNs have increased levels of IL-1α, IL-1β, and IL-1RN and surface expression of IL-1R1/3 on HSCPs. Patients with CML show increased levels of IL-1β and surface expression of IL-1R3 on HSCPs. Increased levels of IL-1β and IL-1R3 surface expression in blasts associates with poorer survival in patients with AML. Increased IL-1 signaling leads to increased proliferation and survival in HSPCs/blasts from these myeloid malignancies. The right lower panel depicts the nonhematological effects of IL-1 production by CH-mutant myeloid cells: increased IL-1 levels in individuals with CH associate with cardiovascular disease, gout, and potentially with lung and other cancer incidence. FLT3, fms-like tyrosine kinase 3; SCF, stem cell factor.

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