Chronic infection drives Dnmt3a-loss-of-function clonal hematopoiesis via IFNγ signaling

Inflammation and Aging of Hematopoietic Stem Cells in Their Niche

“…Nonmalignant clonal hematopoiesis, which is referred to as clonal hematopoiesis of indeterminate potential (CHIP), is mainly driven by DNMT3A and TET2 mutations [19]. It has been demonstrated that chronic inflammation may be a driving the selecting force of HSC clones as it expands specific HSPC subsets and thus may contribute to CHIP [99,100]. For instance, recent data suggests that chronic IFN-γ signaling drives clonal hematopoiesis induced by DNMT3A loss of function [99].…”

“…It has been demonstrated that chronic inflammation may be a driving the selecting force of HSC clones as it expands specific HSPC subsets and thus may contribute to CHIP [99,100]. For instance, recent data suggests that chronic IFN-γ signaling drives clonal hematopoiesis induced by DNMT3A loss of function [99]. In the development of several hematological diseases, including myeloproliferative neoplasms, myelodysplastic syndrome (MDS), acute myelogenous leukemia (AML) and chronic myelogenous leukemia (CML), various cytokines including IL-1, TNF, IL-6 and IFNs are involved [101,102].…”

The vicious and virtuous circles of clonal hematopoiesis

“…Toxic exposures such as chemotherapy or radiotherapy are highly specific for mutations in PPM1D, TP53 and CHEK2, and smoking is specifically associated with mutations in ASXL1 7 . Inflammation has been shown to strongly affect TET2 clonal dynamics via increased IL-6 production 8 and to strongly affect DNMT3A clones via an immune response mediated by the cytokine IFN-γ 9 . Immune attack, as occurs in aplastic anemia, is associated with mutations in BCOR and BCORL1, suggestive of a role of autoimmunity in clonal selection 10 .…”

Clonal hematopoiesis and associated diseases: A review of recent findings

“…In contrast, CHIP-associated mutations in genes such as DNMT3A and TET2 provide HSCs with a competitive advantage under inflammatory conditions. 50,51 In addition, activation of Toll-like receptor (TLR) signaling, which is frequently observed in MDS patients, confers a fitness advantage to HSCs under inflammatory conditions. 52 Moreover, aging or CHIP-associated mutations might also accelerate chronic inflammation.…”