Id1 Promotes Clonal Hematopoiesis in Mice with Tet2 Loss of Function

ABSTRACT

Hematopoietic malignancies emerge through the gradual acquisition of genetic mutations within hematopoietic stem and progenitor cells (HSPCs). Mutations that occur early in disease progression impart a selective growth advantage to HSPCs, which allows them to expand and contribute to a substantial percentage of mature blood cells. This increased expansion is termed clonal hematopoiesis (CH) and is a preleukemic phase associated with an increased risk of developing leukemia. Inhibitor of DNA binding 1 (ID1) protein is a transcriptional regulator of proliferation/differentiation of neuronal, muscle, hematopoietic and other cells, and is frequently overexpressed in cancer.Id1is expressed at low levels in normal HSCs and is induced by growth factors and other mediators of inflammatory stress and promotes HSPC proliferationin vitro and in vivo.Since chronic inflammation is associated with the progression of hematopoietic malignancies, reducingId1expression during CH may be therapeutic. Mutations inTET2are frequently observed in patients with CH, andTet2^−/−mice develop CH that progress to hematopoietic malignancies.Id1is upregulated in murineTet2^−/−HSPCs and in AML, CMML and MDS patient samples withTET2mutations. Genetic ablation ofId1inTet2^−/−HSPCs reduces HSPC expansion/self-renewal/CH, extramedullary hematopoiesis, myeloid skewing, genetic instability and delays the onset of disease. Mechanistically, p16 expression, senescence and apoptosis were increased and proliferation decreased inTet2^−/−; Id1^−/−HSPCs. Thus, ID1 may represent a potential therapeutic target to reduce CH, hematopoietic hyperplasia, and delay the onset of disease.