Ablation of Id1 Reduces Clonal Hematopoiesis, Genomic Instability and Delays Leukemia in Mice with Tet2 Loss of Function [RNA-seq]

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, and other cells, and is frequently overexpressed in cancer. Id1 is expressed at low levels in normal HSCs and is induced by growth factors and other mediators of inflammatory stress and promotes HSPC proliferation. HSCs that lack Id1 (Id1-/-) show reduced cycling/activation and are protected from exhaustion under chronic stress including bone marrow transplantation (BMT), genotoxic and inflammatory stress, and aging. Since chronic inflammation is associated with the progression of hematopoietic malignancies, reducing Id1 expression during CH may be therapeutic. Mutations in TET2 are frequently observed in patients with CH, and Tet2-/- mice show CH. ID1 is upregulated in HSPCs from patients with TET2 mutations and Tet2-/- mice. Genetic ablation of Id1 in Tet2-/- 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 in Tet2-/-; Id1-/- HSPCs. Thus, ID1 may represent a potential therapeutic target to reduce CH and delay the onset of leukemia.