<i>Id1</i> promotes clonal hematopoiesis in mice with <i>Tet2</i> loss of function.

Abstract

Hematopoietic malignancies emerge through the acquisition of genetic mutations within hematopoietic stem and progenitor cells (HSPCs). Some mutations impart a selective growth advantage to HSPCs, which expand and contribute to mature blood cells. This expansion is termed clonal hematopoiesis (CH). Inhibitor of DNA binding 1 (ID1) protein is a transcriptional regulator of proliferation/differentiation of hematopoietic cells. HSPCs express low levels of <i>Id1</i> that is induced by growth factors and other mediators of inflammatory during stress to promote HSPC expansion. Since chronic inflammation is associated with the progression of hematopoietic malignancies, reducing <i>Id1</i> expression may reduce CH. Genetic ablation of <i>Id1</i> in <i>Tet2^-/-</i> HSPCs reduces HSPC expansion/CH, extramedullary hematopoiesis, myeloid skewing, and genetic instability and delays the onset of disease. Mechanistically, p16 expression, senescence, and apoptosis were increased, and proliferation decreased in <i>Tet2^-/-;Id1^-/-</i> HSPCs. Thus, ID1 may represent a therapeutic target to reduce CH and delay the onset of disease.