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Id1 promotes clonal hematopoiesis in mice with Tet2 loss of function

Shweta Singh,K. Gudmundsson,Tanmoy Sarkar,Brad L. Jakubison,Holly M. Morris,Sandra S. Burkett,Karim Baktiar,Gary T. Pauly,D. Sigano,Joel P. Schneider,L. Tessarollo,Jonathan R. Keller

Published 2025 in Science Advances

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 Id1 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 Id1 expression may reduce CH. Genetic ablation of Id1 in Tet2−/− 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 Tet2−/−;Id1−/− HSPCs. Thus, ID1 may represent a therapeutic target to reduce CH and delay the onset of disease.

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