The Clonal Hematopoiesis-associated Gene Plays an Essential Role in Hematopoiesis.

Somatic mutations arising in hematopoietic stem cells (HSCs) may provide the latter with a fitness advantage, allowing the mutant HSC to clonally expand. Such mutations have been recurrently identified in the chromatin modifier, , in both non-malignant and leukemic clones, suggesting that this gene plays a significant role in hematopoiesis. We generated a conditional loss of function murine model and determined the consequences of hematopoietic-specific loss of this gene. We show that is essential for normal fetal liver erythropoiesis and monocytopoiesis. In deficient fetal livers, the number of phenotypic HSCs is similar to that of controls, but these HSCs exhibit a profound repopulating defect. Likewise, conditional deletion of during adult hematopoiesis results in a rapid loss of HSCs. Loss of is associated with evidence of increased DNA damage in HSCs and lineage-restricted progenitors as assessed by y-H2AX expression. Consistent with this finding, we observed strong transcriptional upregulation of the p53 pathway in deficient erythroid precursors. Collectively our data highlight the importance of in maintaining HSC function and supporting hematopoietic differentiation and suggests that it plays an essential role in maintaining genomic integrity.