E2F‐6 Suppresses Growth‐Associated Apoptosis of Human Hematopoietic Progenitor Cells by Counteracting Proapoptotic Activity of E2F‐1

E2F‐6 is a dominant‐negative transcriptional repressor against other members of the E2F family. In this study, we investigated the expression and function of E2F‐6 in human hematopoietic progenitor cells to clarify its role in hematopoiesis. We found that among E2F subunits, E2F‐1, E2F‐2, E2F‐4, and E2F‐6 were expressed in CD34+ human hematopoietic progenitor cells. The expression of E2F‐6 increased along with proliferation and decreased during differentiation of hematopoietic progenitors, whereas the other three species were upregulated in CD34− bone marrow mononuclear cells. Overexpression of E2F‐6 did not affect the growth of immature hematopoietic cell line K562 but suppressed E2F‐1‐induced apoptosis, whereas it failed to inhibit apoptosis induced by differentiation inducers and anticancer drugs. Among E2F‐1‐dependent apoptosis‐related molecules, E2F‐6 specifically inhibited upregulation of Apaf‐1 by competing with E2F‐1 for promoter binding. E2F‐6 similarly suppressed apoptosis and Apaf‐1 upregulation in primary hematopoietic progenitor cells during cytokine‐induced proliferation but had no effect when they were differentiated. As a result, E2F‐6 enhanced the clonogenic growth of colony‐forming unit‐granulocyte, erythroid, macrophage, and megakaryocyte. These results suggest that E2F‐6 provides a failsafe mechanism against loss of hematopoietic progenitor cells during proliferation. Disclosure of potential conflicts of interest is found at the end of this article.