The PAF1c Subunit CDC73 Is Required for Mouse Hematopoietic Stem Cell Maintenance but Displays Leukemia-Specific Gene Regulation

Abstract

Summary: The Polymerase Associated Factor 1 complex (PAF1c) functions at the interface of epigenetics and gene transcription. The PAF1c is required for MLL fusion-driven acute myeloid leukemia (AML) through direct regulation of pro-leukemic target genes such as Hoxa9 and Meis1. However, the role of the PAF1c in normal hematopoiesis is unknown. Here, we discovered that the PAF1c subunit, CDC73, is required for both fetal and adult hematopoiesis. Loss of Cdc73 in hematopoietic cells is lethal because of extensive bone marrow failure. Cdc73 has an essential cell-autonomous role for adult hematopoietic stem cell function in vivo, and deletion of Cdc73 results in cell-cycle defects in hematopoietic progenitors. Gene expression profiling indicated a differential regulation of Hoxa9/Meis1 gene programs by CDC73 in progenitors compared with AML cells, suggesting disease-specific functions. Thus, the PAF1c subunit, CDC73 is essential for hematopoietic stem cell function but exhibits leukemia-specific regulation of self-renewal gene programs in AML cells. : In this article, Muntean and colleagues show that a component of the polymerase-associated factor complex, CDC73, is essential for hematopoietic stem and progenitor cell survival and function. CDC73 displays differential regulation of self-renewal gene programs, including Hoxa9 and Meis1, in leukemic cells compared with normal hematopoietic progenitors suggestive of disease-specific functions. Keywords: hematopoiesis, MLL1, AML, Hoxa9, Meis1, cell cycle, bone marrow failure