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

• Published in: Stem cell reports Vol. 12; no. 5; pp. 1069 - 1083
• Main Authors: Saha, Nirmalya, Ropa, James, Chen, Lili, Hu, Hsiangyu, Mysliwski, Maria, Friedman, Ann, Maillard, Ivan, Muntean, Andrew G.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.05.2019; Elsevier
• Subjects: Acute Disease; AML; Animals; bone marrow failure; cell cycle; Cell Line, Tumor; Fetus - metabolism; Gene Expression Profiling - methods; Gene Expression Regulation; hematopoiesis; Hematopoiesis - genetics; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Hoxa9; Humans; Leukemia, Myeloid - genetics; Leukemia, Myeloid - metabolism; Leukemia, Myeloid - pathology; Meis1; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; MLL1; Myeloid Ecotropic Viral Integration Site 1 Protein - genetics; Myeloid Ecotropic Viral Integration Site 1 Protein - metabolism; Pol1 Transcription Initiation Complex Proteins - genetics; Pol1 Transcription Initiation Complex Proteins - metabolism; Protein Subunits - genetics; Protein Subunits - metabolism; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; MLL1; AML; bone marrow failure; hematopoiesis; Hoxa9; Meis1; cell cycle
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2019.03.010

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. •CDC73 is necessary for embryonic and adult hematopoietic stem cell function•Proliferation and survival of cKIT+ hematopoietic progenitors require CDC73•CDC73 regulates unique gene programs in leukemia and hematopoietic progenitor 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.