Department of Pathology, University of Michigan Medical School, 7520B Medical Science Research Building I, 1150 W. Medical Center Dr., Ann Arbor, MI 48109-5602, USA.
Department of Pathology, University of Michigan Medical School, 7520B Medical Science Research Building I, 1150 W. Medical Center Dr., Ann Arbor, MI 48109-5602, USA; Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Stem Cell Reports. 2019 May 14;12(5):1069-1083. doi: 10.1016/j.stemcr.2019.03.010. Epub 2019 Apr 25.
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.
聚合酶相关因子 1 复合物（PAF1c）在表观遗传学和基因转录的界面发挥作用。PAF1c 通过直接调节如 Hoxa9 和 Meis1 等促白血病靶基因，在 MLL 融合驱动的急性髓系白血病（AML）中发挥作用。然而，PAF1c 在正常造血中的作用尚不清楚。在这里，我们发现 PAF1c 亚基 CDC73 对于胎儿和成人造血都是必需的。造血细胞中 Cdc73 的缺失由于广泛的骨髓衰竭而导致致命。Cdc73 在体内对成体造血干细胞功能具有必需的细胞自主作用，并且 Cdc73 的缺失导致造血祖细胞中的细胞周期缺陷。基因表达谱分析表明，与 AML 细胞相比，CDC73 在祖细胞中对 Hoxa9/Meis1 基因程序的调控存在差异，提示存在疾病特异性功能。因此，PAF1c 亚基 CDC73 对于造血干细胞功能是必需的，但在 AML 细胞中表现出对自我更新基因程序的白血病特异性调节。
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