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. Cdc7 3 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.

Nationwide germline whole genome sequencing of 198 consecutive pediatric cancer patients reveals a high incidence of cancer prone syndromes

“…PVs in CDC73 cause ‘hyperparathyroidism-jaw tumor syndrome’ and parathyroid carcinoma,[ 48 ] and have been linked with hematologic cancer in mouse models. [ 49 ] RNA sequencing of leukemic cells from these patients showed no LOH, making a causal association less likely but not impossible. [ 50 ] Furthermore, we identified two patients with heterozygous deleterious variants in ERCC6L2 , a gene linked to a bone marrow failure syndrome.…”

RNA Polymerase II-Associated Factor 1 Regulates Stem Cell Features of Pancreatic Cancer Cells, Independently of the PAF1 Complex, via Interactions With PHF5A and DDX3

“…For instance, the PAF1C subunit CTR9 has been shown to regulate ERα + breast tumorigenesis and control morphology, proliferative capacity, and tamoxifen sensitivity of luminal breast cancer cells, while no other PAF1C subunit except PAF1 could modulate these features 27 . Similarly, CDC73, another PAF1C subunit, was recently shown to play an indispensable role in maintaining mouse hematopoietic stem cells and in regulating leukemia-specific gene programs 28 . Our observation of differential expression of PAF1C subunits in CSCs (SP) versus non-CSCs (NSP) following PAF1 loss alludes to the concept that PAF1 directs unique gene programs in undifferentiated versus differentiated cells.…”

Occurrence of chronic myeloid leukemia in a patient with CDC73 gene deletion: “Chance or Causality?”

“…The PAF1c binds to RNA polymerase II through the CDC73, PAF1, and LEO1 subunits. 5 Looking at the possible hematologic role of CDC73, it is known that parafibromin is required for hematopoiesis; its loss in hematopoietic stem cells (HSCs) induces lethality because of consequent extensive bone marrow failure. 5 Nevertheless, CDC73 exhibits also leukemia-specific regulation of self-renewal gene programs in acute myeloid leukemia (AML) cells.…”

“…5 Looking at the possible hematologic role of CDC73, it is known that parafibromin is required for hematopoiesis; its loss in hematopoietic stem cells (HSCs) induces lethality because of consequent extensive bone marrow failure. 5 Nevertheless, CDC73 exhibits also leukemia-specific regulation of self-renewal gene programs in acute myeloid leukemia (AML) cells. In fact, gene expression profiling indicates a differential regulation of genes critical for leukemogenesis, such as HOXA9 and MEIS1, by CDC73 in normal progenitors compared with AML cells, suggesting disease-specific functions.…”