title: The Paf oncogene is essential for hematopoietic stem cell function and development.
abstract: Hematopoietic stem cells (HSCs) self-renew to maintain the lifelong production of all blood populations. Here, we show that the proliferating cell nuclear antigen-associated factor (Paf) is highly expressed in cycling bone marrow HSCs and plays a critical role in hematopoiesis. Mice lacking Paf exhibited reduced bone marrow cellularity; reduced numbers of HSCs and committed progenitors; and leukopenia. These phenotypes are caused by a cell-intrinsic blockage in the development of long-term (LT)-HSCs into multipotent progenitors and preferential loss of lymphoid progenitors caused by markedly increased p53-mediated apoptosis. In addition, LT-HSCs from Paf(-/-) mice had increased levels of reactive oxygen species (ROS), failed to maintain quiescence, and were unable to support LT hematopoiesis. The loss of lymphoid progenitors was likely due the increased levels of ROS in LT-HSCs caused by treatment of Paf(-/-) mice with the anti-oxidant N-acetylcysteine restored lymphoid progenitor numbers to that of Paf(+/+) mice. Collectively, our studies identify Paf as a novel and essential regulator of early hematopoiesis.
authors.affiliation: Immunology Program, Sloan-Kettering Institute, 3 Department of Pediatrics, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Yacine M
authors.initials: YM
authors.lastname: Amrani
authors.forename: Jonathan
authors.initials: J
authors.lastname: Gill
authors.forename: Armine
authors.initials: A
authors.lastname: Matevossian
authors.forename: Eric S
authors.initials: ES
authors.lastname: Alonzo
authors.forename: Chingwen
authors.initials: C
authors.lastname: Yang
authors.forename: Jae-Hung
authors.initials: JH
authors.lastname: Shieh
authors.forename: Malcolm A
authors.initials: MA
authors.lastname: Moore
authors.forename: Christopher Y
authors.initials: CY
authors.lastname: Park
authors.forename: Derek B
authors.initials: DB
authors.lastname: Sant'Angelo
authors.forename: Lisa K
authors.initials: LK
authors.lastname: Denzin
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D016166:Free Radical Scavengers / Q000494:pharmacology; D006410:Hematopoiesis / Q000187:drug effects / Q000502:physiology*; D007970:Leukopenia / Q000235:genetics / Q000378:metabolism; D054503:Lymphoid Progenitor Cells / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D016166:Free Radical Scavengers; D015513:Oncogene Proteins; C561966:PAF protein, mouse; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D000111:Acetylcysteine