TY - JOUR
T1 - The Paf oncogene is essential for hematopoietic stem cell function and development
AU - Amrani, Yacine M.
AU - Gill, Jonathan
AU - Matevossian, Armine
AU - Alonzo, Eric S.
AU - Yang, Chingwen
AU - Shieh, Jae Hung
AU - Moore, Malcolm A.
AU - Park, Christopher Y.
AU - Sant'Angelo, Derek B.
AU - Denzin, Lisa K.
PY - 2011/8/29
Y1 - 2011/8/29
N2 - 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 cellintrinsic 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. 2011 Amrani et al.
AB - 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 cellintrinsic 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. 2011 Amrani et al.
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U2 - 10.1084/jem.20102170
DO - 10.1084/jem.20102170
M3 - Article
C2 - 21844206
AN - SCOPUS:80054834594
SN - 0022-1007
VL - 208
SP - 1757
EP - 1765
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 9
ER -