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 Blood, 1 December 2007, Vol. 110, No. 12, pp. 3853-3861.
Prepublished online as a Blood First Edition Paper on August 16, 2007; DOI 10.1182/blood-2007-03-079582.

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Submitted March 13, 2007
Accepted August 6, 2007

Cdc42 critically regulates the balance between myelopoiesis and erythropoiesis

Linda Yang, Lei Wang, Theodosia Kalfa, Jose A Cancelas, Xun Shang, Suvarnamala Pushkaran, Jun Mo, David A Williams, and Yi Zheng*

Division of Experimental Hematology, Children's Hospital Medical Center, Molecular Developmental Biology Grad Prog, Univ of Cincinnati, Cincinnati, OH, United States

* Corresponding author; email: yi.zheng{at}chmcc.org.

The Rho GTPase Cdc42 regulates adhesion, migration and homing, as well as cell cycle progression, of hematopoietic stem cells, but its role in multi-lineage blood development remains unclear. We report here that inducible deletion of cdc42 in cdc42-floxed mouse bone marrow by the interferon-responsive, Mx1-Cre mediated excision led to myeloid and erythroid developmental defects. Cdc42-deletion affected the number of early myeloid progenitors while suppressing erythroid differentiation. Cdc42 deficient mice developed a fatal myeloproliferative disorder manifested by significant leukocytosis with neutrophilia, myeloid hyper-proliferation, and myeloid cell infiltration into distal organs. Concurrently, Cdc42-deficiency caused anemia and splenomegaly accompanied with decreased bone marrow BFU-E and CFU-E activities and reduced immature erythroid progenitors, suggesting that Cdc42-deficiency causes a block in the early stage of erythropoiesis. Cdc42 activity is responsive to stimulation by SCF, IL3, SDF-1{alpha}, and fibronectin. The increased myelopoiesis and decreased erythropoiesis of the knockout mice are associated with an altered gene transcription program in hematopoietic progenitors, including upregulation of pro-myeloid genes such as PU.1, C/EBP1{alpha}, and Gfi-1 in the common myeloid progenitors and granulocyte-macrophage progenitors and downregulation of pro-erythroid gene such as GATA-2 in the megakaryocyte-erythroid progenitors. Thus, Cdc42 is an essential regulator of the balance between myelopoiesis and erythropoiesis.


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