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Blood, 28 May 2009, Vol. 113, No. 22, pp. 5466-5475. Prepublished online as a Blood First Edition Paper on April 3, 2009; DOI 10.1182/blood-2008-09-179747. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2008-09-179747v1 113/22/5466    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Google Scholar Articles by Horman, S. R. Articles by Grimes, H. L. PubMed PubMed Citation Articles by Horman, S. R. Articles by Grimes, H. L. Related Collections Hematopoiesis and Stem Cells Phagocytes, Granulocytes, and Myelopoiesis Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMATOPOIESIS AND STEM CELLS Gfi1 integrates progenitor versus granulocytic transcriptional programming Shane R. Horman1,*, Chinavenmeni S. Velu1,*, Aditya Chaubey1, Tristan Bourdeau1, Jinfang Zhu2, William E. Paul2, Brian Gebelein3, and H. Leighton Grimes1 1 Divisions of Immunobiology, and Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, OH; 2 National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD; and 3 Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, OH In patients with severe congenital neutropenia (SCN) and mice with growth factor independent-1 (Gfi1) loss of function, arrested myeloid progenitors accumulate, whereas terminal granulopoiesis is blocked. One might assume that Gfi-null progenitors accumulate because they lack the ability to differentiate. Instead, our data indicate that Gfi1 loss of function deregulates 2 separable transcriptional programs, one of which controls the accumulation and lineage specification of myeloid progenitors, but not terminal granulopoiesis. We demonstrate that Gfi1 directly represses HoxA9, Pbx1, and Meis1 during normal myelopoiesis. Gfi1–/– progenitors exhibit elevated levels of HoxA9, Pbx1 and Meis1, exaggerated HoxA9-Pbx1-Meis1 activity, and progenitor transformation in collaboration with oncogenic K-Ras. Limiting HoxA9 alleles corrects, in a dose-dependent manner, in vivo and in vitro phenotypes observed with loss of Gfi1 in myeloid progenitor cells but did not rescue Gfi1–/– blocked granulopoiesis. Thus, Gfi1 integrates 2 events during normal myeloid differentiation; the suppression of a HoxA9-Pbx1-Meis1 progenitor program and the induction of a granulopoietic transcription program. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. J. Salipante, M. E. B. Rojas, B. Korkmaz, Z. Duan, J. Wechsler, K. F. Benson, R. E. Person, H. L. Grimes, and M. S. Horwitz Contributions to Neutropenia from PFAAP5 (N4BP2L2), a Novel Protein Mediating Transcriptional Repressor Cooperation between Gfi1 and Neutrophil Elastase Mol. Cell. Biol., August 15, 2009; 29(16): 4394 - 4405. [Abstract] [Full Text] [PDF]

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