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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 (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 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 Citing Articles via Google Scholar Google Scholar Articles by Horman, S. R. Articles by Grimes, H. L. Search for Related Content PubMed PubMed Citation Articles by Horman, S. R. Articles by Grimes, H. L. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted September 16, 2008 Accepted March 29, 2009 Gfi1 integrates progenitor versus granulocytic transcriptional programming Shane R. Horman, Chinavenmeni S. Velu, Aditya Chaubey, Tristan Bourdeau, Jinfang Zhu, William E. Paul, Brian Gebelein, and H. Leighton Grimes* Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States * Corresponding author; email: lee.grimes{at}cchmc.org. In severe congenital neutropenia (SCN) patients and mice with Growth factor independent-1 (Gfi1) loss of function, arrested myeloid progenitors accumulate while terminal granulopoiesis is blocked. One might assume that Gfi1 null progenitors accumulate because they lack the ability to differentiate. Instead, our data indicate that Gfi1 loss of function deregulates two 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 two events during normal myeloid differentiation; the suppression of a HoxA9-Pbx1-Meis1 progenitor program and the induction of a granulopoeitic 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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