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Blood, 1 June 2007, Vol. 109, No. 11, pp. 4732-4738. Prepublished online as a Blood First Edition Paper on February 27, 2007; DOI 10.1182/blood-2006-08-043356. This Article Full Text Full Text (PDF) Supplemental Methods All Versions of this Article: blood-2006-08-043356v1 109/11/4732    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 Citing Articles via Google Scholar Google Scholar Articles by Hu, Y.-L. Articles by Lawrence, H. J. Search for Related Content PubMed PubMed Citation Articles by Hu, Y.-L. Articles by Lawrence, H. J. Related Collections Gene Expression Hematopoiesis Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMATOPOIESIS Evidence that the Pim1 kinase gene is a direct target of HOXA9 Yu-Long Hu1, Emmanuelle Passegué3, Stephen Fong1, Corey Largman1,2, and Hugh Jeffrey Lawrence1,2 1 Medical Service, Veterans Affairs Medical Center, San Francisco, CA; 2 Department of Medicine, University of California San Francisco Medical School; 3 University of California San Francisco Comprehensive Cancer Center, Developmental & Stem Cell Biology Program The HOXA9 homeoprotein exerts dramatic effects in hematopoiesis. Enforced expression of HOXA9 enhances proliferation of primitive blood cells, expands hematopoietic stem cells (HSCs), and leads to myeloid leukemia. Conversely, loss of HOXA9 inhibits proliferation and impairs HSC function. The pathways by which HOXA9 acts are largely unknown, and although HOXA9 is a transcription factor, few direct target genes have been identified. Our previous study suggested that HOXA9 positively regulates Pim1, an oncogenic kinase. The hematologic phenotypes of Hoxa9- and Pim1-deficient animals are strikingly similar. Here we show that HOXA9 protein binds to the Pim1 promoter and induces Pim1 mRNA and protein in hematopoietic cells. Pim1 protein is diminished in Hoxa9–/– cells, and Hoxa9 and Pim1 mRNA levels track together in early hematopoietic compartments. Induction of Pim1 protein by HOXA9 increases the phosphorylation and inactivation of the proapoptotic BAD protein, a target of Pim1. Hoxa9–/– cells show increased apoptosis and decreased proliferation, defects that are ameliorated by reintroduction of Pim1. Thus Pim1 appears to be a direct transcriptional target of HOXA9 and a mediator of its antiapoptotic and proproliferative effects in early cells. Since HOXA9 is frequently up-regulated in acute myeloid leukemia, Pim1 may be a therapeutic target in human disease. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: V. Pogacic, A. N. Bullock, O. Fedorov, P. Filippakopoulos, C. Gasser, A. Biondi, S. Meyer-Monard, S. Knapp, and J. Schwaller Structural Analysis Identifies Imidazo[1,2-b]Pyridazines as PIM Kinase Inhibitors with In vitro Antileukemic Activity Cancer Res., July 15, 2007; 67(14): 6916 - 6924. [Abstract] [Full Text] [PDF]

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