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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.
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Submitted August 24, 2006
Accepted January 11, 2007
Evidence that the Pim1 kinase gene is a direct target of HOXA9 and a mediator of HOXA9's effects on hematopoiesis
Yu-Long Hu, Emmanuelle Passegue, Stephen Fong, Corey Largman, and Hugh Jeffrey Lawrence*
Medical Service, Veterans Affairs Medical Center, Department of Medicine, University of California San Francisco Medical School, San Francisco, CA, United States
Developmental and Stem Cell Biology Program, University of California San Francisco Comprehensive Cancer Center, San Francisco, CA, United States
* Corresponding author; email: jeffl{at}medicine.ucsf.edu.
The HOXA9 homeoprotein exerts dramatic effects in hematopoiesis. Enforced expression of HOXA9 enhances proliferation of primitive blood cells, expands hematopoietic stem cell (HSC) 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 hematological 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 pro-apoptotic BAD protein, a target of Pim1. Hoxa9-/- cells show increased apoptosis and decreased proliferation, defects that are ameliorated by re-introduction of Pim1. Thus Pim1 appears to be a direct transcriptional target of HOXA9 and a mediator of its anti-apoptotic and pro-proliferative effects in early cells. Since HOXA9 is frequently upregulated in acute myeloid leukemia, Pim1 may be a therapeutic target in human disease.
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