Evidence that the Pim1 kinase gene is a direct target of HOXA9.
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.
Hu
Yu-Long
YL
Hematology Research, Medical Service, UCSF Veterans Affairs Medical Center, University of California-San Francisco, 4150 Clement Street, San Francisco, CA 94121, USA.
Passegué
Emmanuelle
E
Fong
Stephen
S
Largman
Corey
C
Lawrence
Hugh Jeffrey
HJ
D017209:Apoptosis; D001854:Bone Marrow Cells / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D015973:Gene Expression Regulation, Leukemic; D006412:Hematopoietic Stem Cells / Q000166:cytology; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D020014:K562 Cells; D007951:Leukemia, Myeloid / Q000378:metabolism; D010766:Phosphorylation; D051573:Proto-Oncogene Proteins c-pim-1 / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D013997:Time Factors; D019076:Transgenes; D020298:U937 Cells
D018398:Homeodomain Proteins; D012333:RNA, Messenger; C097899:homeobox protein HOXA9; D051573:Proto-Oncogene Proteins c-pim-1