Pbx1 is a downstream target of Evi-1 in hematopoietic stem/progenitors and leukemic cells.
Ecotropic viral integration site-1 (Evi-1) is a nuclear transcription factor, which is essential for the proliferation/maintenance of hematopoietic stem cells (HSCs). Aberrant expression of Evi-1 has been frequently found in myeloid leukemia, and is associated with a poor patient survival. Recently, we reported candidate target genes of Evi-1 shared in HSCs and leukemic cells using gene expression profiling analysis. In this study, we identified Pbx1, a proto-oncogene in hematopoietic malignancy, as a target gene of Evi-1. Overexpression of Evi-1 increased Pbx1 expression in hematopoietic stem/progenitor cells. An analysis of the Pbx1 promoter region revealed that Evi-1 upregulates Pbx1 transcription. Furthermore, reduction of Pbx1 levels through RNAi-mediated knockdown significantly inhibited Evi-1-induced transformation. In contrast, knockdown of Pbx1 did not impair bone marrow transformation by E2A/HLF or AML1/ETO, suggesting that Pbx1 is specifically required for the maintenance of bone marrow transformation mediated by Evi-1. These results indicate that Pbx1 is a target gene of Evi-1 involved in Evi-1-mediated leukemogenesis.
Shimabe
M
M
Department of Hematology and Oncology, Graduate school of Medicine, University of Tokyo, Tokyo, Japan.
Goyama
S
S
Watanabe-Okochi
N
N
Yoshimi
A
A
Ichikawa
M
M
Imai
Y
Y
Kurokawa
M
M
D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D005786:Gene Expression Regulation; D015973:Gene Expression Regulation, Leukemic; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D007938:Leukemia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000074008:MDS1 and EVI1 Complex Locus Protein; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D008969:Molecular Sequence Data; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D011519:Proto-Oncogenes / Q000502:physiology*; D012689:Sequence Homology, Nucleic Acid; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*
D004268:DNA-Binding Proteins; C000715470:MAS1 protein, human; D000074008:MDS1 and EVI1 Complex Locus Protein; C063575:MECOM protein, human; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; C083400:PBX1 protein, human