Evi-1 is a critical regulator for hematopoietic stem cells and transformed leukemic cells.
Evi-1 has been recognized as one of the dominant oncogenes associated with murine and human myeloid leukemia. Here, we show that hematopoietic stem cells (HSCs) in Evi-1-deficient embryos are severely reduced in number with defective proliferative and repopulating capacity. Selective ablation of Evi-1 in Tie2(+) cells mimics Evi-1 deficiency, suggesting that Evi-1 function is required in Tie2(+) hematopoietic stem/progenitors. Conditional deletion of Evi-1 in the adult hematopoietic system revealed that Evi-1-deficient bone marrow HSCs cannot maintain hematopoiesis and lose their repopulating ability. In contrast, Evi-1 is dispensable for blood cell lineage commitment. Evi-1(+/-) mice exhibit the intermediate phenotype for HSC activity, suggesting a gene dosage requirement for Evi-1. We further demonstrate that disruption of Evi-1 in transformed leukemic cells leads to significant loss of their proliferative activity both in vitro and in vivo. Thus, Evi-1 is a common and critical regulator essential for proliferation of embryonic/adult HSCs and transformed leukemic cells.
Goyama
Susumu
S
Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, The University of Tokyo Hospital, Tokyo 113-8655, Japan.
Yamamoto
Go
G
Shimabe
Munetake
M
Sato
Tomohiko
T
Ichikawa
Motoshi
M
Ogawa
Seishi
S
Chiba
Shigeru
S
Kurokawa
Mineo
M
D000818:Animals; D001854:Bone Marrow Cells; D002461:Cell Line, Transformed; D019070:Cell Lineage / Q000235:genetics; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D018628:Gene Dosage; D006410:Hematopoiesis / Q000235:genetics*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000473:pathology; D006801:Humans; D007951:Leukemia, Myeloid / Q000473:pathology*; D000074008:MDS1 and EVI1 Complex Locus Protein; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046228:Microarray Analysis; D011519:Proto-Oncogenes / Q000235:genetics*; D042787:Receptor, TIE-2 / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
D004268:DNA-Binding Proteins; D000074008:MDS1 and EVI1 Complex Locus Protein; C499305:Mecom protein, mouse; D014157:Transcription Factors; D042787:Receptor, TIE-2