AML1-ETO rapidly induces acute myeloblastic leukemia in cooperation with the Wilms tumor gene, WT1.
AML1-ETO, a chimeric gene frequently detected in acute myelogenous leukemia (AML), inhibits the differentiation of myeloid progenitors by suppressing genes associated with myeloid differentiation and increases the replating ability of clonogenic myeloid progenitors. However, AML1-ETO alone cannot induce AML and thus additional genetic events are required for the onset of AML. The Wilms tumor gene (WT1), which has been identified as the gene responsible for Wilms tumor, is expressed at high levels in almost all human leukemias. In this study, we have generated transgenic mice (WT1-Tg) that overexpress WT1 in hematopoietic cells to investigate the effects of WT1 on AML1-ETO-associated leukemogenesis. AML1-ETO-transduced bone marrow (BM) cells from WT1-Tg mice exhibited inhibition of myeloid differentiation at more immature stages and higher in vitro colony-forming ability compared with AML1-ETO-transduced BM cells from wild-type mice. Most importantly, all of the mice that received a transplant of AML1-ETO-transduced BM cells from the WT1-Tg mice rapidly developed AML. These results demonstrate that AML1-ETO may exert its leukemogenic function in cooperation with the expression of WT1.
Nishida
Sumiyuki
S
Department of Molecular Medicine, Osaka University Graduate School of Medicine, 1-7, Yamada-Oka, Suita City, Osaka 565-0871, Japan.
Hosen
Naoki
N
Shirakata
Toshiaki
T
Kanato
Keisuke
K
Yanagihara
Masashi
M
Nakatsuka
Shin-ichi
S
Hoshida
Yoshihiko
Y
Nakazawa
Tsutomu
T
Harada
Yukie
Y
Tatsumi
Naoya
N
Tsuboi
Akihiro
A
Kawakami
Manabu
M
Oka
Yoshihiro
Y
Oji
Yusuke
Y
Aozasa
Katsuyuki
K
Kawase
Ichiro
I
Sugiyama
Haruo
H
D000818:Animals; D016026:Bone Marrow Transplantation / Q000379:methods; D002454:Cell Differentiation / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D023461:Myeloid Progenitor Cells / Q000378:metabolism* / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D000075142:RUNX1 Translocation Partner 1 Protein; D014161:Transduction, Genetic; D025721:WT1 Proteins / Q000235:genetics* / Q000378:metabolism
C107844:AML1-ETO fusion protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein; D025721:WT1 Proteins