The AML1-ETO fusion gene and the FLT3 length mutation collaborate in inducing acute leukemia in mice

被引:176
作者
Schessl, C
Rawat, VPS
Cusan, M
Deshpande, A
Kohl, TM
Rosten, PM
Spiekermann, K
Humphries, RK
Schnittger, S
Kern, W
Hiddemann, W
Quintanilla-Martinez, L
Bohlander, SK
Feuring-Buske, M
Buske, C
机构
[1] Univ Munich, Dept Med 3, D-81377 Munich, Germany
[2] GSF Munich, Natl Res Ctr Environm & Hlth, Clin Cooperat Grp Leukemia, Munich, Germany
[3] British Columbia Canc Agcy, Terry Fox Lab, Vancouver, BC V5Z 1L3, Canada
[4] Univ British Columbia, Dept Med, Vancouver, BC, Canada
[5] GSF Munich, Dept Pathol, Munich, Germany
关键词
D O I
10.1172/JCI24225
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
The molecular characterization of leukemia has demonstrated that genetic alterations in the leukemic clone frequently fall into 2 classes, those affecting transcription factors (e.g., AML1-ETO) and mutations affecting genes involved in signal transduction (e.g., activating mutations of FLT3 and KIT'). This finding has favored a model of leukemogenesis in which the collaboration of these 2 classes of genetic alterations is necessary for the malignant transformation of hematopoietic progenitor cells. The model is supported by experimental data indicating that AML1-ETO and FLT3 length mutation (FLT3-LM), 2 of the most frequent genetic alterations in AML, are both insufficient on their own to cause leukemia in animal models. Here we report that AML1-ETO collaborates with FLT3-LM in inducing acute leukemia in a murine BM transplantation model. Moreover, in a series of 135 patients with AML1-ETO-positive AML, the most frequently identified class of additional mutations affected genes involved in signal transduction pathways including FLT3-LM or mutations of KIT and NRAS. These data support the concept of oncogenic cooperation between AML1-ETO and a class of activating mutations, recurrently found in patients with t(8;21), and provide a rationale for therapies targeting signal transduction pathways in AML1-ETO-positive leukemias.
引用
收藏
页码:2159 / 2168
页数:10
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