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Schessl, C. ; Rawat, V.P.S. ; Cusan, M. ; Deshpande, A. ; Kohl, T.M. ; Spiekermann, K. ; Hiddemann, W. ; Quintanilla-Martinez, L. ; Bohlander, S.K. ; Feuring-Buske, M. ; Buske, C.

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

J. Clin. Invest. 115, 2159-2186 (2005)
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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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
ISSN (print) / ISBN 0021-9738
e-ISSN 1558-8238
Journal Journal of Clinical Investigation
Quellenangaben Volume: 115, Issue: 8, Pages: 2159-2186 Article Number: , Supplement: ,
Publisher American Society of Clinical Investigation
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) CCG Pathogenesis of Acute Myeloid Leukemia (KKG-KPL)
Institute of Pathology (PATH)