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Christina Schessl, Vijay P.S. Rawat, Monica Cusan, Aniruddha Deshpande, Tobias M. Kohl, Patricia M. Rosten, Karsten Spiekermann, R. Keith Humphries, Susanne Schnittger, Wolfgang Kern, Wolfgang Hiddemann, Leticia Quintanilla-Martinez, Stefan K. Bohlander, Michaela Feuring-Buske, Christian Buske
J Clin Invest. 2005;
115(8):2159
doi:10.1172/JCI24225
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T
he 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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