[HTML][HTML] The AML1-ETO fusion gene and the FLT3 length mutation collaborate in inducing acute leukemia in mice
The Journal of clinical investigation, 2005•Am Soc Clin Investig
The molecular characterization of leukemia has demonstrated that genetic alterations in the
leukemic clone frequently fall into 2 classes, those affecting transcription factors (eg, AML1-
ETO) and mutations affecting genes involved in signal transduction (eg, 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 …
leukemic clone frequently fall into 2 classes, those affecting transcription factors (eg, AML1-
ETO) and mutations affecting genes involved in signal transduction (eg, 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 …
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.
The Journal of Clinical Investigation