title: The AML1-ETO fusion gene and the FLT3 length mutation collaborate in inducing acute leukemia in mice.
abstract: 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.
authors: Clinical Cooperative Group Leukemia, National Research Center for Environment and Health (GSF), Munich, Germany.
authors: Christina
authors: C
authors: Schessl
authors: Vijay P S
authors: VP
authors: Rawat
authors: Monica
authors: M
authors: Cusan
authors: Aniruddha
authors: A
authors: Deshpande
authors: Tobias M
authors: TM
authors: Kohl
authors: Patricia M
authors: PM
authors: Rosten
authors: Karsten
authors: K
authors: Spiekermann
authors: R Keith
authors: RK
authors: Humphries
authors: Susanne
authors: S
authors: Schnittger
authors: Wolfgang
authors: W
authors: Kern
authors: Wolfgang
authors: W
authors: Hiddemann
authors: Leticia
authors: L
authors: Quintanilla-Martinez
authors: Stefan K
authors: SK
authors: Bohlander
authors: Michaela
authors: M
authors: Feuring-Buske
authors: Christian
authors: C
authors: Buske
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D050676:Core Binding Factor Alpha 2 Subunit; D004195:Disease Models, Animal; D005260:Female; D011905:Genes, ras / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019891:Leukopoiesis / Q000235:genetics; D008297:Male; D051379:Mice; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D000075142:RUNX1 Translocation Partner 1 Protein; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014178:Translocation, Genetic; D051941:fms-Like Tyrosine Kinase 3
chemical_list: C107844:AML1-ETO fusion protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D000075142:RUNX1 Translocation Partner 1 Protein; D014157:Transcription Factors; C497970:FLT3 protein, human; C497971:Flt3 protein, mouse; D019009:Proto-Oncogene Proteins c-kit; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3