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

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

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

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Figure 1

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Schematic diagram and analysis of expression of different constructs. (A...
Schematic diagram and analysis of expression of different constructs. (A) Retroviral constructs for expression of AML1-ETO and of the AML1-ETO-L148D (31, 47), FLT3-LM, and FLT3-LM-KD mutant proteins. The GFP vector served as a control. AE, AML1-ETO; LTR, long-terminal repeat; RHD, runt homology domain; TAF110, TATA-binding protein–associated factor 110; HHR, hydrophobic heptad repeat; ZNF, zinkfinger; TM, transmembrane; JM, juxtamembrane; PTK, protein tyrosine kinase; KI, kinase insert. (B, C, and E) Western blot analysis of cellular extracts from GP+ E86 and NIH 3T3 cells transfected with the different constructs (the molecular mass is indicated). Kasumi cells served as a positive control. (D) α-pTyr plot demonstrating phosphorylation of FLT3-LM and FLT3-WT but not of FLT3-LM-KD. (F) FACS analysis of Ba/F3 cells transduced with the FLT3 constructs. (G) Growth of IL-3–dependent Ba/F3 cells infected with the different constructs. (H and I) Flow cytometry and RT-PCR analysis of cells coexpressing FLT3-LM/YFP and AML1-ETO/GFP, isolated from a representative leukemic mouse. FL, FLT3 ligand; PB, peripheral blood.