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myeloproliferative disorder and a propensity

Activation of FGFR1 as a result of chromosome translocations that create chimeric kinases is responsible for a syndromic form of AML that is accompanied by a myeloproliferative disorder and a propensity to also develop T-cell and B-cell lymphomas. Work in the Cowell Laboratory has developed syngeneic and humanized models of these FGFR1-driven leukemias. FGFR1 can be activated by a variety of different chromosome translocations, and one feature of this disorder is the variable phenotypes associated with the different chimeric kinases. To address this issue, we have created a human AML model driven by BCR-FGFR1 in immunocompromized mice (Br. J Hematol, in press) and demonstrate a genetic fingerprint that is similar to other human and mouse models driven by CNTRL-FGFR1 kinase. In addition, we have also created a syngeneic mouse model for the FGFR1OP2-FGFR1 chimeric kinase-driven disease, which develops an aggressive T-lymphoma associated with Notch1 upregulation and AML that shows molecular hallmarks of myeloid cell arrest at early stages in development (Haematologica. 2016, 101(3):e91-4). The development of these models, which are highly representative of the human disease, are now being used to evaluate anti-FGFR1 therapies as an approach to treat this almost invariably lethal disease. In a second project, the Cowell laboratory has been studying the role of the WASF3 gene in invasion and metastasis of breast and prostate cancer cells. In some breast cancer cells, invasion is driven by activation of an overexpressed HER2/HER3 receptor complex in response to ligand binding. It has now been shown that WASF3 is recruited to the HER2/3 membrane-bound protein complex, leading to its phosphoactivation, which is known to be essential to drive invasion and metastasis (Oncogene, doi: 10.1038/ onc.2015.527, in press). Knockdown of WASF3 in the same cells leads to suppression of invasion, demonstrating that WASF3 is critical for the HER2/3 promotion of invasion. When WASF3 and HER2 are overexpressed in non-metastasizing breast cancer cells, invasion and metastasis is induced, demonstrating the importance of these protein-protein interactions for this phenotype.