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Rawat, Vijay Pal Singh (2006): Ectopic expression of the homeobox gene Cdx2 is the key transforming event in a mouse model of t(12;13)(p13;q12) acute myeloid leukemia; a novel mechanism in AML. Dissertation, LMU München: Medizinische Fakultät



This thesis demonstrates for the first time that activation of a proto-oncogene by a chromosomal translocation can be the key step in myeloid leukemogenesis, even if a fusion gene is generated and expressed in parallel. This mechanism of AML leukemogenesis was proven in a murine model of t(12;13)(p13;q12) AML, showing that myeloid leukemogenesis is induced by the ectopic expression of Cdx2 and not by the ETV6/CDX2 chimeric gene. Mice transplanted with bone marrow cells retrovirally engineered to express Cdx2 rapidly succumbed to fatal and transplantable AML. In contrast, mice which were transplanted with BM cells expressing the fusion gene alone did not develop AML. The transforming activity of Cdx2 was dependent on an intact homeodomain and the N-terminal transactivation domain. Although mice transplanted with ETV6/CDX2 expressing BM cells did not develop overt disease, these animals suffered from a mild myeloproliferation. Experiments testing the effect of simultaneous expression of the Cdx2 and the fusion gene showed no acceleration or change in phenotype of the disease compared to expression of Cdx2 alone, again demonstrating that the ectopic expression of Cdx2 was the key event in this leukemia model. These findings link proto-oncogene activation to myeloid leukemogenesis, an oncogenic mechanism so far associated mainly with lymphoid leukemias and lymphomas. Our model constitutes the first functional proof that activation of a proto-oncogene by a chromosomal translocation is the key leukemogenic event in AML. As many fusion proteins expressed in AML have clearly no leukemogenic potential in experimental in vivo models, this mechanism might be more important for the development of AML than previously thought and should be included in the pathogenetic models of this disease.