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

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.