Directing Oncogenic Fusion Genes into Stem Cells Via an Scl Enhancer.

Chimeric fusion genes generated by chromosomal translocation are a consistent feature of leukemias and some other cancer types, including sarcomas, and usually specific to particular subtypes of leukemia or tumors. One favoured explanation for this selective transformation is that it may reflect context-dependent oncogenic functions in particular stem cells and their progeny rather than highly restricted origins of fusion gene recombination itself. We have assessed this proposition by directing the expression of fusion oncogenes in stem cells in vivo.

TEL-TRKC is a fusion gene generated by chromosomal translocation and encodes an activated tyrosine kinase. Uniquely, it associates with both rare solid tumors (congenital fibrosarcoma, congenital mesoblastic nephroma and secretory breast carcinoma) and acute leukemia, but a single exon difference (in TEL) between the two phenotypes. We expressed the two TEL-TRKC variants in mice using the 3′ regulatory element of SCL that is selectively active in a subset of mesodermal cell lineages including endothelial and hematopoietic stem cells and progenitors. The leukemia form of TEL-TRKC (- exon 5 of TEL) enhanced hematopoietic stem cell renewal and initiated leukemia in transgenic mice. In contrast, the TEL-TRKC solid tumor variant (+ TEL exon 5) elicited an embryonic lethal phenotype around day 12.5 (E12.5) with impairment of both angiogenesis and hematopoiesis indicative of an effect at the level of the hemangioblasts. These data indicate that oncogenic fusion proteins similarly expressed in a hierarchy of early stem cells can have selective, cell type specific developmental impacts dependent upon their intrinsic molecular properties.