Directing oncogenic fusion genes into stem cells via an SCL enhancer.
TEL-TRKC is a fusion gene generated by chromosomal translocation and encodes an activated tyrosine kinase. Uniquely, it is found in both solid tumors and leukemia. However, a single exon difference (in TEL) in TEL-TRKC fusions is associated with the two sets of cancer phenotypes. We expressed the two TEL-TRKC variants in vivo by 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 contrast, the TEL-TRKC solid tumor variant (+ TEL exon 5) elicited an embryonic lethal phenotype with impairment of both angiogenesis and hematopoiesis indicative of an effect at the level of the hemangioblasts. The ability of TEL-TRKC to repress expression of Flk1, a critical regulator of early endothelial and hematopoietic cells, depended on TEL exon 5. These data indicate that related oncogenic fusion proteins similarly expressed in a hierarchy of early stem cells can have selective, cell type-specific developmental impacts.
Eguchi
Mariko
M
Section of Haemato-Oncology, Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Road, London SW3 6JB, United Kingdom.
Eguchi-Ishimae
Minenori
M
Green
Anthony
A
Enver
Tariq
T
Greaves
Mel
M
D000818:Animals; D001808:Blood Vessels / Q000196:embryology; D049109:Cell Proliferation; D004742:Enhancer Elements, Genetic; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D007942:Leukemia, Experimental / Q000209:etiology*; D051379:Mice; D008822:Mice, Transgenic; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000502:physiology; D010641:Phenotype; D019076:Transgenes; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics
D015514:Oncogene Proteins, Fusion; C409037:TEL-TRKC fusion protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2