Signal transduction and transforming properties of the TEL-TRKC fusions associated with t(12;15)(p13;q25) in congenital fibrosarcoma and acute myelogenous leukemia

The TEL-TRKC fusion is expressed as a consequence of t(12;15)(p13;q25), and is associated with two human cancers: congenital fibrosarcoma and acute my elogenous leukemia (AML), We report that the T/T(F) and T/T(L) fusion varia nts associated with congenital fibrosarcoma and AML, respectively, are cons titutively tyrosine phosphorylated, and confer factor-independent growth to the murine hematopoietic cell line Ba/F3. Retroviral transduction of T/T(L ) causes a rapidly fatal myeloproliferative disease in a murine bone marrow transplant (BMT) model, whereas T/T(F) causes a long-latency, pre-B-cell l ymphoblastic lymphoma. TEL-TRKC variants are potent activators of the MAP k inase pathway, but neither variant activates Stat5 or other Stat family mem bers. T/T(L), but not T/T(F), induces tyrosine phosphorylation of phospholi pase C gamma (PLC gamma), phosphoinositol-3 kinase and SHC, However, mutati on analysis demonstrates that PLC gamma tyrosine phosphorylation by TIT(L) is dispensable for induction of the myeloproliferative phenotype by T/T(L), Collectively, these data demonstrate that the TEL-TRKC fusion variants are oncoproteins that activate the MAP kinase pathway, and do not require acti vation of either PLC gamma or Stat5 for efficient induction of a myeloproli ferative phenotype in the murine BMT model.