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 myelogenous leukemia (AML). We report that the T/T(F) and T/T(L) fusion variants associated with congenital fibrosarcoma and AML, respectively, are constitutively 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 lymphoblastic lymphoma. TEL-TRKC variants are potent activators of the MAP kinase pathway, but neither variant activates Stat5 or other Stat family members. T/T(L), but not T/T(F), induces tyrosine phosphorylation of phospholipase Cgamma (PLCgamma), phosphoinositol-3 kinase and SHC. However, mutation analysis demonstrates that PLCgamma tyrosine phos phorylation by T/T(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 activation of either PLCgamma or Stat5 for efficient induction of a myeloproliferative phenotype in the murine BMT model.
Liu
Q
Q
Departments of Medicine, Brigham and Women's Hospital, Harvard Institutes of Medicine, 4 Blackfan Circle, Room 420, Boston, MA 02115, USA.
Schwaller
J
J
Kutok
J
J
Cain
D
D
Aster
J C
JC
Williams
I R
IR
Gilliland
D G
DG
D016475:3T3 Cells; D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D002881:Chromosomes, Human, Pair 12; D002884:Chromosomes, Human, Pair 15; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005354:Fibrosarcoma / Q000151:congenital / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D020935:MAP Kinase Signaling System; D051379:Mice; D008894:Milk Proteins; D018482:Muscle, Skeletal / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051966:Phospholipase C gamma; D010766:Phosphorylation; D050783:Proto-Oncogene Proteins c-ets; D020812:Receptor, trkC / Q000378:metabolism*; D012097:Repressor Proteins; D050799:STAT5 Transcription Factor; D015398:Signal Transduction; D014018:Tissue Distribution; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured; D010738:Type C Phospholipases / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D000097764:ETS Translocation Variant 6 Protein
D004268:DNA-Binding Proteins; D007527:Isoenzymes; D008894:Milk Proteins; D015514:Oncogene Proteins, Fusion; D019869:Phosphatidylinositol 3-Kinases; D051966:Phospholipase C gamma; D050783:Proto-Oncogene Proteins c-ets; D020812:Receptor, trkC; D012097:Repressor Proteins; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D014157:Transcription Factors; D010738:Type C Phospholipases; D014443:Tyrosine; D000097764:ETS Translocation Variant 6 Protein; C409037:TEL-TRKC fusion protein, human