title: Transforming property of TEL-FGFR3 mediated through PI3-K in a T-cell lymphoma that subsequently progressed to AML.
abstract: We previously reported a novel fusion between TEL and FGFR3 in a patient with peripheral T-cell lymphoma with t(4; 12)(p16;p13). Disease in this patient subsequently progressed to acute myelogenous leukemia (AML) with the same translocation. Sequence analysis of TEL-FGFR3 fusion transcripts suggested that these diseases originated from the same multipotent stem cell. To determine the transforming property of TEL-FGFR3, we established transfectants of this chimeric fusion gene and investigated the major signal pathways of TEL-FGFR3-induced transformation using various signal transduction inhibitors including SU5402 (fibroblast growth factor tyrosine kinase [FGFR TK] inhibitor). Our results indicated that (1) the expression of TEL-FGFR3 but not DeltaHLH-TEL-FGFR3 resulted in efficient focus formation in NIH/3T3 cells and conferred interleukin 3 independence to Ba/F3 cells by a constitutive tyrosine kinase activity probably through oligomerization by the HLH domain of TEL; (2) although effector proteins including classical mitogen-activated protein kinase (MAPK), p38 MAPK, phosphatidylinositol 3-kinase (PI3-K), mammalian target or rapamycin (mTOR), signal transducer and activator of transcription 3 (STAT-3) and STAT-5 were activated in TEL-FGFR3 transformants, the growth of the transformants was inhibited by SU5402 (concentration that inhibits 50% [IC5)]=5 microM) and the PI3-K inhibitor, LY294002 (IC5)=10 microM) and wortmannin (IC50=5 microM), but not by U0126, SB203580, or rapamycin; and (3) injection of TEL-FGFR3 transformants induced lethal leukemia into syngeneic mice. Taken together, the leukemogenic potential of TEL-FGFR3 may be mediated in part through PI3-K.
authors.affiliation: Department of Internal Medicine (Hematology), Saitama Medical School, 38 Morohongou, Moroyama-Machi, Iruma-Gun, 350-0451, Saitama, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Maeda
authors.forename: Fumiharu
authors.initials: F
authors.lastname: Yagasaki
authors.forename: Maho
authors.initials: M
authors.lastname: Ishikawa
authors.forename: Naoki
authors.initials: N
authors.lastname: Takahashi
authors.forename: Masami
authors.initials: M
authors.lastname: Bessho
mesh_terms: D000208:Acute Disease; D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D018450:Disease Progression; D005260:Female; D006801:Humans; D007951:Leukemia, Myeloid / Q000209:etiology*; D016399:Lymphoma, T-Cell / Q000473:pathology*; D051379:Mice; D008875:Middle Aged; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051498:Receptor, Fibroblast Growth Factor, Type 3; D015398:Signal Transduction; D014162:Transfection; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D015514:Oncogene Proteins, Fusion; D019869:Phosphatidylinositol 3-Kinases; D051498:Receptor, Fibroblast Growth Factor, Type 3; C442581:ETV6-FGFR3 protein, human; D000097764:ETS Translocation Variant 6 Protein