Transforming property of TEL-FGFR3 mediated through PI3-K in a T-cell lymphoma that subsequently progressed to AML
| Autor: | Masami Bessho, Tomoya Maeda, Fumiharu Yagasaki, Naoki Takahashi, Maho Ishikawa |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
musculoskeletal diseases
MAPK/ERK pathway Oncogene Proteins Fusion Immunology Biology Lymphoma T-Cell Transfection Biochemistry Cell Line Wortmannin Fusion gene chemistry.chemical_compound Mice Phosphatidylinositol 3-Kinases hemic and lymphatic diseases Animals Humans Receptor Fibroblast Growth Factor Type 3 LY294002 Protein kinase A Interleukin 3 Cell Proliferation Cell Biology Hematology Middle Aged Cell Transformation Neoplastic chemistry Leukemia Myeloid Acute Disease Cancer research Disease Progression Female Signal transduction Tyrosine kinase Signal Transduction |
| Zdroj: | Blood. 105(5) |
| ISSN: | 0006-4971 |
| Popis: | 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 ΔHLH-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% [IC50] = 5 μM) and the PI3-K inhibitor, LY294002 (IC50 = 10 μM) and wortmannin (IC50 = 5 μM), 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. |
| Databáze: | OpenAIRE |
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