| RRC ID |
1527
|
| 著者 |
Maeda T, Yagasaki F, Ishikawa M, Takahashi N, Bessho M.
|
| タイトル |
Transforming property of TEL-FGFR3 mediated through PI3-K in a T-cell lymphoma that subsequently progressed to AML.
|
| ジャーナル |
Blood
|
| 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.
|
| 巻・号 |
105(5)
|
| ページ |
2115-23
|
| 公開日 |
2005-3-1
|
| DOI |
10.1182/blood-2003-12-4290
|
| PII |
S0006-4971(20)45825-2
|
| PMID |
15514005
|
| MeSH |
Acute Disease
Animals
Cell Line
Cell Proliferation
Cell Transformation, Neoplastic*
Disease Progression
Female
Humans
Leukemia, Myeloid / etiology*
Lymphoma, T-Cell / pathology*
Mice
Middle Aged
Oncogene Proteins, Fusion / genetics
Oncogene Proteins, Fusion / physiology*
Phosphatidylinositol 3-Kinases / metabolism*
Receptor, Fibroblast Growth Factor, Type 3
Signal Transduction
Transfection
|
| IF |
17.794
|
| 引用数 |
24
|
|
WOS 分野
|
HEMATOLOGY
|
| リソース情報 |
| ヒト・動物細胞 |
Ba/F3(RCB0805) |
