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Blood, 1 March 2005, Vol. 105, No. 5, pp. 2115-2123.
Prepublished online as a Blood First Edition Paper on October 28, 2004; DOI 10.1182/blood-2003-12-4290.
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Submitted December 18, 2003
Accepted October 25, 2004
Transforming property of TEL-FGFR3 mediated through PI3-K in a T-cell lymphoma that subsequently progressed to AML
Tomoya Maeda, Fumiharu Yagasaki*, Maho Ishikawa, Naoki Takahashi, and Masami Bessho
Department of Internal Medicine (Hematology), Saitama Medical School, Saitama, Japan
* Corresponding author; email: fyagasak{at}saitama-med.ac.jp.
We previously reported a novel fusion between TEL and FGFR3 in a patient with peripheral T-cell lymphoma with t(4;12)(p16;p13). 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 multi-potent stem cell. To determine the TEL-FGFR3 transforming property, 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 (FGFR TK inhibitor). Our results indicated that: (1) the expression of TEL-FGFR3 but not  HLH-TEL-FGFR3 resulted in efficient focus formation in NIH/3T3 cells and conferred IL-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 MAPK, p38 MAPK, PI3-K, mTOR, STAT-3 and STAT-5 were activated in TEL-FGFR3 transformants, the growth of the transformants was inhibited by SU5402 (IC50=5 µM) and the PI3-K inhibitor, LY294002 (IC50=10 µM) and Wortmannin (IC50=5 µM), but not by U0126, SB203580 nor 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.
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