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J. Biol. Chem., Vol. 282, Issue 40, 29384-29393, October 5, 2007

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Hepatocyte Growth Factor Receptor c-MET Is Associated with FAS and When Activated Enhances Drug-induced Apoptosis in Pediatric B Acute Lymphoblastic Leukemia with TEL-AML1 Translocation^*

Benedetta Accordi¹, Serena Pillozzi, Marta Campo Dell'Orto, Giovanni Cazzaniga^¶, Annarosa Arcangeli, Geertruy te Kronnie, and Giuseppe Basso

From the Oncohematology Laboratory, Department of Pediatrics, University of Padova, 35128, Padova Italy, the Department of Experimental Pathology and Oncology, University of Firenze, 50134 Firenze Italy, and the ^¶M. Tettamanti Research Center, University of Milano-Bicocca, San Gerardo Hospital, 20052 Monza (MI) Italy

Expression of c-MET, the HGF (hepatocyte growth factor) tyrosine kinase receptor, was investigated in pediatric B-acute lymphoblastic leukemia (ALL) patients. c-MET was found to be expressed in normal B cells and in B-ALL patients with the t(12;21) TEL-AML1 translocation, but it is not expressed in the most part of B-ALL without the t(12;21). We also found that c-MET, related to proliferation and protection from apoptosis, is associated with the pro-apoptotic protein FAS in TEL-AML1 B-ALL cells and in normal B lymphocytes. The possible role of this protein complex in drug-induced apoptosis was thus investigated in REH TEL-AML1 B-ALL cell line. REH cells prestimulated with HGF and treated with doxorubicin had shown a higher apoptotic rate than non-HGF-prestimulated ones (p = 0.03). REH cells stimulated with IL-3 and treated with doxorubicin did not undergo apoptosis more than nonstimulated cells, demonstrating that increased proliferation in itself is not directly related to the higher apoptotic sensitivity observed with HGF stimulation. These results indicate that c-MET activation enhances specifically FAS-mediated apoptosis in TEL-AML1 ALL cells and, considering that the c-MET/FAS complex is present only in normal B lymphocytes and in TEL-AML1 leukemias, this implies that it may have an important contribution in cellular homeostasis and in high sensitivity of TEL-AML1 ALL to chemotherapeutic regimens.

Received for publication, July 31, 2007

^* This work was supported by grants from the Programmi di Ricerca di Interesse Nazionale (PRIN) (to G.B. and A.A.), the Associazione Italiana per la Ricerca sul Cancro (AIRC) (to G.B. and A.A.), the Consiglio Nazionale delle Ricerche (Progetto Oncologia) (CNR) (to G.B.), the Fondazione Città Della Speranza (to G.B.), the Ministero dell'Istruzione dell'Università e della Ricerca (MIUR) (to G.B.), the Fondazione Cariplo (to G.B.), the Associazione Italiana contro le Leucemie (AIL) (Firenze and Pistoia sections) (to S.P.), the Ente Cassa di Risparmio Firenze (to A.A.), and the Associazione Genitori contro le Leucemie e Tumori Infantili Noi per Voi (to A.A.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Laboratory of Pediatric Oncohematology, University of Padova, via Giustiniani 3, 35128 Padova, Italy. Tel.: 39-049-8211453; Fax: 39-049-8211462; E-mail: benedetta.accordi{at}unipd.it.

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