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 Blood, 9 July 2009, Vol. 114, No. 2, pp. 360-370.
Prepublished online as a Blood First Edition Paper on May 7, 2009; DOI 10.1182/blood-2007-11-125658.

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LYMPHOID NEOPLASIA

IGF-IR tyrosine kinase interacts with NPM-ALK oncogene to induce survival of T-cell ALK+ anaplastic large-cell lymphoma cells

Ping Shi1, Raymond Lai2, Quan Lin1, Abid S. Iqbal1, Leah C. Young3, Larry W. Kwak4, Richard J. Ford1, and Hesham M. Amin1

Department of Hematopathology, The University of Texas M. D. Anderson Cancer Center, Houston Departments of 2 Laboratory Medicine and Pathology and 3 Medical Genetics, The University of Alberta, Edmonton, AB; and 4 Department of Lymphoma and Myeloma, The University of Texas M. D. Anderson CancerCenter, Houston

Type I insulin-like growth factor receptor (IGF-IR) tyrosine kinase plays important roles in the pathogenesis of several malignancies. Although it promotes the growth of stimulated hematopoietic cells, a direct role of IGF-IR in malignant lymphoma has not been identified. Anaplastic lymphoma kinase-positive anaplastic large-cell lymphoma (ALK+ ALCL) is a unique type of T-cell lymphoma. Approximately 85% of ALK+ ALCL cases harbor the translocation t(2;5)(p23;q35), which generates the chimeric oncogene NPM-ALK. In the present study, we explored a possible role of IGF-IR in ALK+ ALCL. Our results demonstrate that IGF-IR and IGF-I are widely expressed in ALK+ ALCL cell lines and primary tumors. Importantly, we identified novel reciprocal functional interactions between IGF-IR and NPM-ALK. Antagonism of IGF-IR decreased the viability, induced apoptosis and cell-cycle arrest, and decreased proliferation and colony formation of ALK+ ALCL cell lines. These effects could be explained by alterations of cell survival regulatory proteins downstream of IGF-IR signaling. Our findings improve current understanding of the biology of IGF-IR and NPM-ALK and have significant therapeutic implications as they identify IGF-IR signaling as a potential therapeutic target in ALK+ ALCL and possibly other types of malignant lymphoma.


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