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ALK rearrangement in sickle cell trait-associated renal medullary carcinoma

Authors

  • Adrián Mariño-Enríquez,

    1. Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
    2. Departamento de Anatomía Patológica, Hospital Universitario La Paz, Universidad Autónoma de Madrid, Spain
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    • Adrián Mariño-Enriquez and Wen-Bin Ou contributed equally to this work.

  • Wen-Bin Ou,

    1. Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
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    • Adrián Mariño-Enriquez and Wen-Bin Ou contributed equally to this work.

  • Christopher B. Weldon,

    1. Department of Surgery, Children's Hospital Boston, Harvard Medical School, Boston, MA
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  • Jonathan A. Fletcher,

    Corresponding author
    1. Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
    • Department of Pathology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA
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  • Antonio R. Pérez-Atayde

    Corresponding author
    1. Department of Pathology, Children's Hospital Boston, Harvard Medical School, Boston, MA
    • Department of Pathology, Children's Hospital Boston, 300 Longwood Ave, Boston, MA 02115, USA
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Abstract

Renal Medullary Carcinoma (RMC) is an aggressive malignancy that affects young black individuals with sickle cell trait. No effective treatment is available, resulting in an ominous clinical course, with overall survival averaging less than four months. We report rearrangement of the ALK receptor tyrosine kinase in a pediatric case of RMC harboring a t(2;10)(p23;q22) translocation. Mass spectrometry-based proteomic evaluation identified a novel ALK oncoprotein in which the cytoskeletal protein vinculin (VCL) was fused to the ALK kinase domain. The resulting VCL-ALK fusion does not contain known self-association domains, but includes the talin binding domains of vinculin. We demonstrate coprecipitation of strongly tyrosine phosphorylated talins with the VCL-ALK oncoprotein, suggesting that ALK oncogenic crossphosphorylation is mediated by interactions between neighboring VCL-ALK proteins on a talin scaffold. This report widens the spectrum of ALK-related tumors and ALK fusion partners, and provides a rationale for treating RMC with targeted ALK inhibitors. © 2010 Wiley-Liss, Inc.

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