Editors' ChoiceCancer

A Chemokine Receptor Drives Lymphoma

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Sci. Signal.  23 Dec 2014:
Vol. 7, Issue 357, pp. ec352
DOI: 10.1126/scisignal.aaa5268

Adult T cell leukemia/lymphoma (ATLL) is an aggressive lymphoma with a poor prognosis and it is caused by infection with human T cell lymphotropic virus 1 (HTLV-1). However, fewer than 10% of HTLV-1–infected individuals develop ATLL, suggesting that somatic mutations in cellular genes may drive development of the disease. Nakagawa et al. performed RNA transcriptome analysis of two ATLL patients and found mutations in CCR4, which encodes the chemokine receptor CCR4, a G protein–coupled receptor that mediates T cell migration and is highly abundant on leukemic cells in ATLL patients. Similar mutations were found in more than 25% of samples from additional patients and ATLL cell lines. These mutations resulted in truncated CCR4 proteins devoid of the cytoplasmic region that is required for receptor desensitization and internalization. Indeed, analysis of cell-surface receptor abundance on ATLL cells showed that ligand-induced internalization of truncated CCR4 was impaired compared with that of wild-type CCR4. ATLL cell lines expressing only the truncated form of CCR4 displayed enhanced migration to the CCR4 ligands CCL17 and CCL22 compared to cells that had equivalent amounts of only wild-type CCR4. Chemokine-dependent signaling by truncated CCR4 resulted in enhanced activation of the kinase PI3K compared to that of stimulated by wild-type CCR4. Competitive growth assays showed that ATLL cells expressing mutant CCR4 proliferated to a greater extent than did ATLL cells expressing wild-type CCR4. As Shannon discusses, these results implicate CCR4 mutations in the pathogenesis of ATLL and suggest that targeting CCR4 signaling may provide a therapeutic strategy to treat this disease.

M. Nakagawa, R. Schmitz, W. Xiao, C. K. Goldman, W. Xu, Y. Yang, X. Yu, T. A. Waldmann, L. M. Staudt, Gain-of-function CCR4 mutations in adult T cell leukemia/lymphoma. J. Exp. Med. 211, 2497–2505 (2014). [Abstract] [Full Text]

K. M. Shannon, CCR4 drives ATLL jail break. J. Exp. Med. 211, 2485 (2014). [Full Text]

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