Gain-of-function CCR4 mutations in adult T cell leukemia/lymphoma

• DOI: 10.1084/jem.20140987
• Publication Date: 2014-12-09T05:20:04Z
• Authors: Masao Nakagawa; Roland Schmitz; Wenming Xiao; Carolyn K. Goldman; Weihong Xu; Yandan Yang; Xin Yu; Thomas A. Waldmann; Louis M. Staudt
• Keywords: CCR4; Adult T-cell leukemia/lymphoma; Nonsense mutation

Adult T cell leukemia/lymphoma (ATLL) is an aggressive malignancy caused by human lymphotropic virus type-I (HTLV-I) without curative treatment at present. To illuminate the pathogenesis of ATLL we performed whole transcriptome sequencing purified patient samples and discovered recurrent somatic mutations in CCR4, encoding CC chemokine receptor 4. CCR4 were detected 14/53 (26%) consisted exclusively nonsense or frameshift that truncated coding region C329, Q330, Y331 carboxy terminus. Functionally, CCR4-Q330 isoform was gain-of-function because it increased migration toward ligands CCL17 CCL22, part impairing internalization. This mutant enhanced PI(3) kinase/AKT activation after engagement CCL22 cells conferred a growth advantage long-term vitro cultures. These findings implicate suggest inhibition signaling might have therapeutic potential this refractory malignancy.