Frequent gain-of-function CCR4 mutations in Adult T-cell Leukemia/Lymphoma

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Authors

• M Nakagawa
• R Schmitz
• W Xiao
• CK Goldman
• W Xu
• Y Yang
• X Yu
• TA Waldmann
• LM Staudt

Abstract

Adult T-cell leukemia/lymphoma (ATLL) is an aggressive malignancy caused by human T cell lymphoma virus 1 (HTLV1) without curative treatment at present. High expression of CC chemokine receptor 4 (CCR4) has been identified as a hallmark gene in ATLL. CCR4 is a chemokine receptor, which has a critical role in immune cell trafficking. CCR4 ligands, CCL17 and CCL22, were produced in lymph nodes and skin from dendritic cells, macrophages and Langerhans cells. Most ATLL cases express surface CCR4 (90%) and infiltrate to lymph nodes and skin. These observations suggest that CCR4 could have a role in ATLL biology, but it is still unclear whether dysregulation of CCR4 function contributes to ATLL pathogenesis. In this study, we performed whole transcriptome sequencing of purified ATLL patient samples and discovered recurrent somatic mutations in CCR4. CCR4 mutations were detected in 14/53 ATLL samples (26%) and consisted exclusively of nonsense or frameshift mutations that truncated the coding region at C329, Q330 or Y331 in the carboxy-terminus. Functionally, the CCR4-Q330 nonsense isoform was gain-of-function since it increased cell migration towards the CCR4 ligands CCL17 and CCL22, in part by impairing receptor internalization. This mutant enhanced PI(3) kinase/AKT activation following receptor engagement by CCL22 in ATLL cells, and conferred a growth advantage in long term in vitro cultures. These findings implicate somatic gain-of-function CCR4 mutations in the pathogenesis of ATLL and suggest that inhibition of CCR4 signaling might have therapeutic potential in this refractory malignancy.

Scientific Focus Area: Cancer Biology

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