title: Gain-of-function CCR4 mutations in adult T cell leukemia/lymphoma.
abstract: Adult T cell leukemia/lymphoma (ATLL) is an aggressive malignancy caused by human T cell lymphotropic virus type-I (HTLV-I) without curative treatment at present. To illuminate the pathogenesis of ATLL we performed whole transcriptome sequencing of purified ATLL patient samples and discovered recurrent somatic mutations in CCR4, encoding CC chemokine receptor 4. 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 because it increased cell migration toward the CCR4 ligands CCL17 and CCL22, in part by impairing receptor internalization. This mutant enhanced PI(3) kinase/AKT activation after 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.
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Masao
authors.initials: M
authors.lastname: Nakagawa
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Roland
authors.initials: R
authors.lastname: Schmitz
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Wenming
authors.initials: W
authors.lastname: Xiao
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Carolyn K
authors.initials: CK
authors.lastname: Goldman
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Weihong
authors.initials: W
authors.lastname: Xu
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Yandan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Xin
authors.initials: X
authors.lastname: Yu
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Waldmann
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 lstaudt@mail.nih.gov.
authors.forename: Louis M
authors.initials: LM
authors.lastname: Staudt
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D049109:Cell Proliferation; D054422:Chemokine CCL22; D002633:Chemotaxis; D004705:Endocytosis; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008024:Ligands; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011485:Protein Binding; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D054398:Receptors, CCR4 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C515482:CCL22 protein, human; C515354:CCR4 protein, human; D054422:Chemokine CCL22; D008024:Ligands; D050505:Mutant Proteins; D020033:Protein Isoforms; D054398:Receptors, CCR4; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt