Gain-of-function CCR4 mutations in adult T cell leukemia/lymphoma
Open Access
- 8 December 2014
- journal article
- Published by Rockefeller University Press in The Journal of Experimental Medicine
- Vol. 211 (13), 2497-2505
- https://doi.org/10.1084/jem.20140987
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.Keywords
This publication has 32 references indexed in Scilit:
- Molecular Hallmarks of Adult T Cell LeukemiaFrontiers in Microbiology, 2012
- FERM domain mutations induce gain of function in JAK3 in adult T-cell leukemia/lymphomaBlood, 2011
- The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applicationsBlood, 2011
- Autocrine/paracrine cytokine stimulation of leukemic cell proliferation in smoldering and chronic adult T-cell leukemiaBlood, 2010
- Molecular signatures to improve diagnosis in peripheral T-cell lymphoma and prognostication in angioimmunoblastic T-cell lymphomaBlood, 2010
- Specific Recruitment of CC Chemokine Receptor 4–Positive Regulatory T Cells in Hodgkin Lymphoma Fosters Immune PrivilegeCancer Research, 2006
- Enhanced function with decreased internalization of carboxy-terminus truncated CXCR4 responsible for WHIM syndromeExperimental Hematology, 2005
- WHIM syndromes with different genetic anomalies are accounted for by impaired CXCR4 desensitization to CXCL12Blood, 2005
- CXCR4 mutations in WHIM syndrome: a misguided immune system?Immunological Reviews, 2005
- Expression of CCR4 in adult T-cell leukemiaLeukemia & Lymphoma, 2005