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

被引:120
作者
Nakagawa, Masao [1 ]
Schmitz, Roland [1 ]
Xiao, Wenming [1 ]
Goldman, Carolyn K. [1 ]
Xu, Weihong [1 ]
Yang, Yandan [1 ]
Yu, Xin [1 ]
Waldmann, Thomas A. [1 ]
Staudt, Louis M. [1 ]
机构
[1] NCI, Lymphoid Malignancies Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA
基金
美国国家卫生研究院;
关键词
MACROPHAGE-DERIVED CHEMOKINE; CLINICAL-SIGNIFICANCE; LEUKEMIA-LYMPHOMA; WHIM-SYNDROME; RECEPTOR; IN-VITRO; EXPRESSION; CXCR4; LIGAND; ACTIVATION;
D O I
10.1084/jem.20140987
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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.
引用
收藏
页码:2497 / 2505
页数:9
相关论文
共 32 条
[21]  
Luttrell LM, 2002, J CELL SCI, V115, P455
[22]   Human T-cell leukaemia virus type 1 (HTLV-1) infectivity and cellular transformation [J].
Matsuoka, Masao ;
Jeang, Kuan-Teh .
NATURE REVIEWS CANCER, 2007, 7 (04) :270-280
[23]   Recent progress in the development of antagonists to the chemokine receptors CCR3 and CCR4 [J].
Pease, James Edward ;
Horuk, Richard .
EXPERT OPINION ON DRUG DISCOVERY, 2014, 9 (05) :467-483
[24]   C1013G/CXCR4 acts as a driver mutation of tumor progression and modulator of drug resistance in lymphoplasmacytic lymphoma [J].
Roccaro, Aldo M. ;
Sacco, Antonio ;
Jimenez, Cristina ;
Maiso, Patricia ;
Moschetta, Michele ;
Mishima, Yuji ;
Aljawai, Yosra ;
Sahin, Ilyas ;
Kuhne, Michelle ;
Cardarelli, Pina ;
Cohen, Lewis ;
San Miguel, Jesus F. ;
Garcia-Sanz, Ramon ;
Ghobrial, Irene M. .
BLOOD, 2014, 123 (26) :4120-4131
[25]   Somatic mutations in MYD88 and CXCR4 are determinants of clinical presentation and overall survival in Waldenstrom macroglobulinemia [J].
Treon, Steven P. ;
Cao, Yang ;
Xu, Lian ;
Yang, Guang ;
Liu, Xia ;
Hunter, Zachary R. .
BLOOD, 2014, 123 (18) :2791-2796
[26]  
Vissers JLM, 2001, J LEUKOCYTE BIOL, V69, P785
[27]  
Vulcano M, 2001, EUR J IMMUNOL, V31, P812, DOI 10.1002/1521-4141(200103)31:3<812::AID-IMMU812>3.0.CO
[28]  
2-L
[29]   Molecular hallmarks of adult T cell leukemia [J].
Yamagishi, Makoto ;
Watanabe, Toshiki .
FRONTIERS IN MICROBIOLOGY, 2012, 3
[30]   Phase I Study of KW-0761, a Defucosylated Humanized Anti-CCR4 Antibody, in Relapsed Patients With Adult T-Cell Leukemia-Lymphoma and Peripheral T-Cell Lymphoma [J].
Yamamoto, Kazuhito ;
Utsunomiya, Atae ;
Tobinai, Kensei ;
Tsukasaki, Kunihiro ;
Uike, Naokuni ;
Uozumi, Kimiharu ;
Yamaguchi, Kazunari ;
Yamada, Yasuaki ;
Hanada, Shuichi ;
Tamura, Kazuo ;
Nakamura, Shigeo ;
Inagaki, Hiroshi ;
Ohshima, Koichi ;
Kiyoi, Hitoshi ;
Ishida, Takashi ;
Matsushima, Kouji ;
Akinaga, Shiro ;
Ogura, Michinori ;
Tomonaga, Masao ;
Ueda, Ryuzo .
JOURNAL OF CLINICAL ONCOLOGY, 2010, 28 (09) :1591-1598