The Potent Oncogene NPM-ALK Mediates Malignant Transformation of Normal Human CD4+ T Lymphocytes

被引:29
作者
Zhang, Qian [1 ]
Wei, Fang [2 ]
Wang, Hong Yi [1 ]
Liu, Xiaobin [1 ]
Roy, Darshan [1 ]
Xiong, Qun-Bin [1 ]
Jiang, Shuguang [1 ]
Medvec, Andrew [2 ]
Danet-Desnoyers, Gwenn [3 ]
Watt, Christopher [1 ]
Tomczak, Ewa [1 ]
Kalos, Michael. [1 ]
Riley, James L. [2 ]
Wasik, Mariusz A. [1 ]
机构
[1] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA USA
[2] Univ Penn, Dept Microbiol, Philadelphia, PA 19104 USA
[3] Univ Penn, Dept Med, Philadelphia, PA 19104 USA
关键词
ANAPLASTIC LYMPHOMA KINASE; LARGE-CELL LYMPHOMA; PROTEIN; STAT3; MICE; EXPRESSION; CANCER; PATHOGENESIS; ONCOPROTEIN; ACTIVATION;
D O I
10.1016/j.ajpath.2013.08.030
中图分类号
R36 [病理学];
学科分类号
100104 ;
摘要
With this study we have demonstrated that in vitro transduction of normal human CD4(+) T lymphocytes with NPM-ALK results in their malignant transformation. The transformed cells become immortalized and display morphology and immunophenotype characteristic of patient-derived anaplastic large-cell lymphomas. These unique features, which are strictly dependent on NPM-ALK activity and expression, include perpetual. cell growth, proliferation, and survival; activation of the key signal transduction pathways STAT3 and mTORC1; and expression of CD30 (the hallmark of anaplastic large-cell lymphoma) and of immunosuppressive cytokine IL-10 and cell-surface protein PD-L1/CD274. Implantation of NPM-ALK-transformed CD4(+) T lymphocytes into immunodeficient mice resulted in formation of tumors indistinguishable from patients' anaplastic large-cell Lymphomas. Our findings demonstrate that the key aspects of human carcinogenesis closely recapitulating the features of the native tumors can be faithfully reproduced in vitro when an appropriate oncogene is used to transform its natural target cells; this in turn points to the fundamental role in malignant cell transformation of potent oncogenes expressed in the relevant target cells. Such transformed cells should permit study of the early stages of carcinogenesis, and in particular the initial oncogene-host cell. interactions. This experimental design could also be useful for studies of the effects of early therapeutic intervention and likely also the mechanisms of malignant progression.
引用
收藏
页码:1971 / 1980
页数:10
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