title: The potent oncogene NPM-ALK mediates malignant transformation of normal human CD4(+) T lymphocytes.
abstract: 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.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.forename: Fang
authors.initials: F
authors.lastname: Wei
authors.forename: Hong Yi
authors.initials: HY
authors.lastname: Wang
authors.forename: Xiaobin
authors.initials: X
authors.lastname: Liu
authors.forename: Darshan
authors.initials: D
authors.lastname: Roy
authors.forename: Qun-Bin
authors.initials: QB
authors.lastname: Xiong
authors.forename: Shuguang
authors.initials: S
authors.lastname: Jiang
authors.forename: Andrew
authors.initials: A
authors.lastname: Medvec
authors.forename: Gwenn
authors.initials: G
authors.lastname: Danet-Desnoyers
authors.forename: Christopher
authors.initials: C
authors.lastname: Watt
authors.forename: Ewa
authors.initials: E
authors.lastname: Tomczak
authors.forename: Michael
authors.initials: M
authors.lastname: Kalos
authors.forename: James L
authors.initials: JL
authors.lastname: Riley
authors.forename: Mariusz A
authors.initials: MA
authors.lastname: Wasik
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis* / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics
chemical_list: D015514:Oncogene Proteins, Fusion; C107023:p80(NPM-ALK) protein; D011505:Protein-Tyrosine Kinases