Nucleophosmin/anaplastic Lymphoma Kinase (NPM/ALK) Oncoprotein Induces the T Regulatory Cell Phenotype by Activating STAT3

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2006 Jun 13

PMID 16766651

Citations 69

Authors

Monika Kasprzycka

Michal Marzec

Xiaobin Liu

Qian Zhang

Mariusz A Wasik

Affiliations

Soon will be listed here.

Abstract

The mechanisms of malignant cell transformation mediated by the oncogenic, chimeric nucleophosmin/anaplastic lymphoma kinase (NPM/ALK) tyrosine kinase remain only partially understood. Here we report that the NPM/ALK-carrying T cell lymphoma (ALK+TCL) cells secrete IL-10 and TGF-beta and express FoxP3, indicating their T regulatory (Treg) cell phenotype. The secreted IL-10 suppresses proliferation of normal immune, CD3/CD28-stimulated peripheral blood mononuclear cells and enhances viability of the ALK+TCL cells. The Treg phenotype of the affected cells is strictly dependent on NPM/ALK expression and function as demonstrated by transfection of the kinase into BaF3 cells and inhibition of its enzymatic activity and expression in ALK+TCL cells. NPM/ALK, in turn, induces the phenotype through activation of its key signal transmitter, signal transducer and activator of transcription 3 (STAT3). These findings identify a mechanism of NPM/ALK-mediated oncogenesis based on induction of the Treg phenotype of the transformed CD4(+) T cells. These results also provide an additional rationale to therapeutically target the chimeric kinase and/or STAT3 in ALK+TCL.

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References

Chen W, Jin W, Hardegen N, Lei K, Li L, Marinos N . Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med. 2003; 198(12):1875-86. PMC: 2194145. DOI: 10.1084/jem.20030152. View

Wang T, Niu G, Kortylewski M, Burdelya L, Shain K, Zhang S . Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nat Med. 2004; 10(1):48-54. DOI: 10.1038/nm976. View

Yu H, Jove R . The STATs of cancer--new molecular targets come of age. Nat Rev Cancer. 2004; 4(2):97-105. DOI: 10.1038/nrc1275. View

Marshall N, Christie L, Munro L, Culligan D, Johnston P, Barker R . Immunosuppressive regulatory T cells are abundant in the reactive lymphocytes of Hodgkin lymphoma. Blood. 2003; 103(5):1755-62. DOI: 10.1182/blood-2003-07-2594. View

Gamero A, Young H, Wiltrout R . Inactivation of Stat3 in tumor cells: releasing a brake on immune responses against cancer?. Cancer Cell. 2004; 5(2):111-2. DOI: 10.1016/s1535-6108(04)00028-5. View

Turkson J, Kim J, Zhang S, Yuan J, Huang M, Glenn M . Novel peptidomimetic inhibitors of signal transducer and activator of transcription 3 dimerization and biological activity. Mol Cancer Ther. 2004; 3(3):261-9. View

Pestka S, Krause C, Sarkar D, Walter M, Shi Y, Fisher P . Interleukin-10 and related cytokines and receptors. Annu Rev Immunol. 2004; 22:929-79. DOI: 10.1146/annurev.immunol.22.012703.104622. View

Crockett D, Lin Z, Elenitoba-Johnson K, Lim M . Identification of NPM-ALK interacting proteins by tandem mass spectrometry. Oncogene. 2004; 23(15):2617-29. DOI: 10.1038/sj.onc.1207398. View

Vieira P, Christensen J, Minaee S, ONeill E, Barrat F, Boonstra A . IL-10-secreting regulatory T cells do not express Foxp3 but have comparable regulatory function to naturally occurring CD4+CD25+ regulatory T cells. J Immunol. 2004; 172(10):5986-93. DOI: 10.4049/jimmunol.172.10.5986. View

10.

Karube K, Ohshima K, Tsuchiya T, Yamaguchi T, Kawano R, Suzumiya J . Expression of FoxP3, a key molecule in CD4CD25 regulatory T cells, in adult T-cell leukaemia/lymphoma cells. Br J Haematol. 2004; 126(1):81-4. DOI: 10.1111/j.1365-2141.2004.04999.x. View

11.

Viguier M, Lemaitre F, Verola O, Cho M, Gorochov G, Dubertret L . Foxp3 expressing CD4+CD25(high) regulatory T cells are overrepresented in human metastatic melanoma lymph nodes and inhibit the function of infiltrating T cells. J Immunol. 2004; 173(2):1444-53. DOI: 10.4049/jimmunol.173.2.1444. View

12.

OGarra A, Vieira P . Regulatory T cells and mechanisms of immune system control. Nat Med. 2004; 10(8):801-5. DOI: 10.1038/nm0804-801. View

13.

Curiel T, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P . Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med. 2004; 10(9):942-9. DOI: 10.1038/nm1093. View

14.

Chan K, Sano S, Kiguchi K, Anders J, Komazawa N, Takeda J . Disruption of Stat3 reveals a critical role in both the initiation and the promotion stages of epithelial carcinogenesis. J Clin Invest. 2004; 114(5):720-8. PMC: 514583. DOI: 10.1172/JCI21032. View

15.

Taga K, Mostowski H, Tosato G . Human interleukin-10 can directly inhibit T-cell growth. Blood. 1993; 81(11):2964-71. View

16.

Shiota M, Fujimoto J, Semba T, Satoh H, Yamamoto T, Mori S . Hyperphosphorylation of a novel 80 kDa protein-tyrosine kinase similar to Ltk in a human Ki-1 lymphoma cell line, AMS3. Oncogene. 1994; 9(6):1567-74. View

17.

Fujimoto J, Shiota M, IWAHARA T, Seki N, Satoh H, Mori S . Characterization of the transforming activity of p80, a hyperphosphorylated protein in a Ki-1 lymphoma cell line with chromosomal translocation t(2;5). Proc Natl Acad Sci U S A. 1996; 93(9):4181-6. PMC: 39508. DOI: 10.1073/pnas.93.9.4181. View

18.

Bischof D, Pulford K, Mason D, Morris S . Role of the nucleophosmin (NPM) portion of the non-Hodgkin's lymphoma-associated NPM-anaplastic lymphoma kinase fusion protein in oncogenesis. Mol Cell Biol. 1997; 17(4):2312-25. PMC: 232080. DOI: 10.1128/MCB.17.4.2312. View

19.

Morris S, Naeve C, Mathew P, JAMES P, Kirstein M, Cui X . ALK, the chromosome 2 gene locus altered by the t(2;5) in non-Hodgkin's lymphoma, encodes a novel neural receptor tyrosine kinase that is highly related to leukocyte tyrosine kinase (LTK). Oncogene. 1997; 14(18):2175-88. DOI: 10.1038/sj.onc.1201062. View

20.

Kuefer M, Look A, Pulford K, Behm F, Pattengale P, Mason D . Retrovirus-mediated gene transfer of NPM-ALK causes lymphoid malignancy in mice. Blood. 1997; 90(8):2901-10. View