NPM-ALK-induced reprogramming of mature TCR-stimulated T cells results in dedifferentiation and malignant transformation

Jan M. Pawlicki; David L. Cookmeyer; Damian Maseda; John K. Everett; Fang Wei; Hong Kong; Qian Zhang; Hong Y. Wang; John W. Tobias; David M. Walter; Kelly M. Zullo; Sarah Javaid; Amanda Watkins; Mariusz A. Wasik; Frederic D. Bushman; James L. Riley

doi:10.1158/0008-5472.CAN-20-2297

NPM-ALK-induced reprogramming of mature TCR-stimulated T cells results in dedifferentiation and malignant transformation

Jan M. Pawlicki, David L. Cookmeyer, Damian Maseda, John K. Everett, Fang Wei, Hong Kong, Qian Zhang, Hong Y. Wang, John W. Tobias, David M. Walter, Kelly M. Zullo, Sarah Javaid, Amanda Watkins, Mariusz A. Wasik, Frederic D. Bushman, James L. Riley

Research output: Contribution to journal › Article › peer-review

13 Scopus citations

Abstract

Fusion genes including NPM-ALK can promote T-cell transformation, but the signals required to drive a healthy T cell to become malignant remain undefined. In this study, we introduce NPM-ALK into primary human T cells and demonstrate induction of the epithelial-to-mesenchymal transition (EMT) program, attenuation of most T-cell effector programs, reemergence of an immature epigenomic profile, and dynamic regulation of c-Myc, E2F, and PI3K/mTOR signaling pathways early during transformation. A mutant of NPM-ALK failed to bind several signaling complexes including GRB2/SOS, SHC1, SHC4, and UBASH3B and was unable to transform T cells. Finally, T-cell receptor (TCR)-generated signals were required to achieve T-cell transformation, explaining how healthy individuals can harbor T cells with NPM-ALK translocations. These findings describe the fundamental mechanisms of NPM-ALK-mediated oncogenesis and may serve as a model to better understand factors that regulate tumor formation.

Original language	English
Pages (from-to)	3241-3254
Number of pages	14
Journal	Cancer Research
Volume	81
Issue number	12
DOIs	https://doi.org/10.1158/0008-5472.CAN-20-2297
State	Published - Jun 2021

Keywords

Apoptosis
Cell Dedifferentiation
Cell Proliferation
Cell Transformation, Neoplastic/immunology
Cellular Reprogramming
Humans
Lymphoma, Large-Cell, Anaplastic/genetics
Phosphorylation
Protein-Tyrosine Kinases/genetics
Receptors, Antigen, T-Cell/genetics
T-Lymphocytes/immunology
TOR Serine-Threonine Kinases/genetics
Tumor Cells, Cultured

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1158/0008-5472.CAN-20-2297

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Pawlicki, J. M., Cookmeyer, D. L., Maseda, D., Everett, J. K., Wei, F., Kong, H., Zhang, Q., Wang, H. Y., Tobias, J. W., Walter, D. M., Zullo, K. M., Javaid, S., Watkins, A., Wasik, M. A., Bushman, F. D., & Riley, J. L. (2021). NPM-ALK-induced reprogramming of mature TCR-stimulated T cells results in dedifferentiation and malignant transformation. Cancer Research, 81(12), 3241-3254. https://doi.org/10.1158/0008-5472.CAN-20-2297

@article{7f5e1bf98eeb423e854f213b71111a6f,

title = "NPM-ALK-induced reprogramming of mature TCR-stimulated T cells results in dedifferentiation and malignant transformation",

abstract = "Fusion genes including NPM-ALK can promote T-cell transformation, but the signals required to drive a healthy T cell to become malignant remain undefined. In this study, we introduce NPM-ALK into primary human T cells and demonstrate induction of the epithelial-to-mesenchymal transition (EMT) program, attenuation of most T-cell effector programs, reemergence of an immature epigenomic profile, and dynamic regulation of c-Myc, E2F, and PI3K/mTOR signaling pathways early during transformation. A mutant of NPM-ALK failed to bind several signaling complexes including GRB2/SOS, SHC1, SHC4, and UBASH3B and was unable to transform T cells. Finally, T-cell receptor (TCR)-generated signals were required to achieve T-cell transformation, explaining how healthy individuals can harbor T cells with NPM-ALK translocations. These findings describe the fundamental mechanisms of NPM-ALK-mediated oncogenesis and may serve as a model to better understand factors that regulate tumor formation.",

keywords = "Apoptosis, Cell Dedifferentiation, Cell Proliferation, Cell Transformation, Neoplastic/immunology, Cellular Reprogramming, Humans, Lymphoma, Large-Cell, Anaplastic/genetics, Phosphorylation, Protein-Tyrosine Kinases/genetics, Receptors, Antigen, T-Cell/genetics, T-Lymphocytes/immunology, TOR Serine-Threonine Kinases/genetics, Tumor Cells, Cultured",

author = "Pawlicki, {Jan M.} and Cookmeyer, {David L.} and Damian Maseda and Everett, {John K.} and Fang Wei and Hong Kong and Qian Zhang and Wang, {Hong Y.} and Tobias, {John W.} and Walter, {David M.} and Zullo, {Kelly M.} and Sarah Javaid and Amanda Watkins and Wasik, {Mariusz A.} and Bushman, {Frederic D.} and Riley, {James L.}",

note = "Publisher Copyright: {\textcopyright} 2021 American Association for Cancer Research.",

year = "2021",

month = jun,

doi = "10.1158/0008-5472.CAN-20-2297",

language = "English",

volume = "81",

pages = "3241--3254",

journal = "Cancer Research",

issn = "0008-5472",

publisher = "American Association for Cancer Research Inc.",

number = "12",

}

Pawlicki, JM, Cookmeyer, DL, Maseda, D, Everett, JK, Wei, F, Kong, H, Zhang, Q, Wang, HY, Tobias, JW, Walter, DM, Zullo, KM, Javaid, S, Watkins, A, Wasik, MA, Bushman, FD & Riley, JL 2021, 'NPM-ALK-induced reprogramming of mature TCR-stimulated T cells results in dedifferentiation and malignant transformation', Cancer Research, vol. 81, no. 12, pp. 3241-3254. https://doi.org/10.1158/0008-5472.CAN-20-2297

TY - JOUR

T1 - NPM-ALK-induced reprogramming of mature TCR-stimulated T cells results in dedifferentiation and malignant transformation

AU - Pawlicki, Jan M.

AU - Cookmeyer, David L.

AU - Maseda, Damian

AU - Everett, John K.

AU - Wei, Fang

AU - Kong, Hong

AU - Zhang, Qian

AU - Wang, Hong Y.

AU - Tobias, John W.

AU - Walter, David M.

AU - Zullo, Kelly M.

AU - Javaid, Sarah

AU - Watkins, Amanda

AU - Wasik, Mariusz A.

AU - Bushman, Frederic D.

AU - Riley, James L.

PY - 2021/6

Y1 - 2021/6

N2 - Fusion genes including NPM-ALK can promote T-cell transformation, but the signals required to drive a healthy T cell to become malignant remain undefined. In this study, we introduce NPM-ALK into primary human T cells and demonstrate induction of the epithelial-to-mesenchymal transition (EMT) program, attenuation of most T-cell effector programs, reemergence of an immature epigenomic profile, and dynamic regulation of c-Myc, E2F, and PI3K/mTOR signaling pathways early during transformation. A mutant of NPM-ALK failed to bind several signaling complexes including GRB2/SOS, SHC1, SHC4, and UBASH3B and was unable to transform T cells. Finally, T-cell receptor (TCR)-generated signals were required to achieve T-cell transformation, explaining how healthy individuals can harbor T cells with NPM-ALK translocations. These findings describe the fundamental mechanisms of NPM-ALK-mediated oncogenesis and may serve as a model to better understand factors that regulate tumor formation.

AB - Fusion genes including NPM-ALK can promote T-cell transformation, but the signals required to drive a healthy T cell to become malignant remain undefined. In this study, we introduce NPM-ALK into primary human T cells and demonstrate induction of the epithelial-to-mesenchymal transition (EMT) program, attenuation of most T-cell effector programs, reemergence of an immature epigenomic profile, and dynamic regulation of c-Myc, E2F, and PI3K/mTOR signaling pathways early during transformation. A mutant of NPM-ALK failed to bind several signaling complexes including GRB2/SOS, SHC1, SHC4, and UBASH3B and was unable to transform T cells. Finally, T-cell receptor (TCR)-generated signals were required to achieve T-cell transformation, explaining how healthy individuals can harbor T cells with NPM-ALK translocations. These findings describe the fundamental mechanisms of NPM-ALK-mediated oncogenesis and may serve as a model to better understand factors that regulate tumor formation.

KW - Apoptosis

KW - Cell Dedifferentiation

KW - Cell Proliferation

KW - Cell Transformation, Neoplastic/immunology

KW - Cellular Reprogramming

KW - Humans

KW - Lymphoma, Large-Cell, Anaplastic/genetics

KW - Phosphorylation

KW - Protein-Tyrosine Kinases/genetics

KW - Receptors, Antigen, T-Cell/genetics

KW - T-Lymphocytes/immunology

KW - TOR Serine-Threonine Kinases/genetics

KW - Tumor Cells, Cultured

UR - http://www.scopus.com/inward/record.url?scp=85108081113&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-20-2297

DO - 10.1158/0008-5472.CAN-20-2297

M3 - Article

C2 - 33619116

AN - SCOPUS:85108081113

SN - 0008-5472

VL - 81

SP - 3241

EP - 3254

JO - Cancer Research

JF - Cancer Research

IS - 12

ER -

NPM-ALK-induced reprogramming of mature TCR-stimulated T cells results in dedifferentiation and malignant transformation

Abstract

Keywords

UN SDGs

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