ALK-transformed mature T lymphocytes restore early thymus progenitor features.
J Clin Invest
; 130(12): 6395-6408, 2020 12 01.
Article
em En
| MEDLINE
| ID: mdl-33141118
ABSTRACT
Anaplastic large cell lymphoma (ALCL) is a mature T cell neoplasm that often expresses the CD4+ T cell surface marker. It usually harbors the t(2;5) (p23;q35) translocation, leading to the ectopic expression of NPM-ALK, a chimeric tyrosine kinase. We demonstrated that in vitro transduction of normal human CD4+ T lymphocytes with NPM-ALK results in their immortalization and malignant transformation. The tumor cells displayed morphological and immunophenotypical characteristics of primary patient-derived anaplastic large cell lymphomas. Cell growth, proliferation, and survival were strictly dependent on NPM-ALK activity and include activation of the key factors STAT3 and DNMT1 and expression of CD30 (the hallmark of anaplastic large-cell lymphoma). Implantation of NPM-ALK-transformed CD4+ T lymphocytes into immunodeficient mice resulted in the formation of tumors indistinguishable from patients' anaplastic large cell lymphomas. Integration of "Omic" data revealed that NPM-ALK-transformed CD4+ T lymphocytes and primary NPM-ALK+ ALCL biopsies share similarities with early T cell precursors. Of note, these NPM-ALK+ lymphoma cells overexpress stem cell regulators (OCT4, SOX2, and NANOG) and HIF2A, which is known to affect hematopoietic precursor differentiation and NPM-ALK+ cell growth. Altogether, for the first time our findings suggest that NPM-ALK could restore progenitor-like features in mature CD30+ peripheral CD4+ T cells, in keeping with a thymic progenitor-like pattern.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Timo
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Células-Tronco Neoplásicas
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Linfócitos T CD4-Positivos
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Transformação Celular Neoplásica
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Linfoma Anaplásico de Células Grandes
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Quinase do Linfoma Anaplásico
Limite:
Animals
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Female
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Humans
Idioma:
En
Revista:
J Clin Invest
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
França