De novo generation of the NPM-ALK fusion recapitulates the pleiotropic phenotypes of ALK+ ALCL pathogenesis and reveals the ROR2 receptor as target for tumor cells - MNHN - Muséum national d'Histoire naturelle Access content directly
Journal Articles Molecular Cancer Year : 2022

De novo generation of the NPM-ALK fusion recapitulates the pleiotropic phenotypes of ALK+ ALCL pathogenesis and reveals the ROR2 receptor as target for tumor cells

Loélia Babin
Elie Robert
  • Function : Author
Zakia Aid
  • Function : Author
Claire Soudais
  • Function : Author
Marion Piganeau
  • Function : Author
Anne de Cian
Olivia Bawa
  • Function : Author
Charlotte Rigaud
  • Function : Author
Jean-Yves Scoazec
  • Function : Author
Lucile Couronné
  • Function : Author
Layla Veleanu
  • Function : Author
Agata Cieslak
  • Function : Author
Vahid Asnafi
  • Function : Author
David Sibon
  • Function : Author
Erika Brunet

Abstract

Abstract Background Anaplastic large cell lymphoma positive for ALK (ALK+ ALCL) is a rare type of non-Hodgkin lymphoma. This lymphoma is caused by chromosomal translocations involving the anaplastic lymphoma kinase gene (ALK). In this study, we aimed to identify mechanisms of transformation and therapeutic targets by generating a model of ALK+ ALCL lymphomagenesis ab initio with the specific NPM-ALK fusion. Methods We performed CRISPR/Cas9-mediated genome editing of the NPM-ALK chromosomal translocation in primary human activated T lymphocytes. Results Both CD4+ and CD8+ NPM-ALK-edited T lymphocytes showed rapid and reproducible competitive advantage in culture and led to in vivo disease development with nodal and extra-nodal features. Murine tumors displayed the phenotypic diversity observed in ALK+ ALCL patients, including CD4+ and CD8+ lymphomas. Assessment of transcriptome data from models and patients revealed global activation of the WNT signaling pathway, including both canonical and non-canonical pathways, during ALK+ ALCL lymphomagenesis. Specifically, we found that the WNT signaling cell surface receptor ROR2 represented a robust and genuine marker of all ALK+ ALCL patient tumor samples. Conclusions In this study, ab initio modeling of the ALK+ ALCL chromosomal translocation in mature T lymphocytes enabled the identification of new therapeutic targets. As ROR2 targeting approaches for other cancers are under development (including lung and ovarian tumors), our findings suggest that ALK+ ALCL cases with resistance to current therapies may also benefit from ROR2 targeting strategies.
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Dates and versions

mnhn-03868576 , version 1 (25-11-2022)

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Loélia Babin, Alice Darchen, Elie Robert, Zakia Aid, Rosalie Borry, et al.. De novo generation of the NPM-ALK fusion recapitulates the pleiotropic phenotypes of ALK+ ALCL pathogenesis and reveals the ROR2 receptor as target for tumor cells. Molecular Cancer, 2022, 21 (1), pp.65. ⟨10.1186/s12943-022-01520-0⟩. ⟨mnhn-03868576⟩
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