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.

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.

• Authors: Loélia Babin, Alice Darchen, Elie Robert, Zakia Aid, Rosalie Borry, Claire Soudais, Marion Piganeau, Anne De Cian, Carine Giovannangeli, Olivia Bawa, Charlotte Rigaud, Jean-Yves Scoazec, Lucile Couronné, Layla Veleanu, Agata Cieslak, Vahid Asnafi, David Sibon, Laurence Lamant, Fabienne Meggetto, Thomas Mercher, Erika Brunet
• Journal: Molecular cancer (Mol Cancer) Vol. 21 Issue 1 Pg. 65 (03 04 2022) ISSN: 1476-4598 [Electronic] England
• PMID: 35246138 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Anaplastic Lymphoma Kinase
• Protein-Tyrosine Kinases
• ROR2 protein, human
• Receptor Protein-Tyrosine Kinases
• Receptor Tyrosine Kinase-like Orphan Receptors
• Ror2 protein, mouse

Topics

• Anaplastic Lymphoma Kinase (genetics)
• Animals
• Humans
• Lymphoma, Large-Cell, Anaplastic (genetics, metabolism, pathology)
• Mice
• Phenotype
• Protein-Tyrosine Kinases (metabolism)
• Receptor Protein-Tyrosine Kinases (genetics, metabolism)
• Receptor Tyrosine Kinase-like Orphan Receptors (genetics)
• Translocation, Genetic