Certification of the Fabienne Megetto group by the Fondation pour la Recherche Médicale for 3 years

Deciphering the impact of circular RNAs for the resistance of pediactric T-cell lymphomas associated with alterations of the ALK tyrosine kinase.

Anaplastic large-cell lymphoma (ALCL) is an aggressive T lymphoma mainly occurring in children. Approximately 84% of ALCL cases harbour a fusion involving the anaplastic lymphoma kinase (ALK) gene.

This results in constitutively activated fusion protein driving the disease by activating oncogenic signalling pathways. Most ALK+ ALCL cases initially respond well to the frontline chemotherapy, but ~30% of patients experience a relapse, of bad prognosis. For chemo-resistant forms, ALK inhibitors (ALKi) can be used, but the emergence of therapeutic resistance to ALKi poses a growing challenge. Understanding the oncogenesis and the origins of therapy resistance is of major importance to improve treatment and prognosis. To date, we and others have linked microRNAs and long non-coding RNAs to pathogenesis and drug resistance in ALK+ ALCL. Circular RNAs (circRNAs) are a new class of highly stable ncRNAs. CirRNAs can control target gene expression by e.g. interacting with microRNAs or proteins. Tumor suppressive or promoting functions have been demonstrated for selected circRNAs in various cancer entities. Our projects aim to elucidate the role of circRNAs in ALK+ ALCL biology including their impact on ncRNA networks and RNA-binding-proteins and the establishment of therapy resistance.

This project will

1. identify circRNAs associated with therapy resistance in ALK+ ALCL,
2. analyze their effect on oncogenesis and treatment response in vitro and in vivo,
3. elucidate their mechanism of action.

Project results will add to the current mechanistic understanding of ALK+ ALCL pathogenesis and the origins of therapy resistance, and could define new druggable targets and associated predictive biomarkers for highrisk disease.

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