Deciphering the role of circular RNAs in the pathogenesis and therapy resistance of ALK-positive anaplastic large-cell lymphoma

• Applicant: Dr. Steffen Fuchs
• Subject Area: Hematology, Oncology ; Pediatric and Adolescent Medicine
• Term: from 2020 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 439441203

Anaplastic large-cell lymphoma (ALCL) is a non-Hodgkin hematological neoplasm of the lymph nodes mainly occurring in children. Approximately 84% of ALK+ ALCL cases harbor a fusion between the nucleophosmin (NPM) and anaplastic lymphoma kinase (ALK) genes that results in constitutively activated ALK in the NPM-ALK fusion protein driving this disease. Fusions between ALK and other genes, such as TPM3 (13%) or ATIC (1%) also occur in ALK+ ALCL, all of which produce a constitutively active ALK protein driving oncogenic signaling pathways in the disease. Most ALK+ ALCL cases initially respond well to the currently applied frontline chemotherapy, but are prone to develop resistance with ~40% of patients relapsing. Understanding the origins of therapy resistance is of major importance to improve treatment and patient prognosis. Current research highlights deregulated expression of regulatory RNAs as an important factor in therapy resistance. For the most part, these RNAs do not code for protein products. To date, microRNAs and long non-coding RNAs up to 200nt in length have been linked to therapy resistance in ALK+ ALCL. Circular RNAs (circRNAs) are a class of highly stable (due to their circular structure) non-coding RNAs that have recently come into the focus of researchers. Circular RNAs can control target gene expression by interacting with microRNAs or proteins, and oncogenic or tumor suppressive functions have been demonstrated for selected circRNAs in various cancer entities. This project aims to elucidate the role of circRNAs in ALK+ ALCL biology including their impact on non-coding RNA networks in this disease and the establishment of therapy resistance. This project will (1) identify circRNAs associated with therapy resistance in ALK+ ALCL, (2) analyze their effect on treatment response in vitro and in vivo, (3) elucidate their mechanism of action, and (4) evaluate the circRNA candidates as plasma biomarkers to predict patient response to treatment using liquid biopsies. We aim to characterize the role of candidate circRNAs in this well-defined cancer type, which can serve as a model for other cancers with ALK aberrations acting to drive oncogenesis, including non-small cell lung cancer, anaplastic thyroid cancer and the childhood cancer, neuroblastoma. 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 high-risk disease. Establishing the blood-based alternative confirmation for the ALK+ ALCL diagnosis could also produce a less invasive diagnostic standard capable of longitudinal patient monitoring for treatment response, minimal residual disease or early relapse detection.

• DFG Programme: Research Fellowships
• International Connection: France
• Host: Fabienne Meggetto, Ph.D.