CircRNAs derived from the tyrosine phosphatase PTPN22 impact chemosensitivity in ALK-positive T-cell lymphomas

Anaplastic large cell lymphoma (ALCL) is a subtype of T-cell non-Hodgkin lymphoma (NHL), classified into ALK(+) and ALK(-) subtypes, based on translocations of the ALK gene. ALK(+) ALCL have a favorable prognosis with polychemotherapy, yet some patients develop early chemoresistance, leading to treatment failure. The molecular mechanisms underlying this resistance remain poorly defined. Circular RNAs (circRNAs) have recently emerged as regulators of drug resistance in cancer, but their role in T-NHLs is largely unexplored. A comprehensive analysis of circRNA expression was performed here in primary ALK(+) ALCL biopsies. RNA-Seq identified 12 circRNAs associated with early relapse, including isoforms from the PTPN22 gene (circPTPN22), significantly upregulated in relapsed patients. Functional analyses showed that the ALK/STAT3 signaling pathway regulates circPTPN22 expression, linking oncogenic signaling to circRNA regulation. It was also found that circPTPN22 isoforms modulate responses to chemotherapy by regulating the arginine methyltransferase CARM1, a key enzyme involved in transcriptional regulation. Loss of CARM1 expression promoted drug tolerance in chemosensitive ALK(+) lymphoma cells. These findings identify the circPTPN22/CARM1 axis as a regulator of chemosensitivity and propose CARM1 inhibition as a potential strategy to overcome chemoresistance in patients with ALK(+) ALCL.