NPM1::ALK fusion-derived circular RNAs drive aggressiveness in ALK-positive anaplastic large cell lymphoma

Circular RNAs (circRNAs) derived from the NPM1::ALK fusion have been identified in ALK-positive anaplastic large cell lymphoma (ALK+ ALCL), but their functional contribution to disease progression remains poorly understood. Divergent RT-PCR and long-read Nanopore sequencing identified eight NPM1::ALK-derived circRNA variants across ALK(+) ALCL cell-lines, a CRISPR/Cas9-engineered model, and a patient-derived xenograft. The abundance of f-circA23N2 and f-circA26N3, recurrently detected, steadily increased in crizotinib-resistant cell models. Both, highly stable, were predominantly cytoplasmic. Their overexpression in SU-DHL-1 did not affect NPM1::ALK expression, cell proliferation, or cell-cycle, in the absence or presence of crizotinib. circRNA overexpression delayed subcutaneous tumor-growth without altering response to crizotinib. Xenograft analysis disclosed altered immune response pathways and changes in inflammatory and myeloid-recruiting cytokines. RNA-seq deconvolution identified remodeling of the myeloid compartment. Intravenous f-circA23N2 and f-circA26N3 shortened survival with systemic lymphoma dissemination. NPM1::ALK-derived circRNAs appear to be non-cell-autonomous modulators of cytokine signaling and myeloid remodeling contributing to lymphoma dissemination.