XPO1-mediated mRNA export of genome maintenance regulators drives chemotherapy resistance in aggressive lymphoma.

Diffuse large B cell lymphoma (DLBCL) is the most common lymphoid malignancy and displays vast genetic and transcriptomic heterogeneity. Current treatment guidelines recommend frontline chemoimmunotherapy consisting of an anthracycline backbone, which produces cure rates of ~65%. However, the remaining patients will face relapsed or refractory disease, which, even in the era of CAR-T cells, is difficult to treat. In this issue of Cancer Research, Marullo and colleagues investigate the biological underpinnings of the tumor suppressive activity of the newly approved XPO1 inhibitor selinexor in the treatment of lymphoma. In a translational effort covering genomic and biochemical approaches, combined with in vivo validation experiments and a phase I clinical trial, they demonstrate that upon DNA damage, XPO1 selectively exports transcripts encoding proteins involved in genome maintenance via the RNA-binding proteins THOC4 and eIF4E. Pharmacologic interception of this export process enhances chemosensitivity in various lymphoma models, and combined selinexor plus chemoimmunotherapy displays a favorable toxicity profile and early evidence of efficacy in patients.