XPO1-Mediated mRNA Export of Genome Maintenance Regulators Drives Chemotherapy Resistance in Aggressive Lymphoma

Abstract

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy and displays vast genetic and transcriptomic heterogeneity. Current treatment guidelines recommend first-line chemoimmunotherapy consisting of an anthracycline backbone, which produces cure rates of approximately 65%. However, the remaining patients will face relapsed or refractory disease, which, even in the era of chimeric antigen receptor 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. See related article by Marullo et al., p. 101.