The GATA-3-dependent transcriptome and tumor microenvironment are regulated by eIF4E and XPO1 in T-cell lymphomas

• eIF4E/XPO1 collaboratively transport GATA-3 and GATA-3 targets and are thus therapeutic vulnerabilities in GATA-3-driven T-cell lymphomas.

• Impaired eIF4E/XPO1 nuclear export, by depleting LAM, also has a non-cell-autonomous mechanism of action in the T-cell lymphomas.

The transcription factor GATA-3 and the transcriptional program it regulates have emerged as oncogenic drivers across diverse T-cell lymphomas (TCL), many of which are resistant to conventional chemotherapeutic agents and characterized by recurrent losses of key tumor suppressor genes, including TP53 and PTEN, both of which are clients of the nuclear export protein XPO1. Here we demonstrated that XPO1 is highly expressed by malignant T cells expressing GATA-3 and by lymphoma-associated macrophages (LAM) within their tumor microenvironment (TME). Using complementary genetically engineered mouse (GEM) models, we demonstrated that TP53 and/or PTEN deficient TCL, and LAM within their TME, are sensitive to the selective XPO1 antagonist selinexor. In an effort to identify TP53 and PTEN independent mechanisms, we used complementary and orthogonal approaches to investigate the role of eIF4E and XPO1-dependent mRNA nuclear export in these TCL. We identified a novel role for eIF4E/XPO1 in exporting GATA-3 and GATA-3-dependent transcripts from the nucleus in TCL, and in the export of therapeutically relevant transcripts, including CSF-1R, from LAM. Therefore, XPO1 antagonism, by impairing oncogenic transcriptional programs in TCL and depleting LAM from their TME, is a novel approach to target two independent dependencies in a group of therapeutically challenging TCL.