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 TCLs.

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

The transcription factor GATA-binding protein 3 (GATA-3) and the transcriptional program it regulates have emerged as oncogenic drivers across diverse T-cell lymphomas (TCLs), 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 (LAMs) within their tumor microenvironment (TME). Using complementary genetically engineered mouse models, we demonstrated that TP53- and/or phosphate and tensin homolog (PTEN)-deficient TCLs, and LAMs within their TME, are sensitive to the selective exportin-1 (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 messenger RNA nuclear export in these TCLs. We identified a novel role for eIF4E/XPO1 in exporting GATA-3 and GATA-3–dependent transcripts from the nucleus in TCLs, and in the export of therapeutically relevant transcripts, including colony-stimulating factor-1 receptor, from LAMs. Therefore, XPO1 antagonism, by impairing oncogenic transcriptional programs in TCLs and depleting LAMs from their TME, is a novel approach to target 2 independent dependencies in a group of therapeutically challenging TCLs.