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

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• GATA-binding protein 3 (GATA-3) drives oncogenesis in T-cell lymphomas (TCLs).
• Many TCLs are chemoresistant and lose tumor suppressors like TP53 and PTEN, which are linked to nuclear export protein XPO1.
• XPO1 is upregulated in malignant T cells and lymphoma-associated macrophages (LAMs) within the tumor microenvironment (TME).

Purpose of the Study:

• To investigate the role of XPO1 in TCLs, particularly in TP53- and PTEN-deficient contexts.
• To explore TP53- and PTEN-independent mechanisms involving eIF4E and XPO1 in TCLs.
• To evaluate selinexor, a selective XPO1 antagonist, as a therapeutic agent for TCLs.

Main Methods:

• Utilized genetically engineered mouse models of TCLs.
• Employed complementary and orthogonal approaches to study eIF4E and XPO1 in TCLs.
• Assessed the expression of XPO1 in malignant T cells and LAMs within the TME.

Main Results:

• TP53- and/or PTEN-deficient TCLs and their associated LAMs are sensitive to selinexor.
• Identified a novel role for eIF4E/XPO1 in the nuclear export of GATA-3 and its dependent transcripts in TCLs.
• Demonstrated XPO1's role in exporting therapeutically relevant transcripts, such as colony-stimulating factor-1 receptor, from LAMs.

Conclusions:

• XPO1 antagonism impairs oncogenic transcriptional programs in TCLs.
• XPO1 antagonism depletes LAMs from the TME.
• Targeting XPO1 offers a novel strategy to address two independent dependencies in difficult-to-treat TCLs.