The GATA-3-dependent transcriptome and tumor microenvironment are regulated by eIF4E and XPO1 in T-cell lymphomas
Recommended Citation
Kady N, Abdelrahman S, Rauf A, Burgess A, Weiss J, Gunasekara H, Ramseier NT, Maine IP, Zevallos-Morales A, Perez-Silos V, Wolfe A, Hristov A, Brown NA, Inamdar KV, Sverdlov M, Hu YS, Murga-Zamalloa C, Wang C, and Wilcox RA. The GATA-3-dependent transcriptome and tumor microenvironment are regulated by eIF4E and XPO1 in T-cell lymphomas. Blood 2024.
Document Type
Article
Publication Date
2-6-2025
Publication Title
Blood
Abstract
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.
Medical Subject Headings
Exportin 1 Protein; Receptors, Cytoplasmic and Nuclear; Animals; Karyopherins; Lymphoma, T-Cell; Mice; Tumor Microenvironment; Triazoles; Humans; GATA3 Transcription Factor; Eukaryotic Initiation Factor-4E; Transcriptome; Hydrazines; Gene Expression Regulation, Neoplastic; Tumor Suppressor Protein p53; Macrophages; PTEN Phosphohydrolase
PubMed ID
39652777
ePublication
ePub ahead of print
Volume
145
Issue
6
First Page
597
Last Page
611
