No exit: targeting RNA export in T-cell malignancy

In this issue of Blood, Kady et al report a novel means to simultaneously control the production of a key driver of T-cell malignancy, the transcription factor GATA-3, and its downstream transcriptional clients.¹ The mechanism they unravel relies on dysregulated nuclear messenger RNA (mRNA) export as a means to boost GATA-3 protein production as well as that of its transcriptional clients.

Indeed, the authors found transcripts encoding GATA-3, and its clients’ transcripts were exported through the exportin 1 (XPO1)/eIF4E pathway. XPO1 is a nuclear export factor that escorts cargoes through the nuclear pore complex to the cytoplasm.² The eukaryotic translation initiation factor eIF4E plays multiple roles in mRNA metabolism, aside from its role in translation, including nuclear export of transcripts using XPO1.³ Increased mRNA export in turn increases cytoplasmic availability of transcripts to ribosomes, allowing production of more protein without requisite alterations to transcription or altered translation efficiency (which is defined as more ribosomes per transcript) (see figure). The eIF4E/XPO1 axis is distinct from the bulk mRNA export pathway underpinning expedited export for only a subgroup of functionally related transcripts consistent with the RNA regulon model.³ Kady et al show this is the case for the GATA-3 network, providing novel insights into the control of this critical transcription factor. Coordination of the export of mRNAs involved in related biochemical pathways is usually achieved through the presence of the same complement of cis-acting mRNA elements, known as untranslated sequence elements for regulation (USER) codes, within the targeted mRNAs. In turn, these USER codes bind to specific RNA-binding proteins to engage eIF4E-mRNA export complexes³ (see figure). The best-described eIF4E/XPO1 mRNA export complex involves the leucine-rich pentatricopeptide repeat containing protein (LRPPRC), which binds the target transcripts through their eIF4E-sensitivity element (4ESE) export USER code and also eIF4E, which LRPPRC then bridges to XPO1, permitting export through the nuclear pore (see figure).³ Whether or not LRPPRC or other bridge factors are used for the GATA-3 RNA regulon is an open question, as is whether GATA-3 and its client transcripts employ the 4ESE USER code or other cis-acting elements to coordinate their export. Dissecting this will be important to understand the molecular basis underpinning RNA selection for this pathway in malignant T cells. The observation by Kady et al of increased ribosomal protein levels through enhanced export of the corresponding mRNAs in parallel with GATA-3 has interesting implications. In this way, the combination of increased eIF4E and ribosomal proteins in these T-cell malignancies may also lead to more efficient translation (more ribosomes on each transcript), further amplifying protein levels of GATA-3 and its clients in addition to the reported enhanced mRNA export. This possibility remains to be tested. Interestingly, the authors also find a different set of transcripts are eIF4E/XPO1 dependent in the tumor microenvironment, which supports malignancy. Finding distinct mRNAs associated with nuclear eIF4E in different cell types demonstrates a very adaptable posttranscriptional program to modulate the production of these tumor-facilitating factors. The use of this pathway is found in other lymphomas. For example, eIF4E/XPO1 dysregulation provided increased tolerance to genotoxic stress underpinning poor responses to chemoimmunotherapy, through eIF4E/XPO1-dependent mRNA export of DNA damage repair encoding mRNAs in diffuse large B-cell lymphoma (DLBCL).⁴ Given nuclear eIF4E can also regulate other steps in RNA metabolism, for example, splicing, capping, and alternative polyadenylation,³ it will be interesting to see in the future if eIF4E also modulates any of these features in GATA-3 and its associated transcripts. In all, Kady et al identify an intricate mRNA export-dependent mechanism to drive production of the GATA-3 network, which contributes to malignancy in malignant T cells and the associated microenvironment.

Transcription factors such as GATA-3 are considered difficult to target in patients despite their clear relevance to malignancy. The authors’ mechanistic studies provide the foundation for shutting down the GATA-3 network with an XPO1 inhibitor, selinexor (see figure). Selinexor is the first-in-class of selective inhibitor of nuclear export and is approved by the Food and Drug Administration for use in relapsed and refractory (R/R) settings for both multiple myeloma and DLBCL. Selinexor was originally thought to work primarily through inhibiting export of oncoproteins such as TP53. Kady et al showed that selinexor activity in these types of malignancies was independent of TP53. Given previous studies demonstrated a link between selinexor activity and eIF4E/XPO1, Kady et al used selinexor to impair eIF4E/XPO1-dependent mRNA export and subsequent cancer development in mouse models. Also, the authors report that selinexor had a profound impact on ribosome biogenesis, likely related to the role of eIF4E/XPO1 in the export of transcripts encoding ribosomal proteins, as well its previously reported role in the export of ribosomal subunits to the cytoplasm.⁵ Previous studies in acute myeloid leukemia targeted this pathway from the eIF4E perspective using ribavirin, an m⁷G cap competitor, and demonstrated complete and partial remissions in patients with R/R AML correlating with molecular targeting of eIF4E-dependent mRNA export in patients during clinical responses.^3,6 These strategies have overlapping but distinct activities: ribavirin broadly targets cap-dependent activities of eIF4E including mRNA export,³ and selinexor targets eIF4E/XPO1-dependent mRNA export, rRNA export, and XPO1-mediated selective protein export.⁷ Selinexor has been tested in a wide array of hematological malignancies,⁷ including in 2 patients with peripheral T-cell lymphoma.⁸ Taken together with these previous data, Kady et al provide strong evidence that targeting this pathway in the clinic is a promising future direction for the described T-cell malignancies.

Conflict-of-interest disclosure: K.L.B.B. declares no competing financial interests.