Abstract
Myelodysplastic neoplasms (MDS) are a heterogeneous group of clonal hematopoietic disorders in which the bone marrow acquires genetic alterations leading to ineffective hematopoiesis, cytopenia, and an increased risk of transformation to acute myeloid leukemia (AML). In the past decade, there have been limited treatment options available for patients with MDS, particularly for those with high-risk disease and those refractory to hypomethylating agents. The median survival for patients with high-risk MDS refractory to hypomethylating agents is less than six months. There is, therefore, an urgent unmet need for alternative therapeutic options for these options. Improving our understanding of the biology and genetics of MDS can help lay the groundwork for novel therapeutics for individualized, targeted therapy approaches. Exportin-1 (XPO1) is a nuclear export protein involved in the export of many key regulators, including RNAs and proteins such as p53, ERK, and p21. XPO1 is overexpressed in various cancers, including MDS and AML, and high levels of XPO1 expression have been associated with a poor prognosis. There have been selective inhibitors of nuclear export (SINE) that have been designed to inhibit XPO1. Splicing factor 3b subunit 1 (SF3B1) is the most commonly mutated spliceosome gene in MDS. Here, we wanted to understand the correlation between XPO1 inhibition and SF3B1 mutations, the role RNA export played in the function of the spliceosome, how XPO1 inhibition could affect this process, and how we can further target this response for an improved overall response rate of the single-agent XPO1 inhibitors. We hypothesized that given the role of XPO1 plays in exporting small nuclear RNAs (snRNAs), which form the catalytic portion of the spliceosome, we hypothesized that SF3B1 mutants are sensitive to XPO1 inhibitors because of the increased splicing alterations due to the altered RNA export.