Potential Underlying Genetic Mutations Identified in Patients With Myelodysplastic Syndromes

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Researchers may have uncovered the underlying mechanisms of gene mutations commonly seen in patients with myelodysplastic syndromes and other myeloid neoplasms, according to new findings presented by Chaudhry et al at the American Society of Hematology (ASH) Annual Meeting and Exposition (Abstract 44). The new research could lead to the development of more effective drug combinations and targeted therapies for patients with myelodysplastic syndromes carrying these mutations.


About 50% of patients with myelodysplastic syndromes may carry gene mutations in the spliceosome genes—with SF3B1 mutations being the most common type. However, no therapies currently exist to effectively target this pathway.

Previous findings from a phase II clinical trial involving patients with relapsed or refractory myelodysplastic syndromes treated with the exportin-1 (XPO1) inhibitor selinexor demonstrated increased efficacy in patients with SF3B1-mutated disease. XPO1 is the nuclear export receptor responsible for exporting over 200 proteins, but also plays a role in transporting multiple small nuclear RNAs and select messenger RNAs.

Study Methods and Results

In the new study, the researchers hypothesized that inhibiting XPO1 may preferentially affect SF3B1-mutated cells via altered splicing and that high-risk patients with SF3B1-mutated myelodysplastic syndromes would have a greater response to dose-controlled, targeted drug combinations with next-generation XPO1 inhibitors.

The researchers first conducted RNA sequencing to evaluate the underlying mechanisms for the SF3B1 mutation’s sensitivity to XPO1 inhibitors. They then performed whole-genome clustered regularly interspaced short palindromic repeats (CRISPR) screens in two myeloid leukemia cell lines with the next-generation XPO1 inhibitor eltanexor, which has lower toxicity than selinexor. They discovered several novel targets that were tested for synergy in combination with eltanexor for the SF3B1 mutations. Two drugs—venetoclax and navitoclax—were found to have strong synergy with eltanexor.

Additionally, the researchers carried out in vitro studies to analyze test combinations identified from a CRISPR screen using cell viability tests and western blots as well as in vivo studies to further validate these combinations through the use of transplant tests in mouse models.


“This is the first study to examine the effects of XPO1 inhibition on RNA export to better understand the underlying mechanisms involved with the most common mutation seen in patients [with myelodysplastic syndromes],” emphasized lead study author, Sana Chaudhry, BS, a researcher at the Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine.

“Our study’s findings may contribute to [the] development of synergistic therapeutic combinations to better treat SF3B1-mutant [myelodysplastic syndromes],” underscored senior study author Justin Taylor, MD, a member of the Translational and Clinical Oncology Program at the Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine.

Recent data from human trials has shown that venetoclax may be capable of overcoming the poor prognoses often associated with patients who have acute myeloid leukemia with mutations.

“As a result, combining eltanexor with venetoclax could represent a potentially effective SF3B1-specific therapy,” Dr. Taylor concluded.

Disclosure: For full disclosures of the study authors, visit

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