SF3B1 K666N

Previous findings from a phase 2 clinical trial of the XPO1 inhibitor selinexor in patients with high-risk myelodysplastic syndrome (MDS) relapsed or refractory to hypomethylating agents (HMA) revealed increased activity in patients with SF3B1 mutations...Using the Bliss independence model to calculate synergy, we identifed two drugs that greatly synergized with eltanexor specifically in the SF3B1 mutant cell lines: venetoclax (a BCL2 inhibitor), and navitoclax (a BCL2/BCL-XL inhibitor)...Our findings may also contribute to the development of potentially synergistic therapeutic combinations. In this regard, recent human data have shown that venetoclax can overcome the poor prognosis of spliceosomal mutant AML patients (Senapati et al, Blood 2023); therefore, combining eltanexor with venetoclax could represent a promising SF3B1-specific therapy.

We identified mutation-specific splicing profiles and intricate patterns of tumor suppressor gene expression as potential compound factors to the varied clonal fitness of SF3B1 mutations. This unique patient enabled the identification and tracking of mechanisms underlying long-term clonal expansion and competition, which we aim to verify in further work. Hematopoiesis, Myelodysplastic syndrome, Myelodysplasia, RNA-seq

In conclusion, this case study comprises a unique long-term follow-up of the clonal dynamics underlying two co-existing, distinct and competing SF3B1mt clones which identifies subtle molecular changes and differences underlying the expansion and progression of SF3B1mt clones. *Moura PL, Hofman IJF, Nannya Y and Aliouat A contributed equally to this work.

We therefore hypothesized that combining selinexor and venetoclax would have potential synergy and could be used to target hematologic malignancies bearing XPO1 and SF3B1 mutations.We first determined whether XPO1 and SF3B1 mutant cell lines showed differential response to either selinexor or venetoclax monotherapy. This combination is highly promising as an all oral regimen for hematologic malignancies bearing these mutations. Further, preclinical testing in in vivo using XPO1 and SF3B1 mutant and wildtype mice is ongoing.

1. In sum, we describe that SF3B1 mutations occur in combination with inv(3)/t(3;3) in AML and might represent a subclass of this entity in which lesions in SF3B1 gene could potentially hide a cryptic association between splicing abnormalities and disease phenotypes.