SF3B1 K700E

We identified a highly potent TCR that eliminates cancer cells while sparing mutation negative cells. These data support further development of this TCR as a potential therapeutic for MDS and AML.

This is the first study to describe the genomic landscape of patients with B-cell malignancies who were intolerant to ibrutinib and/or acalabrutinib. Here we show that the gene mutational profile of these patients at baseline or at/after disease progression is comparable with patients with relapse/refractory disease who tolerate ibrutinib and, consistent with other studies, patients with mutations in TP53, SF3B1 or ATM genes had less favorable prognosis on BTKi. Further, intolerant patients who progressed on zanubrutinib acquired new BTK mutations and/or had an increase in the frequency of BTK mutations.

Higher RBC-TI rates were observed in patients with various baseline mutational profiles treated with imetelstat compared with placebo in IMerge. While the sample size for specific mutations was small, consistent with the observation that patients with LR-MDS have a low number of specific mutations, TI responses in patients receiving imetelstat occurred regardless of the presence of mutations associated with poor prognosis or the number of mutations. Imetelstat showed comparable TI rates across different molecularly defined subgroups, suggesting that clinical benefit of imetelstat in patients with LR-MDS is independent of the underlying molecular pattern.

In the MCC cohort 42.9% (52/121) had prior hypomethylating agents (HMA) therapy, and 31.4% (38/121) had prior lenalidomide (len). Low baseline RBC-TB dependency, lower risk IPSS-M, SF3B1 MT, SF3B1-K700E mutation and SF3B1α co-mutations correlated with higher response rates. Our data emphasizes the impact of RBC-TI in LR-MDS.

In conclusion, we developed a precise gene editing strategy of human HSCs to identify prexasertib as a promising therapy for SF3B1m myeloid neoplasms, and implicate the mitotic function of CHK1 as a SF3B1m sensitivity. The safety and toxicity profiles displayed in early phase clinical trials make prexasertib a suitable agent for further clinical investigation in SF3B1m MDS and its advanced stages.

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.

Using the H3B-8800 splicing modulator, we show, for the first time in CLL, cytotoxic effects in vitro in primary CLL samples and in SF3B1-mutated isogenic CLL cell lines, accompanied by major splicing changes and delayed leukemic infiltration in a CLL xenotransplant mouse model. H3B-8800 displayed preferential lethality towards SF3B1-mutated cells and synergism with the BCL2 inhibitor venetoclax, supporting the potential use of SF3B1 inhibitors as a novel therapeutic strategy in CLL.

Furthermore, we validated increased triglyceride synthesis, NADH production, ATP production, and cellular ROS in CLL cell lines (MEC1) and pre-B ALL cell lines (Nalm6) with MGA deletion. Taken together, our results highlight the importance of MYC-driven oncometabolites in RT and reveal glycerophospholipid and glutathione pathways as potential therapeutic targets (Figure 1).

We propose that the altered allostery contributes to cancer-associated missplicing by mutated SF3B1. This finding broadens our comprehension of the elaborate mechanisms underlying pre-mRNA metabolism in eukaryotes.

This is the first comprehensive study to compare the sex ratio of driver genes at the variant level in a large cohort of hematological malignancies. Our findings extend the set of known sex-biased variant and support the hypothesis that male and female may have different mechanisms of oncogenesis, associated with potentiallydifferent outcomes, which needs to be further explored for precision medicine. Somatic mutation, Mutation analysis, MDS/AML

These data provide a high-density roadmap of the distribution of known and novel AML-associated antigens together with the Fc receptor distribution and immune microenvironment in AML. The results motivated discovery of a novel antibody-therapeutic targeting aberrant cell-surface U5 snRNP200 and research into mechanisms for cell surface trafficking of U5 snRNP200.

Taken together, our in vivo and transcriptomic studies show that Sf3b1 point mutations are a stronger driver of stem cell self-renewal and gene expression than Dnmt3a mutations in Sf3b1/Dnmt3a mutant HSPCs. These findings suggest that agents that interfere with the DNA damage response, cell cycle regulation, or spliceosome function may more effectively target SF3B1 and SF3B1/DNMT3A mutant HSCs in patients with MDS.

High-risk genotypes maintained elevated sensitivity to SF3B inhibition, but conferred differential response to novel classes of spliceosome modulators, with STAG2 but not RUNX1 loss selectively promoting response to type I PRMTs inhibitor MS023. By contrast, CHK1 inhibitor Prexasertib was highly selective for SF3B1-mutant cells irrespective of co-mutations, inhibiting growth and cell cycle progression...In conclusion, progression from low-risk SF3B1-mutant MDS to high-risk disease is mediated by molecularly distinct trajectories driven by RUNX1 and STAG2 mutations that converge on expansion of the HSC compartment. Moreover, clonal progression is associated with genotype-specific drug responses and increased resistance to standard agents, and ongoing studies are elucidating how genetic and epigenetic states affect therapeutic responses.

SRSF2P95H and SF3B1K700E cells showed increased sensitivity to olaparib and rucaparib (Fig. In summary, this study provides a pre-clinical rationale for therapeutic targeting of PARP1 in SF-mutant leukemia. Moreover, PARP and ATR inhibitor combination could emerge as a new therapeutic strategy in this genetically distinct disease subtype.

Our integrative analysis reveals mechanistic insight into the role of SF3B1 mutations in endocrine therapy response in ER+ breast cancers, where altered SF3B1 induces ER- transcriptional re-programming. We further identified a robust synthetic-lethal relationship of mutant SF3B1 with PARP inhibition that is caused by a defective response to PARPi induced replication stress. Furthermore, we identified several potential selective combination strategies together with PARPi that are selective for SF3B1MUT cells.

This is the first report describing PGCCs in a cell line derived from a liquid cancer where increased frequency of PGCCs is linked to a specific genetic event. Since SF3B1 mutations are predominantly seen in MDS and other hematologic malignancies, our current findings will have significant clinical implications.

TEAD expression and transcriptional activity were upregulated in SF3B1-mutant iPSC-HSPCs, in support of a Hippo pathway-independent role of TEAD as a potential novel transcriptional regulator of SF3B1K700E cells. This study provides a comprehensive characterization of the transcriptional and chromatin landscape of SF3B1K700E HSPCs and nominates novel mis-spliced genes and transcriptional programs with putative roles in MDS-RS disease biology.

Nevertheless, this set of simulations discloses that the K700E mutation and H3B-8800 binding affect the overall SF3b internal motion, which in turn may influence the way SF3b interacts with other spliceosome components. Finally, we unveil the existence of a putative druggable SF3b pocket in the vicinity of K700E that could be harnessed in future rational drug-discovery efforts to specifically target mutant SF3b.

In summary, PRMT5 inhibition with PRT543 can release a differentiation block in MDS/AML, specifically in splicing mutant samples. PRMT5 inhibition decreases IRAK4-long isoform expression providing a potential mechanism for its activity in splicing factor mutant cases.