SF3B1 mutation

Cases harboring biallelic TET2 inactivation or TET2+SRSF2 co-mutation show the highest bone marrow monocyte burden, frequent classical monocyte (MO1; CD14+/CD16-) elevation, and highest progression risk representing biologically true OM-CMML, whereas SF3B1-mutated and biallelic TP53 mutated cases show MDS-directed biology and warrant reclassification. This review synthesizes current diagnostic frameworks, molecular heterogeneity, risk stratification approaches, and evolving classification proposals, thereby providing a practical guide for pathologists navigating OM-CMML in the modern genomic era.

SF3B1 mutation enhances U1-U3 binding and increases the association of the U1-U3 complex with caRNA, driving chromatin-accessibility remolding, R-loop formation, DNA damage, and copy-number abnormalities that promote tumorigenesis. A U1-specific 2'-O-methoxyethyl antisense oligonucleotide that selectively blocks U1-U3 pairing suppresses these genomic abnormalities, reduces leukemic infiltration, and prolongs survival in xenograft and patient-derived models, establishing pathological snRNA-snoRNA rewiring as a critical driver of SF3B1-mutant leukemogenesis.

These results support a refined view of SF3B1-mutated MDS as a biologically heterogeneous entity and suggest that variant-specific mitochondrial vulnerabilities may represent exploitable targets for precision-based therapeutic strategies.

Treatment with low-dose Len in transfusion-independent del(5q) MDS reduced the mutational burden of most genes and did not promote the expansion of preexisting clones or AML progression, especially TP53-mutated clones. Early administration of Len in del(5q) MDS patients without TD may be an effective therapeutic approach with a manageable safety profile regarding clonal evolution.

After ruxolitinib therapy, he later developed leukocytosis and 2% circulating blasts. Repeat marrow demonstrated ≥ 15% ring sideroblasts. Retrospectively, the initial biopsy fulfills ICC 2022 criteria for MDS/MPN-SF3B1-T, highlighting the diagnostic value of genetics-integrated classification in fibrotic marrows.

Median OS was 27.2 vs. 17.2 months in AML and 16.7 vs. 23.7 months in MDS/CMML for clearance versus persistence groups, respectively. These findings suggest that SF mutation clearance does not significantly impact OS but may influence other clinical outcomes in patients with myeloid neoplasms harboring SF mutations.

These structural changes are associated with increased ensemble diversity. Our results demonstrate that although there are key structured regions within an RNA, there is also extensive variability where divergent RNA structures allow for accurate splicing.

This dataset is a valuable community resource, enabling detection of new transcripts in short read data sets. An interactive portal to explore splicing patterns in these data is available at https://leylab.org/isoforms/ .

Patients with wild-type SF3B1 have a significantly shorter OS compared to those with SF3B1 mutations, and they also have a higher risk of transformation to AML, which may be associated with TP53 mutations.

Hemophagocytic lymphohistiocytosis (HLH) is a rare occurrence that can present further management challenges. Here, we describe a young adult with GATA2 deficiency presenting with Legionella pneumonia, COVID-19, and HLH with underlying SF3B1-mutated myelodysplasia that responded successfully to allogeneic hematopoietic stem cell transplantation.

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Collectively, our results support that U2AF1S34F and U2AF1Q157R mutations induce distinct hematopoietic, gene expression, and RNA splicing phenotypes in vivo. Larger population studies will be needed to determine if these phenotypic changes translate into clinico-pathologic differences in patients, warranting separate classification.