U2AF1 S34F

Interestingly, HBEC3kts harboring only U2AF1 S34F display increased splicing in stress granule protein genes and viability in cigarette smoke concentrate. Our results suggest that U2AF1 S34F may potentiate transformation by granting precancerous cells survival advantage in environmental stress, permitting accumulation of additional mutations like KRAS G12V , which synergize with U2AF1 S34F to transform the cell.

A pharmacologic inhibitor of ISR, ISRIB, sensitized U2AF1 mutant cells to chemotherapy. These findings highlight a resistance mechanism by which U2AF1 mutations drive chemoresistance and provide a therapeutic approach for AML through targeting the ISR pathway.

Although U2AF1 gene abnormality is known as a poor prognostic factor in primary myelofibrosis, this patient had a favorable long-term prognosis due to prompt transplantation therapy. This case highlights the importance of detailed gene mutation analysis in patients with triple-negative MF.

In conclusion, a germline predisposition to myeloid neoplasms occurred in ~16% of young-onset MDS patients and was largely associated with primary immunodeficiencies, including GATA2 deficiency. Furthermore, the high frequency of somatic U2AF1 mutations in patients with young-onset MDS suggests the presence of a distinct MDS subtype.

In summary, SF-1-8 caused disruption of extra- and intracellular protein transport in K562-U2AF1S34F cells and represented a new class of small-molecule inhibitors to target U2AF1-UHM. Further optimization of this class of compounds will allow us to develop effective chemical probes for study in the U2af1 murine models and assess the potential of U2AF1 as a therapeutic target in MDS and sAML.