FLT3-ITD scaffolds PKCι-STAT1 to drive noncanonical S727 phosphorylation and CD276-driven CD8+ T-cell exhaustion in AML - PubMed
4 hours ago
- #AML
- #FLT3-ITD
- #CD276
- FLT3-ITD mutation in AML leads to poor prognosis and CD8+ T-cell exhaustion.
- FLT3-ITD acts as a scaffold, forming a ternary complex with PKCι and STAT1.
- PKCι phosphorylates STAT1 at S727, driving CD276 transcription independently of Y701.
- S727 phosphorylation is necessary and sufficient for CD276 transactivation.
- CD276 upregulation induces CD8+ T-cell exhaustion, reducing cytotoxicity and IFN-γ production.
- Targeting CD276 restores CD8+ T-cell function in ex vivo co-culture.
- Combined FLT3i and CD276-targeting therapy reduces tumor burden and enhances T-cell function in xenograft models.
- The study supports combined FLT3 and CD276 targeting as a promising AML treatment strategy.