NFATC1
Overview
NFATC1 (Nuclear Factor of Activated T-Cells 1) is a transcription factor regulated by calcineurin/calcium signaling. In CLL, alternative splicing of NFATC1 driven by SF3B1 mutation is a mechanistically central event linking aberrant splicing to mTORC1 activation and MYC upregulation.
Alterations observed in the corpus
- Alternative splicing of exons 8/9 driven by SF3B1-K700E mutation produces a short isoform 5 (exon 9-skipped) preferentially in SF3B1-mutant/del(13q) CLL cells; isoform 5 activates mTORC1 (p-4E-BP1) and upregulates MYC; isoform 2 (full-length) instead activates AKT/S6; validated in HG3, MEC1 isogenic SF3B1-K700E cell lines and Ba/F3-MYC system PMID:26200345
Cancer types (linked)
- Chronic lymphocytic leukemia (CLL/SLL): NFATC1 isoform 5 is a key downstream effector of SF3B1-K700E-driven splicing, selectively activating mTORC1/MYC in the aggressive double-mutant (SF3B1-mut/del(13q)) CLL subtype PMID:26200345
Co-occurrence and mutual exclusivity
- NFATC1 isoform 5 production requires both SF3B1-K700E mutation and del(13q) (MIR15A/DLEU1/DLEU2) for full disease acceleration; isoform-specific signaling divergence (isoform 5 → mTOR vs isoform 2 → AKT) may serve as a biomarker of mTOR-pathway dependence PMID:26200345
Therapeutic relevance
- NFATC1 isoform 5 as mechanistic effector of SF3B1-K700E supports targeting the mTOR pathway (temsirolimus) in combination with SF3B1-directed splicing modulators (H3B-8800) in SF3B1-mut/del(13q) CLL; isoform-specific signaling may serve as a biomarker for mTOR inhibitor sensitivity PMID:26200345
Open questions
- Whether NFATC1 isoform 5 is necessary (vs sufficient) for mTOR activation in CLL is not formally tested; isoform-specific knockdown or exon-9 forced-inclusion rescue experiments were not performed; relevance of this SF3B1/NFATC1 axis in other cancer types remains unexplored PMID:26200345
Sources
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