Abstract
Pediatric histiocytic neoplasms are hematopoietic disorders frequently driven by the BRAF-V600E mutation. Here, we identified two BRAF gene fusions (novel MTAP-BRAF and MS4A6A-BRAF) in two aggressive histiocytic neoplasms. In contrast to previously described BRAF fusions, MTAP-BRAF and MS4A6A-BRAF do not respond to the paradox breaker RAF inhibitor (RAFi) PLX8394 due to stable fusion dimerization mediated by the N-terminal fusion partners. This highlights a significant and clinically relevant shift from the current dogma that BRAF-fusions respond similarly to BRAF-inhibitors. As an alternative, we show suppression of fusion-driven oncogenic growth with the pan-RAFi LY3009120 and MEK inhibition.
| Original language | English (US) |
|---|---|
| Article number | e28933 |
| Journal | Pediatric Blood and Cancer |
| Volume | 68 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jun 2021 |
Funding
The authors would like to thank Dr. Ronald Jaffe for second review of the cases and appraisal of the original manuscript. This work was supported by the Children's Brain Tumor Tissue Consortium funding sources (P.J., A.J.W., P.B.J., and A.C.R).
Keywords
- BRAF-gene fusion
- pediatric histiocytosis
- targeted therapy
ASJC Scopus subject areas
- Hematology
- Oncology
- Pediatrics, Perinatology, and Child Health