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Jain, Payal; Surrey, Lea F.; Straka, Joshua; Russo, Pierre; Womer, Richard; Li, Marilyn M.; Storm, Phillip B.; Waanders, Angela J.; Hogarty, Michael D.; Resnick, Adam C.; Picarsic, Jennifer
Pediatric blood & cancer, June 2021, 2021-06-00, 20210601, Volume: 68, Issue: 6Journal Article
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.
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