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BRAF fusions in pediatric histiocytic neoplasms define distinct therapeutic responsiveness to RAF paradox breakers
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  • Payal Jain,
  • Lea Surrey,
  • Joshua Straka,
  • Richard Womer,
  • Marilyn Li,
  • Phillip Storm,
  • Angela Waanders,
  • Michael Hogarty,
  • Adam Resnick,
  • Jennifer Picarsic
Payal Jain
The Children's Hospital of Philadelphia Research Institute
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Lea Surrey
Children's Hospital of Philadelphia
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Joshua Straka
The Children's Hospital of Philadelphia
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Richard Womer
Children's Hospital of Philadelphia
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Marilyn Li
The Children's Hospital of Philadelphia
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Phillip Storm
University of Pennsylvania
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Angela Waanders
Ann and Robert H Lurie Children's Hospital of Chicago
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Michael Hogarty
Children's Hospital of Philadelphia
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Adam Resnick
Children's Hospital of Philadelphia
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Jennifer Picarsic
Cincinnati Children's Hospital Medical Center
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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.

Peer review status:ACCEPTED

14 Dec 2020Assigned to Editor
14 Dec 2020Submission Checks Completed
14 Dec 2020Submitted to Pediatric Blood & Cancer
14 Dec 2020Reviewer(s) Assigned
12 Jan 2021Review(s) Completed, Editorial Evaluation Pending
12 Jan 2021Editorial Decision: Accept