Prognostic and Therapeutic Implications of BRAF Mutations in Acute Myeloid Leukemia

Mutations in the RAS/MAPK signaling pathway are recurrent in acute myeloid leukemia (AML), primarily involving NRAS and KRAS . In contrast, mutations in the gene encoding an effector protein, BRAF, occur at relatively lower frequencies in AML and are associated with poor outcomes. To date, no comprehensive analysis has assessed the clinical and molecular characteristics of BRAF- mutated AML. In this study, we report the identification of canonical and non-canonical BRAF mutations in ∼1% of 5,779 consecutive clinically and molecularly fully-annotated AML patients treated at two major United States Cancer Centers (50/5779 AML patients: 21 newly diagnosed AML; 9 relapsed/refractory; 20 newly diagnosed secondary AML). We performed single-cell multiomic analysis on a subset of AML samples. BRAF mutations were enriched in myelodysplasia-related AML (AML-MR), and most mutations were located outside the V600 hotspot. Single-cell multiomic profiling delineated BRAF mutation class-specific patterns of co-mutations, clonality, and immunophenotypes. Notably, BRAF mutations and other signaling co-mutation(s) could be found in the same cell, a finding that significantly diverges from prior studies of RAS-mutant AML. In this cohort, BRAF -mutant AML patients had poor overall survival with currently available treatments, including venetoclax-based regimens. Drug sensitivity data suggest possible avenues for targeted treatment of BRAF -mutated AML.