Core-Binding Factor AMLs Have Distinct Genomic Landscapes

The transcription factors RUNX1 and CBFB normally function as a heterodimer, known as the core-binding factor transcriptional complex, and are required for hematopoietic differentiation, but in approximately 30% of pediatric and 15% of adult patients with acute myeloid leukemias (AML), chromosomal translocations or inversions create RUNX1–RUNX1T1 or CBFB–MYH11 fusion proteins that block myeloid differentiation. However, additional mutations are required to induce leukemogenesis. Faber, Chen, Gedman, and colleagues sought to comprehensively characterize the genetic events that contribute to the development of RUNX1–RUNX1T1 and CBFB–MYH11 AML by performing whole-genome or whole-exome sequencing of 165 AML samples, 85 with RUNX1–RUNX1T1 and 80 with CBFB–MYH11 rearrangements. Consistent with previous findings, mutations affecting signaling were common in both AML types, with activating mutations in NRAS, KIT, FLT3, KRAS, or PTPN1, or loss-of-function mutations in NF1 present in 66% of cases, but these collective mutations were not associated with outcome. Mutations in MYC or MGA, a negative regulator of MYC signaling, were observed in 11 RUNX1–RUNX1T1 cases, and in 1 CBFB–MYH11 case. Further, mutations in the downstream MYC target CCND2 were found in 5 RUNX1–RUNX1T1 and 2 CBFB–MYH11 cases, and occurred surrounding a residue that regulates proteasomal degradation, suggesting that CCND2 mutations may promote CCND2 protein stability. Recurrent RUNX1–RUNX1T1 -specific alterations occurred in the RNA helicase DHX15, which were predicted to alter splicing, and in the transcription factor ZBTB7A. RUNX1–RUNX1T1-specific mutations also occurred in cohesin complex components, but were not associated with outcome or increased aneuploidy. Loss-of-function mutations in chromatin modifying genes were identified in 44% of RUNX1–RUNX1T1 cases and only 4% of CBFB–MYH11 cases. These findings suggest that although disruption of the RUNX1–CBFB complex underlies both RUNX1-RUNX1T1 and CBFB-MYH11 AML, they have largely dissimilar landscapes of cooperating leukemogenic mutations

Faber ZJ, Chen X, Gedman AL, Boggs K, Cheng J, Ma J, et al. The genomic landscape of core-binding factor acute myeloid leukemias. Nat Genet 2016 Oct 31 [Epub ahead of print].