Acute myeloid leukemia (AML) comprises a heterogeneous group of leukemias frequently defined by recurrent cytogenetic abnormalities, including rearrangements involving the core-binding factor (CBF) transcriptional complex. To better understand the genomic landscape of CBF-AMLs, we analyzed both pediatric (n = 87) and adult (n = 78) samples, including cases with RUNX1-RUNX1T1 (n = 85) or CBFB-MYH11 (n = 80) rearrangements, by whole-genome or whole-exome sequencing. In addition to known mutations in the Ras pathway, we identified recurrent stabilizing mutations in CCND2, suggesting a previously unappreciated cooperating pathway in CBF-AML. Outside of signaling alterations, RUNX1-RUNX1T1 and CBFB-MYH11 AMLs demonstrated remarkably different spectra of cooperating mutations, as RUNX1-RUNX1T1 cases harbored recurrent mutations in DHX15 and ZBTB7A, as well as an enrichment of mutations in epigenetic regulators, including ASXL2 and the cohesin complex. This detailed analysis provides insights into the pathogenesis and development of CBF-AML, while highlighting dramatic differences in the landscapes of cooperating mutations for these related AML subtypes.
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We thank all the patients and their parents from the St. Jude Children's Research Hospital (USA) and the adult patients and their families from the German-Austrian AML Study Group (AMLSG). We thank the Tissue Resources Laboratory, the Flow Cytometry and Cell Sorting Core, and the Clinical Applications of Core Technology Laboratories of the Hartwell Center for Bioinformatics and Biotechnology of St. Jude Children's Research Hospital. This work was funded by the St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project, the American Lebanese and Syrian Associated Charities of St. Jude Children's Research Hospital and grants from the US National Institutes of Health (P30 CA021765 and K08 HL116605 (J.M.K.)). C.G.M. is a Pew Scholar in Biomedical Sciences and a St. Baldrick's Scholar. J.M.K. holds a Career Award for Medical Scientists from the Burroughs Wellcome Fund. This study was supported in part by grants 01GI9981 and 01KG0605 from the German Bundesministerium für Bildung und Forschung (BMBF), grant 111911 from the Deutsche Krebshilfe and grant DO 704/3-1 from the Deutsche Forschungsgemeinschaft (DFG). K.D., H.D. and L.B. are supported by the Collaborative Research Center SFB 1074 funded by the DFG. L.B. is a Heisenberg Professor of the DFG (BU 1339/8-1).
The authors declare no competing financial interests.
Supplementary Figures 1–24 and Supplementary Note. (PDF 28706 kb)
Clinicopathological information of 165 CBF-AML samples. (XLSX 22 kb)
Coding-region SNVs per case of CBF-AML. (XLSX 18 kb)
Coverage data for WGS cohort. (XLSX 11 kb)
Coverage data for WES cohort. (XLSX 31 kb)
Validated WGS sequence mutations for the 17 pediatric CBF-AML discovery cases. (XLSX 78 kb)
Validated whole-exome sequencing (WES) mutations for recurrency cohort. (XLSX 227 kb)
Recurrent somatic mutations in discovery and recurrency cohorts. (XLSX 114 kb)
Discovery cohort CNAs identified by WGS. (XLSX 12 kb)
Validated structural variants for the 17 pediatric CBF-AML discovery cases. (XLSX 31 kb)
Rank-ordered list of genes differentially expressed in DHX15 knockdown cells and their enrichment in the Reactome mRNA splicing gene set. (XLSX 13 kb)
Rank-ordered list of genes differentially expressed in DHX15 knockdown cells and their enrichment in the KEGG ribosome gene set. (XLSX 12 kb)
GSEA results after DHX15 knockdown. (XLSX 11 kb)
Spectral counts (SCs) of proteins identified in pulldown experiments with wild-type (Wt) or R222G (Mut) DHX15. (XLSX 61 kb)
RNA–seq RUNX1-RUNX1T1 upregulated genes. (XLSX 41 kb)
RNA–seq RUNX1-RUNX1T1 downregulated genes. (XLSX 43 kb)
GSEA gene list. (XLSX 14 kb)
Copy number analysis of de novo–relapse pair. (XLSX 56 kb)
Deep sequencing read counts in diagnosis, germline and relapse trios. (XLSX 47 kb)
Oligonucleotides used in this study. (XLSX 8 kb)
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Faber, Z., Chen, X., Gedman, A. et al. The genomic landscape of core-binding factor acute myeloid leukemias. Nat Genet 48, 1551–1556 (2016). https://doi.org/10.1038/ng.3709
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