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. 2016 Dec;48(12):1551-1556.
doi: 10.1038/ng.3709. Epub 2016 Oct 31.

The Genomic Landscape of Core-Binding Factor Acute Myeloid Leukemias

Free PMC article

The Genomic Landscape of Core-Binding Factor Acute Myeloid Leukemias

Zachary J Faber et al. Nat Genet. .
Free PMC article


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.


Figure 1
Figure 1. Mutational landscape of CBF-AML
(a) Mutational data for 165 CBF-AML cases sequenced either by whole genome (n=17) or whole exome sequencing (n=148). Signaling, epigenetic, and cohesin genes are grouped into functional groups. Cytogenetic abnormalities and patient age group (adult or pediatric) are shown along the bottom of the figure. Mutations in both epigenetic (p=4.3E–10) and cohesin (p=2.2E–16) genes are significantly enriched in RUNX1-RUNX1T1 AML (Fisher’s Exact test). (b) The frequency of recurrently mutated genes (n>3) separated by CBF-AML fusion type is shown. Of the 10 FLT3 mutations, 4 are internal tandem duplications (ITD), 5 are located in the tyrosine kinase domain, and 1 is classified as neither ITD nor TKD.
Figure 2
Figure 2. Recurrent mutations in CCND2 and MGA
Domain structure and the localization of mutations are shown for (a) CCND2 and MGA. (b) Representative western blot (of three independent experiments) of HEK293T cells expressing wild-type, P281R, or T282* CCND2 treated with cyclohexamide (CHX) and harvested at the indicated time points. Data show the expected increase in the levels of mutant CCND2 protein. GAPDH serves as a loading control.
Figure 3
Figure 3
DHX15 is recurrently mutated in RUNX1-RUNX1T1 AML. (a) Domain structure and the localization of mutations for DHX15. (b) Increased numbers of alternative splicing events were observed upon DHX15 knockdown (red bars) or overexpression of the R222G mutant (green bars) compared to overexpression of wildtype DHX15 (blue bars). (c) siRNA mediated knockdown of DHX15 leads to an enrichment of differentially regulated genes associated with splicing and ribosomal biogenesis. (d) Western blot showing the effectiveness of the DHX15 knockdown. Equal amounts of protein were loaded for each sample. An asterisk indicates a non-specific band also used as a loading control. (e) Co-immunoprecipitation of TFIP11 with DHX15 demonstrates reduced binding of TFIP11 to the R222G mutant form of DHX15.
Figure 4
Figure 4. Mutant allele frequency (MAF) at diagnosis and relapse in CBF-AMLs
a) The mutant allele frequencies of mutations in the indicated genes are shown for the eight samples with relapse material available. D – diagnosis, R – relapse. Darker color indicates higher MAF.

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