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The genomic landscape of core-binding factor acute myeloid leukemias

Faber, Zachary J; Chen, Xiang; Gedman, Amanda Larson; Boggs, Kristy; Cheng, Jinjun; Ma, Jing; Radtke, Ina; Chao, Jyh-Rong; Walsh, Michael P and Song, Guangchun, et al. (2016) In Nature Genetics 48. p.1551-1556
Abstract

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... (More)

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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@article{20d7ddf7-6757-4e92-aafa-dd04717edde5,
  abstract     = {<p>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.</p>},
  author       = {Faber, Zachary J and Chen, Xiang and Gedman, Amanda Larson and Boggs, Kristy and Cheng, Jinjun and Ma, Jing and Radtke, Ina and Chao, Jyh-Rong and Walsh, Michael P and Song, Guangchun and Andersson, Anna K and Dang, Jinjun and Dong, Li and Liu, Yu and Huether, Robert and Cai, Zhongling and Mulder, Heather and Wu, Gang and Edmonson, Michael and Rusch, Michael and Qu, Chunxu and Li, Yongjin and Vadodaria, Bhavin and Wang, Jianmin and Hedlund, Erin and Cao, Xueyuan and Yergeau, Donald and Nakitandwe, Joy and Pounds, Stanley B and Shurtleff, Sheila and Fulton, Robert S and Fulton, Lucinda L and Easton, John and Parganas, Evan and Pui, Ching-Hon and Rubnitz, Jeffrey E and Ding, Li and Mardis, Elaine R and Wilson, Richard K and Gruber, Tanja A and Mullighan, Charles G and Schlenk, Richard F and Paschka, Peter and Döhner, Konstanze and Döhner, Hartmut and Bullinger, Lars and Zhang, Jinghui and Klco, Jeffery M and Downing, James R},
  issn         = {1546-1718},
  language     = {eng},
  month        = {10},
  pages        = {1551--1556},
  publisher    = {Nature Publishing Group},
  series       = {Nature Genetics},
  title        = {The genomic landscape of core-binding factor acute myeloid leukemias},
  url          = {http://dx.doi.org/10.1038/ng.3709},
  volume       = {48},
  year         = {2016},
}