title: The genomic landscape of core-binding factor acute myeloid leukemias.
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 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.
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Zachary J
authors: ZJ
authors: Faber
authors: Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Xiang
authors: X
authors: Chen
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Amanda Larson
authors: AL
authors: Gedman
authors: Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Kristy
authors: K
authors: Boggs
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Jinjun
authors: J
authors: Cheng
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Jing
authors: J
authors: Ma
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Ina
authors: I
authors: Radtke
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Jyh-Rong
authors: JR
authors: Chao
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Michael P
authors: MP
authors: Walsh
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Guangchun
authors: G
authors: Song
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Anna K
authors: AK
authors: Andersson
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Jinjun
authors: J
authors: Dang
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Li
authors: L
authors: Dong
authors: Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Yu
authors: Y
authors: Liu
authors: Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Robert
authors: R
authors: Huether
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Zhongling
authors: Z
authors: Cai
authors: Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Heather
authors: H
authors: Mulder
authors: Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Gang
authors: 0000-0002-1678-5864
authors: G
authors: Wu
authors: Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Michael
authors: M
authors: Edmonson
authors: Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Michael
authors: 0000-0002-5363-1848
authors: M
authors: Rusch
authors: Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Chunxu
authors: C
authors: Qu
authors: Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Yongjin
authors: Y
authors: Li
authors: Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Bhavin
authors: B
authors: Vadodaria
authors: Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Jianmin
authors: J
authors: Wang
authors: Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Erin
authors: E
authors: Hedlund
authors: Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Xueyuan
authors: X
authors: Cao
authors: Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Donald
authors: D
authors: Yergeau
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Joy
authors: J
authors: Nakitandwe
authors: Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Stanley B
authors: 0000-0002-9167-2114
authors: SB
authors: Pounds
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Sheila
authors: S
authors: Shurtleff
authors: McDonnell Genome Institute at Washington University, St. Louis, Missouri, USA.
authors: Robert S
authors: RS
authors: Fulton
authors: McDonnell Genome Institute at Washington University, St. Louis, Missouri, USA.
authors: Lucinda L
authors: LL
authors: Fulton
authors: Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: John
authors: J
authors: Easton
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Evan
authors: E
authors: Parganas
authors: Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Ching-Hon
authors: CH
authors: Pui
authors: Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Jeffrey E
authors: JE
authors: Rubnitz
authors: McDonnell Genome Institute at Washington University, St. Louis, Missouri, USA.
authors: Li
authors: 0000-0003-1517-2975
authors: L
authors: Ding
authors: McDonnell Genome Institute at Washington University, St. Louis, Missouri, USA.
authors: Elaine R
authors: ER
authors: Mardis
authors: McDonnell Genome Institute at Washington University, St. Louis, Missouri, USA.
authors: Richard K
authors: RK
authors: Wilson
authors: Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Tanja A
authors: TA
authors: Gruber
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Charles G
authors: 0000-0002-1871-1850
authors: CG
authors: Mullighan
authors: Department of Internal Medicine III, University of Ulm, Ulm, Germany.
authors: Richard F
authors: RF
authors: Schlenk
authors: Department of Internal Medicine III, University of Ulm, Ulm, Germany.
authors: Peter
authors: P
authors: Paschka
authors: Department of Internal Medicine III, University of Ulm, Ulm, Germany.
authors: Konstanze
authors: K
authors: Döhner
authors: Department of Internal Medicine III, University of Ulm, Ulm, Germany.
authors: Hartmut
authors: H
authors: Döhner
authors: Department of Internal Medicine III, University of Ulm, Ulm, Germany.
authors: Lars
authors: L
authors: Bullinger
authors: Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Jinghui
authors: J
authors: Zhang
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Jeffery M
authors: JM
authors: Klco
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: James R
authors: JR
authors: Downing
mesh_terms: D000328:Adult; D014408:Biomarkers, Tumor / Q000235:genetics*; D002648:Child; D050660:Core Binding Factors / Q000235:genetics*; D023281:Genomics / Q000379:methods*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D050660:Core Binding Factors; D015514:Oncogene Proteins, Fusion