The genomic landscape of core-binding factor acute myeloid leukemias

Zachary J. Faber; Xiang Chen; Amanda Larson Gedman; Kristy Boggs; Jinjun Cheng; Jing Ma; Ina Radtke; Jyh Rong Chao; Michael P. Walsh; Guangchun Song; Anna K. Andersson; Jinjun Dang; Li Dong; Yu Liu; Robert Huether; Zhongling Cai; Heather Mulder; Gang Wu; Michael Edmonson; Michael Rusch; Chunxu Qu; Yongjin Li; Bhavin Vadodaria; Jianmin Wang; Erin Hedlund; Xueyuan Cao; Donald Yergeau; Joy Nakitandwe; Stanley B. Pounds; Sheila Shurtleff; Robert S. Fulton; Lucinda L. Fulton; John Easton; Evan Parganas; Ching Hon Pui; Jeffrey E. Rubnitz; Li Ding; Elaine R. Mardis; Richard K. Wilson; Tanja A. Gruber; Charles G. Mullighan; Richard F. Schlenk; Peter Paschka; Konstanze Döhner; Hartmut Döhner; Lars Bullinger; Jinghui Zhang; Jeffery M. Klco; James R. Downing

doi:10.1038/ng.3709

The genomic landscape of core-binding factor acute myeloid leukemias

Zachary J. Faber, Xiang Chen, Amanda Larson Gedman, Kristy Boggs, Jinjun Cheng, Jing Ma, Ina Radtke, Jyh Rong Chao, Michael P. Walsh, Guangchun Song, Anna K. Andersson, Jinjun Dang, Li Dong, Yu Liu, Robert Huether, Zhongling Cai, Heather Mulder, Gang Wu, Michael Edmonson, Michael RuschChunxu Qu, Yongjin Li, Bhavin Vadodaria, Jianmin Wang, Erin Hedlund, Xueyuan Cao, Donald Yergeau, Joy Nakitandwe, Stanley B. Pounds, Sheila Shurtleff, Robert S. Fulton, Lucinda L. Fulton, John Easton, Evan Parganas, Ching Hon Pui, Jeffrey E. Rubnitz, Li Ding, Elaine R. Mardis, Richard K. Wilson, Tanja A. Gruber, Charles G. Mullighan, Richard F. Schlenk, Peter Paschka, Konstanze Döhner, Hartmut Döhner, Lars Bullinger, Jinghui Zhang, Jeffery M. Klco, James R. Downing

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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.

Original language	English
Pages (from-to)	1551-1556
Number of pages	6
Journal	Nature Genetics
Volume	48
Issue number	12
DOIs	https://doi.org/10.1038/ng.3709
State	Published - Dec 1 2016

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Faber, Z. J., Chen, X., Gedman, A. L., Boggs, K., Cheng, J., Ma, J., Radtke, I., Chao, J. R., Walsh, M. P., Song, G., Andersson, A. K., Dang, J., Dong, L., Liu, Y., Huether, R., Cai, Z., Mulder, H., Wu, G., Edmonson, M., ... Downing, J. R. (2016). The genomic landscape of core-binding factor acute myeloid leukemias. Nature Genetics, 48(12), 1551-1556. https://doi.org/10.1038/ng.3709

@article{08a6060e43b34413980673290bf9ebbb,

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.",

author = "Faber, {Zachary J.} and Xiang Chen and Gedman, {Amanda Larson} and Kristy Boggs and Jinjun Cheng and Jing Ma and Ina Radtke and Chao, {Jyh Rong} and Walsh, {Michael P.} and Guangchun Song and Andersson, {Anna K.} and Jinjun Dang and Li Dong and Yu Liu and Robert Huether and Zhongling Cai and Heather Mulder and Gang Wu and Michael Edmonson and Michael Rusch and Chunxu Qu and Yongjin Li and Bhavin Vadodaria and Jianmin Wang and Erin Hedlund and Xueyuan Cao and Donald Yergeau and Joy Nakitandwe and Pounds, {Stanley B.} and Sheila Shurtleff and Fulton, {Robert S.} and Fulton, {Lucinda L.} and John Easton and Evan Parganas and Pui, {Ching Hon} and Rubnitz, {Jeffrey E.} and Li Ding and Mardis, {Elaine R.} and Wilson, {Richard K.} and Gruber, {Tanja A.} and Mullighan, {Charles G.} and Schlenk, {Richard F.} and Peter Paschka and Konstanze D{\"o}hner and Hartmut D{\"o}hner and Lars Bullinger and Jinghui Zhang and Klco, {Jeffery M.} and Downing, {James R.}",

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doi = "10.1038/ng.3709",

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Faber, ZJ, Chen, X, Gedman, AL, Boggs, K, Cheng, J, Ma, J, Radtke, I, Chao, JR, Walsh, MP, Song, G, Andersson, AK, Dang, J, Dong, L, Liu, Y, Huether, R, Cai, Z, Mulder, H, Wu, G, Edmonson, M, Rusch, M, Qu, C, Li, Y, Vadodaria, B, Wang, J, Hedlund, E, Cao, X, Yergeau, D, Nakitandwe, J, Pounds, SB, Shurtleff, S, Fulton, RS , Fulton, LL, Easton, J, Parganas, E, Pui, CH, Rubnitz, JE, Ding, L, Mardis, ER, Wilson, RK, Gruber, TA, Mullighan, CG, Schlenk, RF, Paschka, P, Döhner, K, Döhner, H, Bullinger, L, Zhang, J, Klco, JM & Downing, JR 2016, 'The genomic landscape of core-binding factor acute myeloid leukemias', Nature Genetics, vol. 48, no. 12, pp. 1551-1556. https://doi.org/10.1038/ng.3709

TY - JOUR

T1 - The genomic landscape of core-binding factor acute myeloid leukemias

AU - Faber, Zachary J.

AU - Chen, Xiang

AU - Gedman, Amanda Larson

AU - Boggs, Kristy

AU - Cheng, Jinjun

AU - Ma, Jing

AU - Radtke, Ina

AU - Chao, Jyh Rong

AU - Walsh, Michael P.

AU - Song, Guangchun

AU - Andersson, Anna K.

AU - Dang, Jinjun

AU - Dong, Li

AU - Liu, Yu

AU - Huether, Robert

AU - Cai, Zhongling

AU - Mulder, Heather

AU - Wu, Gang

AU - Edmonson, Michael

AU - Rusch, Michael

AU - Qu, Chunxu

AU - Li, Yongjin

AU - Vadodaria, Bhavin

AU - Wang, Jianmin

AU - Hedlund, Erin

AU - Cao, Xueyuan

AU - Yergeau, Donald

AU - Nakitandwe, Joy

AU - Pounds, Stanley B.

AU - Shurtleff, Sheila

AU - Fulton, Robert S.

AU - Fulton, Lucinda L.

AU - Easton, John

AU - Parganas, Evan

AU - Pui, Ching Hon

AU - Rubnitz, Jeffrey E.

AU - Ding, Li

AU - Mardis, Elaine R.

AU - Wilson, Richard K.

AU - Gruber, Tanja A.

AU - Mullighan, Charles G.

AU - Schlenk, Richard F.

AU - Paschka, Peter

AU - Döhner, Konstanze

AU - Döhner, Hartmut

AU - Bullinger, Lars

AU - Zhang, Jinghui

AU - Klco, Jeffery M.

AU - Downing, James R.

PY - 2016/12/1

Y1 - 2016/12/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84992753537&partnerID=8YFLogxK

U2 - 10.1038/ng.3709

DO - 10.1038/ng.3709

M3 - Article

C2 - 27798625

AN - SCOPUS:84992753537

SN - 1061-4036

VL - 48

SP - 1551

EP - 1556

JO - Nature Genetics

JF - Nature Genetics

IS - 12

ER -

The genomic landscape of core-binding factor acute myeloid leukemias

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