Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes

Jasmijn D. E. De Rooij; Cristyn Branstetter; Jing Ma; Yongjin Li; Michael P. Walsh; Jinjun Cheng; Askar Obulkasim; Jinjun Dang; John Easton; Lonneke J. Verboon; Heather L. Mulder; Martin Zimmermann; Cary Koss; Pankaj Gupta; Michael Edmonson; Michael Rusch; Joshua Yew Suang Lim; Katarina Reinhardt; Martina Pigazzi; Guangchun Song; Allen Eng Juh Yeoh; Lee-Yung Shih; Der-Cherng Liang; Stephanie Halene; Diane S. Krause; Jinghui Zhang; James R. Downing; Franco Locatelli; Dirk Reinhardt; Marry M Van Den Heuvel-Eibrink; C Michel Zwaan; Maarten Fornerod; Tanja A. Gruber

doi:10.1038/ng.3772

Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes

Jasmijn D. E. De Rooij, Cristyn Branstetter, Jing Ma, Yongjin Li, Michael P. Walsh, Jinjun Cheng, Askar Obulkasim, Jinjun Dang, John Easton, Lonneke J. Verboon, Heather L. Mulder, Martin Zimmermann, Cary Koss, Pankaj Gupta, Michael Edmonson, Michael Rusch, Joshua Yew Suang Lim, Katarina Reinhardt, Martina Pigazzi, Guangchun SongAllen Eng Juh Yeoh, Lee-Yung Shih, Der-Cherng Liang, Stephanie Halene, Diane S. Krause, Jinghui Zhang, James R. Downing, Franco Locatelli, Dirk Reinhardt, Marry M Van Den Heuvel-Eibrink, C Michel Zwaan, Maarten Fornerod, Tanja A. Gruber

Risultato della ricerca: Contributo in rivista › Articolo in rivista

Abstract

Acute megakaryoblastic leukemia (AMKL) is a subtype of acute myeloid leukemia (AML) in which cells morphologically resemble abnormal megakaryoblasts. While rare in adults, AMKL accounts for 4-15% of newly diagnosed childhood AML cases. AMKL in individuals without Down syndrome (non-DS-AMKL) is frequently associated with poor clinical outcomes. Previous efforts have identified chimeric oncogenes in a substantial number of non-DS-AMKL cases, including RBM15-MKL1, CBFA2T3-GLIS2, KMT2A gene rearrangements, and NUP98-KDM5A. However, the etiology of 30-40% of cases remains unknown. To better understand the genomic landscape of non-DS-AMKL, we performed RNA and exome sequencing on specimens from 99 patients (75 pediatric and 24 adult). We demonstrate that pediatric non-DS-AMKL is a heterogeneous malignancy that can be divided into seven subgroups with varying outcomes. These subgroups are characterized by chimeric oncogenes with cooperating mutations in epigenetic and kinase signaling genes. Overall, these data shed light on the etiology of AMKL and provide useful information for the tailoring of treatment.

Lingua originale	English
pagine (da-a)	451-456
Numero di pagine	6
Rivista	Nature Genetics
Volume	49
DOI	https://doi.org/10.1038/ng.3772
Stato di pubblicazione	Pubblicato - 2017

Keywords

AML

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10.1038/ng.3772

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De Rooij, J. D. E., Branstetter, C., Ma, J., Li, Y., Walsh, M. P., Cheng, J., Obulkasim, A., Dang, J., Easton, J., Verboon, L. J., Mulder, H. L., Zimmermann, M., Koss, C., Gupta, P., Edmonson, M., Rusch, M., Lim, J. Y. S., Reinhardt, K., Pigazzi, M., ... Gruber, T. A. (2017). Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes. Nature Genetics, 49, 451-456. https://doi.org/10.1038/ng.3772

@article{7c28db48c8134141b9e29528bace0e79,

title = "Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes",

abstract = "Acute megakaryoblastic leukemia (AMKL) is a subtype of acute myeloid leukemia (AML) in which cells morphologically resemble abnormal megakaryoblasts. While rare in adults, AMKL accounts for 4-15% of newly diagnosed childhood AML cases. AMKL in individuals without Down syndrome (non-DS-AMKL) is frequently associated with poor clinical outcomes. Previous efforts have identified chimeric oncogenes in a substantial number of non-DS-AMKL cases, including RBM15-MKL1, CBFA2T3-GLIS2, KMT2A gene rearrangements, and NUP98-KDM5A. However, the etiology of 30-40% of cases remains unknown. To better understand the genomic landscape of non-DS-AMKL, we performed RNA and exome sequencing on specimens from 99 patients (75 pediatric and 24 adult). We demonstrate that pediatric non-DS-AMKL is a heterogeneous malignancy that can be divided into seven subgroups with varying outcomes. These subgroups are characterized by chimeric oncogenes with cooperating mutations in epigenetic and kinase signaling genes. Overall, these data shed light on the etiology of AMKL and provide useful information for the tailoring of treatment.",

keywords = "AML, AML",

author = "{De Rooij}, {Jasmijn D. E.} and Cristyn Branstetter and Jing Ma and Yongjin Li and Walsh, {Michael P.} and Jinjun Cheng and Askar Obulkasim and Jinjun Dang and John Easton and Verboon, {Lonneke J.} and Mulder, {Heather L.} and Martin Zimmermann and Cary Koss and Pankaj Gupta and Michael Edmonson and Michael Rusch and Lim, {Joshua Yew Suang} and Katarina Reinhardt and Martina Pigazzi and Guangchun Song and Yeoh, {Allen Eng Juh} and Lee-Yung Shih and Der-Cherng Liang and Stephanie Halene and Krause, {Diane S.} and Jinghui Zhang and Downing, {James R.} and Franco Locatelli and Dirk Reinhardt and {Van Den Heuvel-Eibrink}, {Marry M} and Zwaan, {C Michel} and Maarten Fornerod and Gruber, {Tanja A.}",

year = "2017",

doi = "10.1038/ng.3772",

language = "English",

volume = "49",

pages = "451--456",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

}

De Rooij, JDE, Branstetter, C, Ma, J, Li, Y, Walsh, MP, Cheng, J, Obulkasim, A, Dang, J, Easton, J, Verboon, LJ, Mulder, HL, Zimmermann, M, Koss, C, Gupta, P, Edmonson, M, Rusch, M, Lim, JYS, Reinhardt, K, Pigazzi, M, Song, G, Yeoh, AEJ, Shih, L-Y, Liang, D-C, Halene, S, Krause, DS, Zhang, J, Downing, JR, Locatelli, F, Reinhardt, D, Van Den Heuvel-Eibrink, MM, Zwaan, CM, Fornerod, M & Gruber, TA 2017, 'Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes', Nature Genetics, vol. 49, pagg. 451-456. https://doi.org/10.1038/ng.3772

TY - JOUR

T1 - Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes

AU - De Rooij, Jasmijn D. E.

AU - Branstetter, Cristyn

AU - Ma, Jing

AU - Li, Yongjin

AU - Walsh, Michael P.

AU - Cheng, Jinjun

AU - Obulkasim, Askar

AU - Dang, Jinjun

AU - Easton, John

AU - Verboon, Lonneke J.

AU - Mulder, Heather L.

AU - Zimmermann, Martin

AU - Koss, Cary

AU - Gupta, Pankaj

AU - Edmonson, Michael

AU - Rusch, Michael

AU - Lim, Joshua Yew Suang

AU - Reinhardt, Katarina

AU - Pigazzi, Martina

AU - Song, Guangchun

AU - Yeoh, Allen Eng Juh

AU - Shih, Lee-Yung

AU - Liang, Der-Cherng

AU - Halene, Stephanie

AU - Krause, Diane S.

AU - Zhang, Jinghui

AU - Downing, James R.

AU - Locatelli, Franco

AU - Reinhardt, Dirk

AU - Van Den Heuvel-Eibrink, Marry M

AU - Zwaan, C Michel

AU - Fornerod, Maarten

AU - Gruber, Tanja A.

PY - 2017

Y1 - 2017

N2 - Acute megakaryoblastic leukemia (AMKL) is a subtype of acute myeloid leukemia (AML) in which cells morphologically resemble abnormal megakaryoblasts. While rare in adults, AMKL accounts for 4-15% of newly diagnosed childhood AML cases. AMKL in individuals without Down syndrome (non-DS-AMKL) is frequently associated with poor clinical outcomes. Previous efforts have identified chimeric oncogenes in a substantial number of non-DS-AMKL cases, including RBM15-MKL1, CBFA2T3-GLIS2, KMT2A gene rearrangements, and NUP98-KDM5A. However, the etiology of 30-40% of cases remains unknown. To better understand the genomic landscape of non-DS-AMKL, we performed RNA and exome sequencing on specimens from 99 patients (75 pediatric and 24 adult). We demonstrate that pediatric non-DS-AMKL is a heterogeneous malignancy that can be divided into seven subgroups with varying outcomes. These subgroups are characterized by chimeric oncogenes with cooperating mutations in epigenetic and kinase signaling genes. Overall, these data shed light on the etiology of AMKL and provide useful information for the tailoring of treatment.

AB - Acute megakaryoblastic leukemia (AMKL) is a subtype of acute myeloid leukemia (AML) in which cells morphologically resemble abnormal megakaryoblasts. While rare in adults, AMKL accounts for 4-15% of newly diagnosed childhood AML cases. AMKL in individuals without Down syndrome (non-DS-AMKL) is frequently associated with poor clinical outcomes. Previous efforts have identified chimeric oncogenes in a substantial number of non-DS-AMKL cases, including RBM15-MKL1, CBFA2T3-GLIS2, KMT2A gene rearrangements, and NUP98-KDM5A. However, the etiology of 30-40% of cases remains unknown. To better understand the genomic landscape of non-DS-AMKL, we performed RNA and exome sequencing on specimens from 99 patients (75 pediatric and 24 adult). We demonstrate that pediatric non-DS-AMKL is a heterogeneous malignancy that can be divided into seven subgroups with varying outcomes. These subgroups are characterized by chimeric oncogenes with cooperating mutations in epigenetic and kinase signaling genes. Overall, these data shed light on the etiology of AMKL and provide useful information for the tailoring of treatment.

KW - AML

UR - http://hdl.handle.net/10807/228212

U2 - 10.1038/ng.3772

DO - 10.1038/ng.3772

M3 - Article

SN - 1061-4036

VL - 49

SP - 451

EP - 456

JO - Nature Genetics

JF - Nature Genetics

ER -

Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes

Abstract

Keywords

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