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

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)451-456
Number of pages6
JournalNature Genetics
Volume49
Issue number3
DOIs
StatePublished - Mar 1 2017

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Leukemia, Megakaryoblastic, Acute
Pediatrics
Oncogenes
Acute Myeloid Leukemia
Megakaryocyte Progenitor Cells
Exome
RNA Sequence Analysis
Gene Rearrangement
Down Syndrome
Epigenomics
Phosphotransferases
Mutation

ASJC Scopus subject areas

  • Genetics

Cite this

De Rooij, J. D. E., Branstetter, C., Ma, J., Li, Y., Walsh, M. P., Cheng, J., ... Gruber, T. A. (2017). Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes. Nature Genetics, 49(3), 451-456. https://doi.org/10.1038/ng.3772

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

In: Nature Genetics, Vol. 49, No. 3, 01.03.2017, p. 451-456.

Research output: Contribution to journalArticle

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, LY, Liang, DC, 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, no. 3, pp. 451-456. https://doi.org/10.1038/ng.3772
De Rooij, Jasmijn D.E. ; Branstetter, Cristyn ; Ma, Jing ; Li, Yongjin ; Walsh, Michael P. ; Cheng, Jinjun ; Obulkasim, Askar ; Dang, Jinjun ; Easton, John ; Verboon, Lonneke J. ; Mulder, Heather L. ; Zimmermann, Martin ; Koss, Cary ; Gupta, Pankaj ; Edmonson, Michael ; Rusch, Michael ; Lim, Joshua Yew Suang ; Reinhardt, Katarina ; Pigazzi, Martina ; Song, Guangchun ; Yeoh, Allen Eng Juh ; Shih, Lee Yung ; Liang, Der Cherng ; Halene, Stephanie ; Krause, Diane S. ; Zhang, Jinghui ; Downing, James R. ; Locatelli, Franco ; Reinhardt, Dirk ; Van Den Heuvel-Eibrink, Marry M. ; Zwaan, C. Michel ; Fornerod, Maarten ; Gruber, Tanja A. / Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes. In: Nature Genetics. 2017 ; Vol. 49, No. 3. pp. 451-456.
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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.",
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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.

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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.

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