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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.

SUBMITTER: de Rooij JD 

PROVIDER: S-EPMC5687824 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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

de Rooij Jasmijn D E JD   Branstetter Cristyn C   Ma Jing J   Li Yongjin Y   Walsh Michael P MP   Cheng Jinjun J   Obulkasim Askar A   Dang Jinjun J   Easton John J   Verboon Lonneke J LJ   Mulder Heather L HL   Zimmermann Martin M   Koss Cary C   Gupta Pankaj P   Edmonson Michael M   Rusch Michael M   Lim Joshua Yew Suang JY   Reinhardt Katarina K   Pigazzi Martina M   Song Guangchun G   Yeoh Allen Eng Juh AE   Shih Lee-Yung LY   Liang Der-Cherng DC   Halene Stephanie S   Krause Diane S DS   Zhang Jinghui J   Downing James R JR   Locatelli Franco F   Reinhardt Dirk D   van den Heuvel-Eibrink Marry M MM   Zwaan C Michel CM   Fornerod Maarten M   Gruber Tanja A TA  

Nature genetics 20170123 3


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 rearrang  ...[more]

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