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.
authors.affiliation: Department of Pediatric Oncology, Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands.
authors.forename: Jasmijn D E
authors.initials: JD
authors.lastname: de Rooij
authors.affiliation: Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Cristyn
authors.initials: C
authors.lastname: Branstetter
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Yongjin
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Walsh
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Jinjun
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Department of Pediatric Oncology, Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands.
authors.forename: Askar
authors.initials: A
authors.lastname: Obulkasim
authors.affiliation: Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Jinjun
authors.initials: J
authors.lastname: Dang
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: John
authors.initials: J
authors.lastname: Easton
authors.affiliation: Department of Pediatric Oncology, Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands.
authors.forename: Lonneke J
authors.initials: LJ
authors.lastname: Verboon
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Heather L
authors.initials: HL
authors.lastname: Mulder
authors.affiliation: Department of Pediatric Hematology/Oncology, Medical School Hannover, Hannover, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Zimmermann
authors.affiliation: Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Cary
authors.initials: C
authors.lastname: Koss
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Gupta
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Edmonson
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Michael
authors.identifier: http://orcid.org/0000-0002-5363-1848
authors.initials: M
authors.lastname: Rusch
authors.affiliation: Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Joshua Yew Suang
authors.initials: JY
authors.lastname: Lim
authors.affiliation: Department of Pediatric Oncology, University of Duisburg-Essen, Essen, Germany.
authors.forename: Katarina
authors.initials: K
authors.lastname: Reinhardt
authors.affiliation: Department of Women's and Children's Health, University of Padova, Padova, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Pigazzi
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Guangchun
authors.initials: G
authors.lastname: Song
authors.affiliation: Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.|Cancer Science Institute, National University of Singapore, Singapore.
authors.forename: Allen Eng Juh
authors.identifier: http://orcid.org/0000-0002-6454-976X
authors.initials: AE
authors.lastname: Yeoh
authors.affiliation: Chang Gung Memorial Hospital-Linkou, Chang Gung University, Taoyuan City, Taiwan.
authors.forename: Lee-Yung
authors.initials: LY
authors.lastname: Shih
authors.affiliation: Department of Pediatrics, Mackay Memorial Hospital, Taipei, Taiwan.
authors.forename: Der-Cherng
authors.initials: DC
authors.lastname: Liang
authors.affiliation: Section of Hematology, Department of Internal Medicine and Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Stephanie
authors.identifier: http://orcid.org/0000-0002-2737-9810
authors.initials: S
authors.lastname: Halene
authors.affiliation: Department of Laboratory Medicine, Yale University, New Haven, Connecticut, USA.
authors.forename: Diane S
authors.initials: DS
authors.lastname: Krause
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Jinghui
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Downing
authors.affiliation: Department of Pediatric Hematology Oncology, University of Pavia, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Locatelli
authors.affiliation: Department of Pediatric Oncology, University of Duisburg-Essen, Essen, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Reinhardt
authors.affiliation: Department of Pediatric Oncology, Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands.|Department of Pediatric Oncology, Princess Maxima Center for Pediatric Oncology, Utrecht, the Netherlands.
authors.forename: Marry M
authors.initials: MM
authors.lastname: van den Heuvel-Eibrink
authors.affiliation: Department of Pediatric Oncology, Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands.
authors.forename: C Michel
authors.initials: CM
authors.lastname: Zwaan
authors.affiliation: Department of Pediatric Oncology, Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands.
authors.forename: Maarten
authors.initials: M
authors.lastname: Fornerod
authors.affiliation: Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.|Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Tanja A
authors.initials: TA
authors.lastname: Gruber
mesh_terms: D000818:Animals; D004314:Down Syndrome / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005260:Female; D015321:Gene Rearrangement / Q000235:genetics; D023281:Genomics / Q000379:methods; D006801:Humans; D007947:Leukemia, Megakaryoblastic, Acute / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012313:RNA / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D056485:Retinoblastoma-Binding Protein 2 / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: C115744:CBFA2T3 protein, human; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; D012313:RNA; C070050:KDM5A protein, human; D056485:Retinoblastoma-Binding Protein 2