title: Characterization of novel genomic alterations and therapeutic approaches using acute megakaryoblastic leukemia xenograft models.
abstract: Acute megakaryoblastic leukemia (AMKL) is a heterogeneous disease generally associated with poor prognosis. Gene expression profiles indicate the existence of distinct molecular subgroups, and several genetic alterations have been characterized in the past years, including the t(1;22)(p13;q13) and the trisomy 21 associated with GATA1 mutations. However, the majority of patients do not present with known mutations, and the limited access to primary patient leukemic cells impedes the efficient development of novel therapeutic strategies. In this study, using a xenotransplantation approach, we have modeled human pediatric AMKL in immunodeficient mice. Analysis of high-throughput RNA sequencing identified recurrent fusion genes defining new molecular subgroups. One subgroup of patients presented with MLL or NUP98 fusion genes leading to up-regulation of the HOX A cluster genes. A novel CBFA2T3-GLIS2 fusion gene resulting from a cryptic inversion of chromosome 16 was identified in another subgroup of 31% of non-Down syndrome AMKL and strongly associated with a gene expression signature of Hedgehog pathway activation. These molecular data provide useful markers for the diagnosis and follow up of patients. Finally, we show that AMKL xenograft models constitute a relevant in vivo preclinical screening platform to validate the efficacy of novel therapies such as Aurora A kinase inhibitors.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 985, 94805 Villejuif, France.
authors.forename: Clarisse
authors.initials: C
authors.lastname: Thiollier
authors.forename: Cécile K
authors.initials: CK
authors.lastname: Lopez
authors.forename: Bastien
authors.initials: B
authors.lastname: Gerby
authors.forename: Cathy
authors.initials: C
authors.lastname: Ignacimouttou
authors.forename: Sandrine
authors.initials: S
authors.lastname: Poglio
authors.forename: Yannis
authors.initials: Y
authors.lastname: Duffourd
authors.forename: Justine
authors.initials: J
authors.lastname: Guégan
authors.forename: Paola
authors.initials: P
authors.lastname: Rivera-Munoz
authors.forename: Olivier
authors.initials: O
authors.lastname: Bluteau
authors.forename: Vinciane
authors.initials: V
authors.lastname: Mabialah
authors.forename: M'boyba
authors.initials: M
authors.lastname: Diop
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wen
authors.forename: Arnaud
authors.initials: A
authors.lastname: Petit
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Bauchet
authors.forename: Dirk
authors.initials: D
authors.lastname: Reinhardt
authors.forename: Beat
authors.initials: B
authors.lastname: Bornhauser
authors.forename: Daniel
authors.initials: D
authors.lastname: Gautheret
authors.forename: Yann
authors.initials: Y
authors.lastname: Lecluse
authors.forename: Judith
authors.initials: J
authors.lastname: Landman-Parker
authors.forename: Isabelle
authors.initials: I
authors.lastname: Radford
authors.forename: William
authors.initials: W
authors.lastname: Vainchenker
authors.forename: Nicole
authors.initials: N
authors.lastname: Dastugue
authors.forename: Stéphane
authors.initials: S
authors.lastname: de Botton
authors.forename: Philippe
authors.initials: P
authors.lastname: Dessen
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Bourquin
authors.forename: John D
authors.initials: JD
authors.lastname: Crispino
authors.forename: Paola
authors.initials: P
authors.lastname: Ballerini
authors.forename: Olivier A
authors.initials: OA
authors.lastname: Bernard
authors.forename: Françoise
authors.initials: F
authors.lastname: Pflumio
authors.forename: Thomas
authors.initials: T
authors.lastname: Mercher
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000368:Aged; D000595:Amino Acid Sequence; D000818:Animals; D064096:Aurora Kinase A; D064127:Aurora Kinases; D001381:Azepines / Q000494:pharmacology; D001483:Base Sequence; D005260:Female; D020869:Gene Expression Profiling; D023281:Genomics / Q000379:methods*; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D007223:Infant; D053208:Kaplan-Meier Estimate; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D007947:Leukemia, Megakaryoblastic, Acute / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000494:pharmacology; D012097:Repressor Proteins / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: C459092:2-methyl-1-((4-methyl-5-isoquinolinyl)sulfonyl)homopiperazine; D001381:Azepines; C110408:CBFA2T2 myeloid-transforming gene-related protein; C577580:CBFA2T3-GLIS2 fusion protein, human; C447919:GLIS2 protein, human; D051741:Kruppel-Like Transcription Factors; C550258:MLN 8237; D015514:Oncogene Proteins, Fusion; D011743:Pyrimidines; D012097:Repressor Proteins; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; C576918:Aurka protein, mouse; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases