title: A 15q24 microdeletion in transient myeloproliferative disease (TMD) and acute megakaryoblastic leukaemia (AMKL) implicates PML and SUMO3 in the leukaemogenesis of TMD/AMKL.
abstract: Transient myeloproliferative disorder (TMD) of the newborn and acute megakaryoblastic leukaemia (AMKL) in children with Down syndrome (DS) represent paradigmatic models of leukaemogenesis. Chromosome 21 gene dosage effects and truncating mutations of the X-chromosomal transcription factor GATA1 synergize to trigger TMD and AMKL in most patients. Here, we report the occurrence of TMD, which spontaneously remitted and later progressed to AMKL in a patient without DS but with a distinct dysmorphic syndrome. Genetic analysis of the leukaemic clone revealed somatic trisomy 21 and a truncating GATA1 mutation. The analysis of the patient's normal blood cell DNA on a genomic single nucleotide polymorphism (SNP) array revealed a de novo germ line 2·58 Mb 15q24 microdeletion including 41 known genes encompassing the tumour suppressor PML. Genomic context analysis of proteins encoded by genes that are included in the microdeletion, chromosome 21-encoded proteins and GATA1 suggests that the microdeletion may trigger leukaemogenesis by disturbing the balance of a hypothetical regulatory network of normal megakaryopoiesis involving PML, SUMO3 and GATA1. The 15q24 microdeletion may thus represent the first genetic hit to initiate leukaemogenesis and implicates PML and SUMO3 as novel components of the leukaemogenic network in TMD/AMKL.
authors.affiliation: Department of Paediatric Oncology, Haematology and Immunology, University of Heidelberg Medical Centre, Heidelberg, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Haemmerling
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Behnisch
authors.forename: Tobias
authors.initials: T
authors.lastname: Doerks
authors.forename: Jan O
authors.initials: JO
authors.lastname: Korbel
authors.forename: Peer
authors.initials: P
authors.lastname: Bork
authors.forename: Ute
authors.initials: U
authors.lastname: Moog
authors.forename: Sabine
authors.initials: S
authors.lastname: Hentze
authors.forename: Ute
authors.initials: U
authors.lastname: Grasshoff
authors.forename: Michael
authors.initials: M
authors.lastname: Bonin
authors.forename: Olaf
authors.initials: O
authors.lastname: Rieß
authors.forename: Johannes W G
authors.initials: JW
authors.lastname: Janssen
authors.forename: Anna
authors.initials: A
authors.lastname: Jauch
authors.forename: Claus R
authors.initials: CR
authors.lastname: Bartram
authors.forename: Dirk
authors.initials: D
authors.lastname: Reinhardt
authors.forename: Karin A
authors.initials: KA
authors.lastname: Koch
authors.forename: Obul R
authors.initials: OR
authors.lastname: Bandapalli
authors.forename: Andreas E
authors.initials: AE
authors.lastname: Kulozik
mesh_terms: D002648:Child; D002675:Child, Preschool; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics*; D004314:Down Syndrome / Q000235:genetics* / Q000473:pathology; D050982:GATA1 Transcription Factor / Q000235:genetics; D006801:Humans; D007223:Infant; D007947:Leukemia, Megakaryoblastic, Acute / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008297:Male; D009196:Myeloproliferative Disorders / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics*; D000071156:Promyelocytic Leukemia Protein; D017384:Sequence Deletion; D014157:Transcription Factors / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D014452:Ubiquitins / Q000235:genetics*
chemical_list: D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; C492189:SUMO3 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D014452:Ubiquitins; C070576:PML protein, human