title: Integrated differential transcriptome maps of Acute Megakaryoblastic Leukemia (AMKL) in children with or without Down Syndrome (DS).
abstract: BACKGROUND
  The incidence of Acute Megakaryoblastic Leukemia (AMKL) is 500-fold higher in children with Down Syndrome (DS) compared with non-DS children, but the relevance of trisomy 21 as a specific background of AMKL in DS is still an open issue. Several Authors have determined gene expression profiles by microarray analysis in DS and/or non-DS AMKL. Due to the rarity of AMKL, these studies were typically limited to a small group of samples.
  
  
  METHODS
  We generated integrated quantitative transcriptome maps by systematic meta-analysis from any available gene expression profile dataset related to AMKL in pediatric age. This task has been accomplished using a tool recently described by us for the generation and the analysis of quantitative transcriptome maps, TRAM (Transcriptome Mapper), which allows effective integration of data obtained from different experimenters, experimental platforms and data sources. This allowed us to explore gene expression changes involved in transition from normal megakaryocytes (MK, n=19) to DS (n=43) or non-DS (n=45) AMKL blasts, including the analysis of Transient Myeloproliferative Disorder (TMD, n=20), a pre-leukemia condition.
  
  
  RESULTS
  We propose a biological model of the transcriptome depicting progressive changes from MK to TMD and then to DS AMKL. The data indicate the repression of genes involved in MK differentiation, in particular the cluster on chromosome 4 including PF4 (platelet factor 4) and PPBP (pro-platelet basic protein); the gene for the mitogen-activated protein kinase MAP3K10 and the thrombopoietin receptor gene MPL. Moreover, comparing both DS and non-DS AMKL with MK, we identified three potential clinical markers of progression to AMKL: TMEM241 (transmembrane protein 241) was the most over-expressed single gene, while APOC2 (apolipoprotein C-II) and ZNF587B (zinc finger protein 587B) appear to be the most discriminant markers of progression, specifically to DS AMKL. Finally, the chromosome 21 (chr21) genes resulted to be the most over-expressed in DS and non-DS AMKL, as well as in TMD, pointing out a key role of chr21 genes in differentiating AMKL from MK.
  
  
  CONCLUSIONS
  Our study presents an integrated original model of the DS AMLK transcriptome, providing the identification of genes relevant for its pathophysiology which can potentially be new clinical markers.
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Unit of Histology, Embryology and Applied Biology, University of Bologna, Via Belmeloro 8, 40126, Bologna, BO, Italy. mariachiara.pelleri2@unibo.it.
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Pelleri
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Unit of Histology, Embryology and Applied Biology, University of Bologna, Via Belmeloro 8, 40126, Bologna, BO, Italy. allison.piovesan2@unibo.it.
authors.forename: Allison
authors.initials: A
authors.lastname: Piovesan
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Unit of Histology, Embryology and Applied Biology, University of Bologna, Via Belmeloro 8, 40126, Bologna, BO, Italy. maria.caracausi2@unibo.it.
authors.forename: Maria
authors.initials: M
authors.lastname: Caracausi
authors.affiliation: Research Laboratory Stem Cells, U.O.C. Immunohematology-Transfusion Medicine and Laboratory of Hematology, Santo Spirito's Hospital, Via del Circuito, 65100, Pescara, Italy. annacberardi@yahoo.it.
authors.forename: Anna Concetta
authors.initials: AC
authors.lastname: Berardi
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Unit of Histology, Embryology and Applied Biology, University of Bologna, Via Belmeloro 8, 40126, Bologna, BO, Italy. lorenza.vitale@unibo.it.
authors.forename: Lorenza
authors.initials: L
authors.lastname: Vitale
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Unit of Histology, Embryology and Applied Biology, University of Bologna, Via Belmeloro 8, 40126, Bologna, BO, Italy. pierluigi.strippoli@unibo.it.|Interdepartmental Center for Cancer Research Giorgio Prodi (CIRC), S. Orsola-Malpighi Hospital, University of Bologna, Via Massarenti 9, 40138, Bologna, BO, Italy. pierluigi.strippoli@unibo.it.
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Strippoli
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D016022:Case-Control Studies; D002478:Cells, Cultured; D002648:Child; D016208:Databases, Factual; D004314:Down Syndrome / Q000150:complications*; D020869:Gene Expression Profiling; D006801:Humans; D007947:Leukemia, Megakaryoblastic, Acute / Q000175:diagnosis* / Q000209:etiology; D008156:Luciferases / Q000378:metabolism; D055016:Megakaryocyte Progenitor Cells / Q000166:cytology / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D008156:Luciferases