title: Microarray transcript profiling distinguishes the transient from the acute type of megakaryoblastic leukaemia (M7) in Down's syndrome, revealing PRAME as a specific discriminating marker.
abstract: Transient myeloproliferative disorder (TMD) is a unique, spontaneously regressing neoplasia specific to Down's syndrome (DS), affecting up to 10% of DS neonates. In 20-30% of cases, it reoccurs as progressive acute megakaryoblastic leukaemia (AMKL) at 2-4 years of age. The TMD and AMKL blasts are morphologically and immuno-phenotypically identical, and have the same acquired mutations in GATA1. We performed transcript profiling of nine TMD patients comparing them with seven AMKL patients using Affymetrix HG-U133A microarrays. Similar overall transcript profiles were observed between the two conditions, which were only separable by supervised clustering. Taqman analysis on 10 TMD and 10 AMKL RNA samples verified the expression of selected differing genes, with statistical significance (P < 0.05) by Student's t-test. The Taqman differences were also reproduced on TMD and AMKL blasts sorted by a fluorescence-activated cell sorter. Among the significant differences, CDKN2C, the effector of GATA1-mediated cell cycle arrest, was increased in AMKL but not TMD, despite the similar level of GATA1. In contrast, MYCN (neuroblastoma-derived oncogene) was expressed in TMD at a significantly greater level than in AMKL. MYCN has not previously been described in leukaemogenesis. Finally, the tumour antigen PRAME was identified as a specific marker for AMKL blasts, with no expression in TMD. This study provides markers discriminating TMD from AMKL-M7 in DS. These markers have the potential as predictive, diagnostic and therapeutic targets. In addition, the study provides further clues into the pathomechanisms discerning self-regressive from the progressive phenotype.
authors.affiliation: Centre for Haematology, Institute of Cell and Molecular Science, Barts and The London, Queen Mary's School of Medicine, University of London, Medical College Building, Turner Street, London, UK.
authors.forename: Suzanne
authors.initials: S
authors.lastname: McElwaine
authors.forename: Claire
authors.initials: C
authors.lastname: Mulligan
authors.forename: Jürgen
authors.initials: J
authors.lastname: Groet
authors.forename: Monica
authors.initials: M
authors.lastname: Spinelli
authors.forename: Andrea
authors.initials: A
authors.lastname: Rinaldi
authors.forename: Gareth
authors.initials: G
authors.lastname: Denyer
authors.forename: Afua
authors.initials: A
authors.lastname: Mensah
authors.forename: Simona
authors.initials: S
authors.lastname: Cavani
authors.forename: Chiara
authors.initials: C
authors.lastname: Baldo
authors.forename: Franca
authors.initials: F
authors.lastname: Dagna-Bricarelli
authors.forename: Ian
authors.initials: I
authors.lastname: Hann
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Basso
authors.forename: Finbarr E
authors.initials: FE
authors.lastname: Cotter
authors.forename: Dean
authors.initials: D
authors.lastname: Nizetic
mesh_terms: D000208:Acute Disease; D000951:Antigens, Neoplasm / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics; D002675:Child, Preschool; D050763:Cyclin-Dependent Kinase Inhibitor p18; D003937:Diagnosis, Differential; D004314:Down Syndrome / Q000276:immunology*; D005260:Female; D005819:Genetic Markers; D006801:Humans; D007231:Infant, Newborn; D007947:Leukemia, Megakaryoblastic, Acute / Q000175:diagnosis*; D008297:Male; D009196:Myeloproliferative Disorders / Q000175:diagnosis; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D015513:Oncogene Proteins / Q000235:genetics; D012075:Remission, Spontaneous; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D000951:Antigens, Neoplasm; C493971:CDKN2C protein, human; D018797:Cell Cycle Proteins; D050763:Cyclin-Dependent Kinase Inhibitor p18; D005819:Genetic Markers; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; C404944:PRAME protein, human; D025521:Tumor Suppressor Proteins