title: Integration of genomic and gene expression data of childhood ALL without known aberrations identifies subgroups with specific genetic hallmarks.
abstract: Pediatric acute lymphoblastic leukemia (ALL) comprises genetically distinct subtypes. However, 25% of cases still lack defined genetic hallmarks. To identify genomic aberrancies in childhood ALL patients nonclassifiable by conventional methods, we performed a single nucleotide polymorphisms (SNP) array-based genomic analysis of leukemic cells from 29 cases. The vast majority of cases analyzed (19/24, 79%) showed genomic abnormalities; at least one of them affected either genes involved in cell cycle regulation or in B-cell development. The most relevant abnormalities were CDKN2A/9p21 deletions (7/24, 29%), ETV6 (TEL)/12p13 deletions (3/24, 12%), and intrachromosomal amplifications of chromosome 21 (iAMP21) (3/24, 12%). To identify variation in expression of genes directly or indirectly affected by recurrent genomic alterations, we integrated genomic and gene expression data generated by microarray analyses of the same samples. SMAD1 emerged as a down-regulated gene in CDKN2A homozygous deleted cases compared with nondeleted. The JAG1 gene, encoding the Jagged 1 ligand of the Notch receptor, was among a list of differentially expressed (up-regulated) genes in ETV6-deleted cases. Our findings demonstrate that integration of genomic analysis and gene expression profiling can identify genetic lesions undetected by routine methods and potential novel pathways involved in B-progenitor ALL pathogenesis.
authors.affiliation: Centro Ricerca Tettamanti, Clinica Pediatrica Università Milano-Bicocca, Ospedale San Gerardo, Monza, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Bungaro
authors.forename: Marta Campo
authors.initials: MC
authors.lastname: Dell'Orto
authors.forename: Andrea
authors.initials: A
authors.lastname: Zangrando
authors.forename: Dario
authors.initials: D
authors.lastname: Basso
authors.forename: Tatiana
authors.initials: T
authors.lastname: Gorletta
authors.forename: Luca
authors.initials: L
authors.lastname: Lo Nigro
authors.forename: Anna
authors.initials: A
authors.lastname: Leszl
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Young
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Basso
authors.forename: Silvio
authors.initials: S
authors.lastname: Bicciato
authors.forename: Andrea
authors.initials: A
authors.lastname: Biondi
authors.forename: Gertruy
authors.initials: G
authors.lastname: te Kronnie
authors.forename: Giovanni
authors.initials: G
authors.lastname: Cazzaniga
mesh_terms: D000293:Adolescent; D002135:Calcium-Binding Proteins / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations; D002872:Chromosome Deletion; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D015973:Gene Expression Regulation, Leukemic; D019942:Genes, p16; D005819:Genetic Markers; D006801:Humans; D007223:Infant; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D000072100:Jagged-1 Protein; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D051757:PAX5 Transcription Factor / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000145:classification / Q000235:genetics* / Q000473:pathology; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D000072099:Serrate-Jagged Proteins; D051898:Smad1 Protein / Q000235:genetics; D024182:Uniparental Disomy; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D002135:Calcium-Binding Proteins; D005819:Genetic Markers; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D051757:PAX5 Transcription Factor; D050783:Proto-Oncogene Proteins c-ets; D012097:Repressor Proteins; D000072099:Serrate-Jagged Proteins; D051898:Smad1 Protein; D000097764:ETS Translocation Variant 6 Protein; C000606273:JAG1 protein, human; C497281:PAX5 protein, human