Genomic profiling in Down syndrome acute lymphoblastic leukemia identifies histone gene deletions associated with altered methylation profiles

Patients with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) have distinct clinical and biological features. Whereas most DS-ALL cases lack the sentinel cytogenetic lesions that guide risk assignment in childhood ALL, JAK2 mutations and CRLF2 overexpression are highly enriched. To further...

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Bibliographic Details
Published in:	Leukemia Vol. 25; no. 10; pp. 1555 - 1563
Main Authors:	Loudin, M G, Wang, J, Eastwood Leung, H-C, Gurusiddappa, S, Meyer, J, Condos, G, Morrison, D, Tsimelzon, A, Devidas, M, Heerema, N A, Carroll, A J, Plon, S E, Hunger, S P, Basso, G, Pession, A, Bhojwani, D, Carroll, W L, Rabin, K R
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-10-2011 Nature Publishing Group
Subjects:	631/1647/2217/2018 631/208/68 692/420/2489/1381 692/699/67/1990/283/2125 Acute lymphoblastic leukemia Acute lymphocytic leukemia Base Sequence Biological and medical sciences Cancer Cancer Research Care and treatment Children Chromosome 6 Chromosome aberrations Copy number Critical Care Medicine Cytogenetics Development and progression DNA Methylation DNA Primers Down syndrome Down Syndrome - complications Down Syndrome - genetics Down's syndrome Gene Deletion Gene expression Gene Expression Profiling Genetic aspects Genomes Hematologic and hematopoietic diseases Hematology Heterogeneity Heterozygosity Histones Histones - genetics Humans Intensive Internal Medicine Janus kinase 2 Kinases Leukemia Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis Localization Loss of heterozygosity Lymphatic leukemia Medical genetics Medical schools Medical sciences Medicine Medicine & Public Health Methylation Mutation Oncology original-article Pediatrics Precursor Cell Lymphoblastic Leukemia-Lymphoma - complications Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics Real-Time Polymerase Chain Reaction Spatial discrimination United States New York Italy United States > US Texas acute lymphoblastic leukemia Down syndrome histone Chromosomal aberration Trisomy Hematology Enzyme JAK2 protein tyrosine kinase Transferases Chromosome G21 Aneuploidy Malignant hemopathy Gene Lymphoproliferative syndrome Deletion Genetics Acute lymphocytic leukemia Genome Histone Methylation JAK2 Protein-tyrosine kinase Cancer CRLF2
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Summary:	Patients with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) have distinct clinical and biological features. Whereas most DS-ALL cases lack the sentinel cytogenetic lesions that guide risk assignment in childhood ALL, JAK2 mutations and CRLF2 overexpression are highly enriched. To further characterize the unique biology of DS-ALL, we performed genome-wide profiling of 58 DS-ALL and 68 non-DS (NDS) ALL cases by DNA copy number, loss of heterozygosity, gene expression and methylation analyses. We report a novel deletion within the 6p22 histone gene cluster as significantly more frequent in DS-ALL, occurring in 11 DS (22%) and only 2 NDS cases (3.1%) (Fisher's exact P =0.002). Homozygous deletions yielded significantly lower histone expression levels, and were associated with higher methylation levels, distinct spatial localization of methylated promoters and enrichment of highly methylated genes for specific pathways and transcription factor-binding motifs. Gene expression profiling demonstrated heterogeneity of DS-ALL cases overall, with supervised analysis defining a 45-transcript signature associated with CRLF2 overexpression. Further characterization of pathways associated with histone deletions may identify opportunities for novel targeted interventions.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 These authors contributed equally.
ISSN:	0887-6924 1476-5551
DOI:	10.1038/leu.2011.128