Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Affymetrix SNP array data for Genomic Instability and Myelodysplasia with Monosomy 7

ABSTRACT: Gene modified autologous hematopoietic stem cells (HSC) can provide significant clinical benefits to patients suffering from X-linked chronic granulomatous disease (X-CGD), a rare inherited immunodeficiency characterized by recurrent, often life threatening bacterial and fungal infections. Here we report on the molecular and cellular events observed in two patients treated by gene therapy in 2004. After the initial resolution of bacterial and fungal infections, both patients exhibited silencing of transgene expression due to methylation of the viral promoter, and myelodysplasia with monosomy 7 as a result of insertional activation of EVI1. One patient died from overwhelming sepsis 27 months after gene therapy, whereas a second patient underwent an allogeneic HSC transplantation. Our data shows that forced overexpression of MDS1/EVI1 or EVI1 in human cells disrupts normal centrosome duplication, linking MDS1/EVI1 activation to the development of genomic instability, monosomy 7 and clonal progression towards myelodysplasia. Genomic copy number alterations were detected by analyzing the fluorescence signal intensities of each SNP on the GeneChip Human Mapping 100K array st (Affymetrix, Santa Clara, Ca) with the Copy Number Analyzer for Affymetrix GeneChip 100K arrays (CNAT) version 2.0. The log2 ratio of each SNP, the local averaged log2 signal ratio (averaged for 10 SNPs) and the inferred chromosome copy number according to the Hidden Markov Model (HMM) were calculated. Copy number analysis of Affymetrix 100K SNP arrays was performed for one young adult with the X-linked chronic granulomatous disease (X-CGD)

ORGANISM(S): Homo sapiens

SUBMITTER: Sandrine Tchatchou

PROVIDER: E-GEOD-19523 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Genomic instability and myelodysplasia with monosomy 7 consequent to EVI1 activation after gene therapy for chronic granulomatous disease.

Stein Stefan S Ott Marion G MG Schultze-Strasser Stephan S Jauch Anna A Burwinkel Barbara B Kinner Andrea A Schmidt Manfred M Krämer Alwin A Schwäble Joachim J Glimm Hanno H Koehl Ulrike U Preiss Carolin C Ball Claudia C Martin Hans H Göhring Gudrun G Schwarzwaelder Kerstin K Hofmann Wolf-Karsten WK Karakaya Kadin K Tchatchou Sandrine S Yang Rongxi R Reinecke Petra P Kühlcke Klaus K Schlegelberger Brigitte B Thrasher Adrian J AJ Hoelzer Dieter D Seger Reinhard R von Kalle Christof C Grez Manuel M

Nature medicine 20100124 2

Gene-modified autologous hematopoietic stem cells (HSC) can provide ample clinical benefits to subjects suffering from X-linked chronic granulomatous disease (X-CGD), a rare inherited immunodeficiency characterized by recurrent, often life-threatening bacterial and fungal infections. Here we report on the molecular and cellular events observed in two young adults with X-CGD treated by gene therapy in 2004. After the initial resolution of bacterial and fungal infections, both subjects showed sile ...[more]

PMID: 20098431

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Project description:Myelodysplastic syndromes (MDS) are clonal disorders of hematopoietic progenitors characterized by ineffective hematopoiesis and high propensity to leukemias. Although a number of gene targets have been identified, in many MDS cases, particular genetic targets are unknown. In this study, we performed genome-wide profiling of copy number (CN) abnormalities and allelic imbalances in MDS genomes in order to clarify the distribution of LOH (loss of heterozygosity) and identify their target genes. We analyzed a total of 171MDS and MDS/MPD specimens, including 7 RA/RARS, 23 RCMD/RCMD-RS, 6 5q-syndrome, 30 RAEB-1, 40 RAEB-2, 4 therapy related-MDS/AML, 5 MDSu, 17 CMML-1, 16 CMML-2, 24 overt AML, using high-density SNP arrays. The data were analyzed by CNAG/AsCNAR software we specifically developed for allele-specific CN analysis and sensitive LOH detection. MDS showed characteristic CN profiles in SNP array analysis. Of particular interest is the finding of high frequency of CN-neutral LOH (Uniparental disomy,UPD), which were observed in 51 of 171 (30%) MDS cases. They preferentially involved 1p, 1q, 4q, 7q, 11q, 17p and other chromosomal segments, which were associated with homozygous mutations of both loss-of-function mutations and gain-of function mutations of tumor suppressor genes and cellular oncogenes, including TP53 (17p UPD), AML1/RUNX1 (21q UPD), Nras and cMPL (1p UPD), JAK-2 (9p UPD), and FLT3 (13q UPD). Next we tried to identify a new gene target in 11q UPD, which was most common UPD region in this study and many of these cases were CMML with a normal karyotype. The minimum 11q UPD segment is about 2Mb which existed in 11q23. We sequenced coding exons of c-cbl and detected homozygous mutations in 8 of 9 MDS cases with 11q UPD (CMML= 5, RAEB= 3, overt leukemia= 1), but very rare in cases without 11q UPD (1/162), demonstrating that the mutation is tightly linked to 11q UPD. These mutations were 8 point mutations and 1 micro-deletion, they were accumulated in the linker or RING domain. These c-cbl mutants can transform NIH3T3 in a dominant manner and these mutants are phosphorylated and activate PI3K-Akt pathway. To investigate the functions of these mutants in hematopoietic cells, we introduced these mutants into c-kit(+)Sca1(+)Lin(-) murine bone marrow cells, it prolonged replating capacity of these hematopoietic progenitors. Keywords: SNP-chip To identify oncogenic lesions in MDS, we performed a genome-wide analysis of primary MDS samples using high-density SNP arrays (Affymetrix GeneChip).

Dataset Information

Affymetrix SNP array data for Genomic Instability and Myelodysplasia with Monosomy 7

Publications

Genomic instability and myelodysplasia with monosomy 7 consequent to EVI1 activation after gene therapy for chronic granulomatous disease.

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