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Series GSE15187 Query DataSets for GSE15187
Status Public on Aug 01, 2009
Title SNP chip data of MDS
Organism Homo sapiens
Experiment type Genome variation profiling by SNP array
Summary 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
Overall design To identify oncogenic lesions in MDS, we performed a genome-wide analysis of primary MDS samples using high-density SNP arrays (Affymetrix GeneChip).
Contributor(s) Sanada M, Suzuki T, Shih L, Kato M, Tamura A, Honda H, Sakata-Yanagimoto M, Kumano K, Oda H, Takita J, Goto N, Nobuyoshi M, Kawamata N, Hayashi Y, Harada H, Kurokawa M, Chiba S, Mori H, Ozawa K, Omine M, Hirai H, Koeffler HP, Ogawa S
Citation(s) 19620960
Submission date Mar 11, 2009
Last update date Dec 22, 2017
Contact name Motohiro Kato
Organization name University of Tokyo
Street address 7-3-1, Hongo, Bunkyo-ku
City Tokyo
ZIP/Postal code 113-8655
Country Japan
Platforms (3)
GPL2004 [Mapping50K_Hind240] Affymetrix Human Mapping 50K Hind240 SNP Array
GPL2005 [Mapping50K_Xba240] Affymetrix Human Mapping 50K Xba240 SNP Array
GPL3718 [Mapping250K_Nsp] Affymetrix Mapping 250K Nsp SNP Array
Samples (171)
GSM379068 MDS.U107
GSM379069 MDS.U122
GSM379070 MDS.U123
BioProject PRJNA116401

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE15187_RAW.tar 2.5 Gb (http)(custom) TAR (of CEL, CHP)
Processed data included within Sample table
Processed data provided as supplementary file

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