Transcriptomics

Dataset Information

181

SNP chip data of MDS


ABSTRACT: 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).

ORGANISM(S): Homo sapiens  

SUBMITTER: H P Koeffler  Shigeru Chiba  Hiroaki Honda  Noriko Goto  Junko Takita  Masashi Sanada  Hideaki Oda  Takahiro Suzuki  Mitsuhiro Omine  Seishi Ogawa  Lee-Yung Shih  Masaharu Nobuyoshi  Keiki Kumano  Keiya Ozawa  Norihiko Kawamata  Hiroshi Harada  Mamiko Sakata-Yanagimoto  Hisamaru Hirai  Yasuhide Hayashi  Hiraku Mori  Mineo Kurokawa  Azusa Tamura  Motohiro Kato 

PROVIDER: E-GEOD-15187 | ArrayExpress | 2010-04-09

SECONDARY ACCESSION(S): GSE15187PRJNA116401

REPOSITORIES: GEO, ArrayExpress

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Publications


Acquired uniparental disomy (aUPD) is a common feature of cancer genomes, leading to loss of heterozygosity. aUPD is associated not only with loss-of-function mutations of tumour suppressor genes, but also with gain-of-function mutations of proto-oncogenes. Here we show unique gain-of-function mutations of the C-CBL (also known as CBL) tumour suppressor that are tightly associated with aUPD of the 11q arm in myeloid neoplasms showing myeloproliferative features. The C-CBL proto-oncogene, a cellu  ...[more]

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