Analysis of AML/MDS patients with 11q/MLL amplification
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE9928 | GEO | 2008/07/01
SECONDARY ACCESSION(S): PRJNA103933
REPOSITORIES: GEO
Similar Datasets
Project description:AML/MDS patients carrying 11q amplifications involving the mixed lineage leukemia gene (MLL) locus are characterized by a later onset, a complex aberrant karyotype (CAK) frequently including deletions within 5q, 17p and 7q, as well as fast progression of the disease with extremely poor prognosis. We and other have shown that the MLL gene is over expressed in amplified cases, however, in most of the cases the amplified region is not restricted to the MLL locus. In the present study we investigated 19 patients with AML/MDS and MLL gain/amplification [15 AML (two secondary, following MDS and PV, and three therapy related) and 4 MDS cases (two therapy related)]. By means of array CGH performed in 12 patients (GSE9928) we were able to delineate the minimal deleted regions within 5q, 17p and 7q and identified three independent regions 11q/I-III that were amplified in all cases. Gene expression profiles established in 15 cases were used to define the candidate genes within these regions. Interestingly, analysis of our data suggests an interdependency of genes influenced by losses of 5q and 17p and expression of genes present in 11q23-25. Additionally, we demonstrate that the gene expression signature can be used to discriminate AML/MDS with MLL amplification from all other types of AML, thus, indicating specific pathogenesis present in this entity. Keywords: AML patients, tumor stratification
2008-11-18 | GSE10258 | GEO
Project description:AML/MDS patients carrying 11q amplifications involving the mixed lineage leukemia gene (MLL) locus are characterized by a complex aberrant karyotype (CAK) frequently including deletions within 5q, 17p and 7q, a later onset and fast progression of the disease with extremely poor prognosis. We and others have shown that the MLL gene is overexpressed in amplified cases; however, in most of the cases the amplified region is not restricted to the MLL locus. In the present study we investigated 19 patients with AML/MDS and MLL gain/amplification. By means of array CGH performed in 12 patients we were able to delineate the minimal deleted regions within 5q, 17p and 7q and identified three independent regions 11q/I-III that were amplified in all cases. Gene expression profiles established in 15 cases (GSE10258) were used to define candidate genes within these regions. Interestingly, analysis of our data suggests an interdependency of loss of 5q and 17p and expression of genes present in 11q23-25. Furthermore, we demonstrate that the gene expression signature can be used to discriminate AML/MDS with MLL amplification from several other types of AML, thus, indicating specific pathogenesis present in this entity. Keywords: comparative genomic hybridization; array CGH In this study, aCGH analysis performed on 12 DNA samples derived from patients with AML, preselected for the presence of MLL amplifications, were analysed on a submegabase resolution BAC array. No replicates, no dye swap was done. Gene expression profiling performed for 15 AML patients (GSE10258).
2008-06-30 | E-GEOD-9928 | biostudies-arrayexpress
Project description:AML/MDS patients carrying 11q amplifications involving the mixed lineage leukemia gene (MLL) locus are characterized by a later onset, a complex aberrant karyotype (CAK) frequently including deletions within 5q, 17p and 7q, as well as fast progression of the disease with extremely poor prognosis. We and other have shown that the MLL gene is over expressed in amplified cases, however, in most of the cases the amplified region is not restricted to the MLL locus. In the present study we investigated 19 patients with AML/MDS and MLL gain/amplification [15 AML (two secondary, following MDS and PV, and three therapy related) and 4 MDS cases (two therapy related)]. By means of array CGH performed in 12 patients (GSE9928) we were able to delineate the minimal deleted regions within 5q, 17p and 7q and identified three independent regions 11q/I-III that were amplified in all cases. Gene expression profiles established in 15 cases were used to define the candidate genes within these regions. Interestingly, analysis of our data suggests an interdependency of genes influenced by losses of 5q and 17p and expression of genes present in 11q23-25. Additionally, we demonstrate that the gene expression signature can be used to discriminate AML/MDS with MLL amplification from all other types of AML, thus, indicating specific pathogenesis present in this entity. Experiment Overall Design: In this study, gene expression profiling performed for 15 AML patients. Experiment Overall Design: aCGH analysis performed on 12 DNA samples derived from patients with AML, preselected for the presence of MLL amplifications, were analysed on a submegabase resolution BAC array. No replicates, no dye swap was done (GSE9928).
2008-11-22 | E-GEOD-10258 | biostudies-arrayexpress
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).
2010-04-09 | E-GEOD-15187 | biostudies-arrayexpress
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
2009-08-01 | GSE15187 | GEO
Project description:Isolated deletions of the long arm of chromosome 5 (del(5q)) are observed in 10% of myelodysplastic syndromes (MDS) and are associated with a more favorable prognosis, although the clinical course varies considerably. If one or more additional chromosomal aberration/s are present this correlates with a significant shorter overall survival. To assess the frequency of hidden abnormalities in cases with an isolated cytogenetic del(5q), we have performed a genome wide high resolution 44K 60mer oligonucleotide array CGH study using DNA from bone marrow cells of 12 MDS and one AML patient. Additional chromosomal aberrations were identified in three of 13 cases (23%): in one case, a single additional hidden 5.6 Mb deletion of 13q14 and in two cases, multiple larger aberrations involving many chromosomes. Fluorescence in situ hybridization (FISH) demonstrated that aberrations present in only 10% of the bone marrow cells were detectable by aCGH. Furthermore with oligonucleotide aCGH the deletion end points in 5q were mapped precisely, revealing a cluster of proximal break points in band q14.3 (n=8) and a distal cluster between bands q33.2 to q34 (n=11). This study shows the high resolution of oligonucleotide CGH arrays for precisely mapping genomic alterations and for refinement of deletion end points. In addition the high sensitivity of this method enables the study of whole bone marrow cells from MDS patients, a disease with a low blast count. Future studies of more patients with isolated del(5q) for hidden abnormalities will be necessary to evaluate the impact of these on the variable prognosis in these patients and to further define new genetic subgroups. Keywords: Myelodysplastic syndromes, MDS, array CGH, del(5q), hidden aberrations
2007-09-11 | GSE8804 | GEO
Project description:Analysis of AML/MDS patients with 11q/MLL amplification
| PRJNA103933 | ENA
Project description:Chromosome 5q deletions (del(5q)) are common in high-risk (HR) Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML); however, the gene regulatory networks that sustain these aggressive diseases are unknown. Reduced miR-146a expression in del(5q) HR-MDS/AML and miR-146a-/- hematopoietic stem/progenitor cells (HSPC) results in TRAF6/NF-M-NM-:M-NM-^R activation. Increased survival and proliferation of HSPC from miR-146alow HR-MDS/AML is sustained by a neighboring haploid gene, SQSTM1 (p62), expressed from the intact 5q allele. Overexpression of p62 from the intact allele occurs through NF-M-NM-:B-dependent feedforward signaling mediated by miR-146a deficiency. p62 is necessary for TRAF6-mediated NF-M-NM-:B signaling, as disrupting the p62-TRAF6 signaling complex results in cell cycle arrest and apoptosis of MDS/AML cells. Thus, del(5q) HR-MDS/AML employs an intrachromosomal gene network involving loss of miR-146a and haploid overexpression of p62 via NF-M-NM-:B to sustain TRAF6/NF-M-NM-:B signaling for cell survival and proliferation. Interfering with the p62-TRAF6 signaling complex represents a therapeutic option in miR-146a-deficient and aggressive del(5q) MDS/AML. Four del(5q) MDS/AML patients with low miR-146a expression (5284, 8839, 8285, 4233) and 5 with high miR-146a expression (7957, 5534, 4688, 4982, 8412) were selected for microarray assay. RNA was reverse transcribed and labeled, and hybridized onto the GeneChip Human Gene 1.0 ST Array. A total of nine samples were included, and two groups are assigned based on miR-146a expression. Comparison comprises mRNA expression profile of low miR-146a group v.s. high miR-146a group.
2014-08-23 | E-GEOD-60649 | biostudies-arrayexpress
Project description:DNMT inhibitors (DNMTi) are finally approved for AML/MDS, also based on their activity in patients with high-risk cytogenetics (often monosomal karyotype) such as -5/del(5q) or -7/del(7q), often - but not always - harboring TP53-mutations. Several studies provided evidence for aberrant hypermethylation/silencing on monoallelic gene loci, including tumor suppressor genes. We hypothesized that transcriptional repression on monosomal gene loci may be preferentially reversed by DNMTi. Using an unbiased RNA-seq approach we aimed to identify preferentially regulated genes in cells monoallelic for chromosome 7q.
2021-03-09 | GSE140347 | GEO
Project description:DNMT inhibitors (DNMTi) are finally approved for AML/MDS, also based on their activity in patients with high-risk cytogenetics (often monosomal karyotype) such as -5/del(5q) or -7/del(7q), often - but not always - harboring TP53-mutations. Several studies provided evidence for aberrant hypermethylation/silencing on monoallelic gene loci, including tumor suppressor genes. We hypothesized that transcriptional repression on monosomal gene loci may be preferentially reversed by DNMTi. Using an unbiased RNA-seq approach we aimed to identify preferentially regulated genes in cells monoallelic for chromosome 7q.
2021-03-09 | GSE138438 | GEO