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  • 1
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    Genetic Profiling of BCR/ABL Negative Myeloproliferative Disorders Using High-Resolution Microarrays
    American Society of Hematology ; 2007
    In:  Blood Vol. 110, No. 11 ( 2007-11-16), p. 1538-1538
    Details
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 1538-1538
    Abstract: Recently, the identification of the gain of function mutation JAK2V617F delivered important insights into the pathogenesis of BCR/ABL negative myeloproliferative disorders (MPD). JAK2V617F is detectable in more than 90% of polycythemia vera (PV) patients (pts) and in approximately 50% of pts with essential thrombocythemia (ET) or primary myelofibrosis (PMF), representing the genetic hallmark of BCR/ABL negative disease. However, about 30% of MPD pts lack the JAK2V617F mutation and previous studies on ET and PV demonstrated that clonality exceeds the percentage of V617F mutated cells. These findings suggest that additional genetic alterations are involved in the pathogenesis of MPD, in both JAK2 mutated and unmutated pts. To identify novel genetic aberrations and to determine whether specific lesions are associated with disease phenotype, genomic DNA from granulocytes of 72 MPD pts classified according to the WHO criteria was analyzed using high-resolution, genome-wide microarray techniques [disease, number analyzed, JAK2 mutation status: PMF, n=14, 9/14; post-ET MF, n=5, 3/5; post-PV MF, n=5, 5/5; PV, n=37, 37/37; ET, n=11, 11/11] . In a first approach, all cases were investigated by comparative genomic hybridization to 8k arrays (array CGH) with an average probe spacing of less than 1 Mb. While no genomic imbalances were found in ET, 11% of PV pts (n=4) exhibited large ( & gt;10 Mb) deletions on 20q (n=2) or gains on 9p and 1q (n=1, each). In addition, small ( & lt;1 Mb) recurrent gains in 1q21.1 (n=2) and 22q11.23 (n=2) were identified. In MF pts the incidence of large genomic imbalances was 25% (n=6) with trisomy 9 (n=3) being the most frequent aberration followed by loss of 20q, 5q, and 13q in single cases. Furthermore, in one pt with post-PV MF small genomic losses in 17q11.2 (2 Mb) and 17p13.2 (0.8 Mb) were identified harbouring NF1 but not TP53. Deletion of the NF1 allele without concomitant loss of TP53 was confirmed by FISH. To further increase resolution and to investigate the role of uniparental disomy (UPD), single nucleotide polymorphism (SNP) analysis using the Affymetrix 250k Nsp SNP array was performed in all MF cases. Copy number estimation and loss of heterozygosity probability were analyzed using a set of 117 remission samples from acute myeloid leukemia pts as a common reference. SNP analysis confirmed all anomalies detected by array CGH. In addition, SNP analysis revealed small genomic losses (1.6–2.6 Mb) in 1q21.2 (n=3), 5q13.2, and 3p13 (n=1, each), and in one secondary MF pt another microdeletion in 17q11.2 (1.2 Mb). UPDs recurrently affected 9p (n=5) in a region harbouring the JAK2 locus. In single cases, large UPDs of 1q (25 Mb), 2p (14 Mb), 5q (4 Mb), 6p (11 Mb), and 7q (11 Mb) were identified. Of note, all JAK2V617F mutated post-PV and post-ET MF cases exhibited 9p abnormalities represented either by trisomy 9 or UPD of 9p. In conclusion, using a combined microarray approach we were able to detect novel submicroscopic alterations in addition to known abnormalities. Parallel analysis of both techniques clearly demonstrated the superiority of array-SNP mapping. Further analyses on larger pt populations and correlation with global gene expression data will facilitate the identification of disease-related genes that are involved in the pathogenesis of BCR/ABL negative MPD.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V110.11.1538.1538
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
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  • 2
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    NF1 Alterations Are Common In AML with Complex Karyotype and Correlate with Specific Genomic Imbalances
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 4179-4179
    Details
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 4179-4179
    Abstract: Abstract 4179 In acute myeloid leukemia (AML), complex karyotype is defined as the presence of three or more chromosome abnormalities in the absence of one of the recurrent genetic abnormalities as defined by the recent WHO classification. AML with complex karyotype (CK-AML) account for approximately 10 to 15% of all cases and are associated with preceding myelodysplasia (MDS) or exposure to toxic agents; the prognosis of patients is very poor. So far, little is known about the molecular mechanisms underlying initiation or progression of CK-AML. To identify genomic regions of potential pathogenic relevance, we used microarray-based techniques [array-comparative genomic hybridization (CGH) and single-nucleotide polymorphism (SNP) analysis] for high-resolution genome-wide analysis in 242 cases, including 171 (71%) cases enrolled on clinical protocols using intensive chemotherapy. Among other genomic imbalances, we identified loss of chromosome band 17q11.2 encompassing the NF1 locus in 55 (23%) of the 242 cases. Interestingly, three of these cases exhibited homozygous loss of NF1. Based on these findings and the fact that NF1 is recurrently altered in myeloid malignancies, we further investigated its role in CK-AML. Therefore, we analyzed 11 cases with heterozygous microdeletions of NF1 for mutations in the remaining allele by direct sequencing of exons 1 to 60 and identified 5 mutations in 4 cases; all of these mutations resulted in a premature stop codon (3 frameshift mutations, 2 nonsense mutations); one frameshift mutation (c.2033dupC) was recurrent. Combining the findings from array-based and mutation analyses, we so far identified 7 patients with biallelic NF1 gene alterations, i.e. homozygous loss or loss of one allele and at least one mutation in the remaining allele. Since correlation of NF1 alteration with data from array-based genomic profiling revealed a significant correlation with loss of chromosome band 17p13 encompassing TP53 (P 〈 .001), we correlated NF1 alteration with the TP53 status (mutation and/or loss), which was available for all 242 cases, and found a positive correlation with both TP53 alteration (mutation and/or loss) and TP53 mutation (P 〈 .001 each). In addition, NF1 alteration was significantly correlated with biallelic TP53 alterations (loss and mutation or homozygous mutations) (P 〈 .001). We than further investigated the two genotypes NF1alteration/TP53alteration (n=50) and NF1no alteration/TP53alteration (n=109) with regard to their association with other genomic imbalances. The genotype NF1alteration/TP53alteration was significantly correlated to the total number of deletions (median 9 vs 7; P = .025), the genomic complexity as measured by the total number of aberrations per case (median 13 vs 11; P = .039), and the presence of 16q loss (50% [25/50] vs 29% [32/109], P = .014) when compared with the NF1no alteration/TP53alteration genotype. Notably, in a recently published murine model deficiency of ICSBP, located on 16q24, was shown to synergize with NF1 haplo-insufficiency in leukemogenesis. In conclusion, the NF1 gene is found to be recurrently altered in CK-AML. Being associated with specific genomic aberrations, NF1 alteration is likely cooperating in myeloid leukemogenesis or disease progression. One important co-player might be TP53 that has an important role in genomic stability. The exact mechanism of interaction between NF1 and TP53 or other concurrent genetic alterations have to be further investigated. Disclosures: Döhner: Pfizer: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V116.21.4179.4179
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 3
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    SNP-Array Profiling Identifies Complex Aberrations and Candidate Genes in Myeloproliferative Neoplasms with Leukemic Transformation.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 2608-2608
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 2608-2608
    Abstract: Abstract 2608 Poster Board II-584 Background: Myeloproliferative neoplasms (MPN) represent a heterogeneous group of acquired hematopoietic stem cell disorders. Clonality leads to exceeding production of myeloid cells resulting in an inherent tendency for thrombotic and hemorrhagic complications as well as transformation into acute myeloid leukemia (sAML). While vascular complications predominantly account for the morbidity in essential thrombocythemia (ET) and polycythemia vera (PV), the mortality of MPN is significantly related to leukemic transformation. Secondary AML occurs more frequently in primary and secondary myelofibrosis (PMF and SMF) than in ET and PV, and the risk for leukemic transformation increases with the duration of the disease. The molecular basis underlying the progression of MPN is poorly understood. Clonal evolution due to genomic instability is considered to play an important role. Aim: To identify genomic lesions associated with leukemic transformation, we applied 250K single-nucleotide polymorphism (SNP) arrays that allow for genome-wide screening of both copy-number alterations (CNAs) and copy-neutral runs of homozygosity (ROH) at high resolution. Method: An unpaired SNP-array analysis of 23 sAML samples was performed [former diagnosis: ET, n=5; PV, n=7; PMF, n=9; SMF, n=2;]. An own set of 30 reference samples was used for normalization. CNAs and ROH were analyzed by CNAG 3.0 software. Aberrations were compared with the 250K SNP-array dataset of 151 MPN patients [ET, n=45; PV, n=45; PMF, n=47, SMF, n=14] . In one sAML patient corresponding SNP-array data from the time of ET diagnosis were available. Results: CNAs were present in 15 of 23 (65%) sAML patients. Thirty-five percent of cases (n=8) exhibited complex genomic aberrations with up to 20 CNAs in one patient (range 5–20). The most frequent larger ( 〉 5 Mb) CNAs were trisomy 8 (n=7), gain of 1q, loss of 5q, and deletion in 6p25-pter (16.2–26.7 Mb) and 20q11-q13 (13.6–16.9 Mb) in three cases each, followed by gain in 3q24-qter (51.7 and 54.1 Mb) in two patients. Of note, one case with deletion in 17p12-pter (64.4 Mb) encompassing TP53 and a second with gain in 21q22.12-qter (11.8 Mb) were identified; in the latter one the proximal breakpoint of the gain was located at RUNX1. Smaller CNAs ( 〈 5 Mb) were restricted to single cases with four cases exhibiting micro-deletions ranging from 0.7 to 2.7 Mb in size. Interestingly, three chromosomal regions harbour single genes: 11p11.2 (FOLH1), 18q21.2 (TCF4), and 21q22.12 (RUNX1). ROH comprising the terminal end of the chromosome were detectable in 13 of 23 (57%) sAML cases. The most frequent ROH included the JAK2 locus in 9p24 (n=6; 15.6–38.7 Mb), followed by ROH in 17p13-pter (16.3 and 17.7 Mb) covering TP53 and an overlapping segment in 1p32-pter (53 Mb) affecting MPL in two cases each. All cases with 9p ROH were JAK2 V617F mutated, whereas the MPL W515L mutation was found in one of the two 1p ROH cases. Moreover, sequencing analyses in both patients with ROH in 17p revealed TP53 missense mutations in exon 7 and exon 8, respectively. In addition, non-recurrent ROH covering the long arm of chromosome 7, 11, and 21 as well as ROH in the chromosomal segments 14q32-qter (12.6 Mb) and 17q31-qter (31 Mb) were identified. In one sAML patient SNP-array data performed at the time of ET were available for comparative analysis. While 20q deletion was present as sole aberration in ET, complex genomic aberrations (7 CNAs) were identified after development of sAML. Merging the results from our recent 250K SNP-array analysis (Stegelmann et al., Blood 2008; 112: Abstract #2794) on 61 PMF and SMF cases with data from this study, we were able to identify a second case with micro-deletion in 12q24. The commonly deleted region of both cases is 1.3 Mb in size and encompasses TCF1 as a novel recurrent aberration in MPN. Conclusion: In summary, our data on a large series of well-defined sAML cases that evolved from MPN demonstrate that 250K SNP-array profiling is an excellent tool to identify genomic aberrations. In contrast to MPN, genomic alterations in sAML are characterized by a marked complexity reflecting both genomic instability and genetic heterogeneity of sAML. However, in our study several regions of interest including recurrently affected candidate genes such as TCF1, RUNX1, and TP53 were identified that need to be further investigated on a single gene level. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.2608.2608
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 4
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    Identification of High-Level DNA Amplifications in AML with Complex Karyotype Using Array-CGH.
    American Society of Hematology ; 2006
    In:  Blood Vol. 108, No. 11 ( 2006-11-16), p. 1914-1914
    Details
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 1914-1914
    Abstract: Complex karyotype acute myeloid leukemia (AML), commonly defined as the presence of three or more chromosome abnormalities without specific fusion transcripts, is seen in approximately 10–15% of all AML cases. In this subset of cases, genomic losses and gains are much more frequent than balanced translocations, indicating other mechanisms of leukemogenesis. One possible mechanism is the activation of oncogenes through high-level DNA amplifications. To detect high-level DNA amplifications and to identify corresponding candidate genes, we applied comparative genomic hybridization to microarrays (array-CGH) in 100 cases of complex karyotype AML and correlated the findings with gene expression profiling (GEP) data. For array-CGH a custom-made 2.8k-microarray was used consisting of 2799 different BAC- or PAC-vectors with an average resolution of approximately 2 Mb. Hybridization experiments were performed in a dye-swap setting; significant aberrations were defined as mean plus/minus three times the standard deviation of a set of balanced clones for each individual experiment. In selected cases correlation with global gene expression studies was performed to further delineate candidate genes. We identified 50 high-level DNA amplifications in 20 different genomic regions. Amplifications occurring in at least two cases mapped to (candidate genes in the amplicon) 11q23.3-q24.1 (n=10; ETS, FLI1, APLP2); 11q23.3 (n=8;MLL, DDX6, LARG, SC5DL); 21q22 (n=5; ERG, ETS2); 9p24 (n=4; JAK2); 13q12 (n=4; CDX2, FLT3, PAN3); 8q24 (n=3; C8FW, MYC); 12p13 (n=2; FGF6, CCND2); 20q11 (n=2; ID1, BCL2L1); and 11q13 (n=2; STARD10, GARP, RAD30, DLG2). To better characterize the genomic architecture of the amplicons, we applied array-CGH using an 8.0k-microarray with an average resolution of approximately 1 Mb. Using this approach highly complex amplicon structures with several distinct amplicon peaks were identified for e.g. the amplified regions in 8q24, 11q23, and 13q12. In addition, parallel analysis of GEP in a subset of 43 of 100 cases displayed overexpressed candidate genes in the critical amplified regions; for some of the genes an oncogenic role has been implicated e.g. C8FW and MYC in 8q24, ETS1, FLI1 and APLP2 in 11q24.1, as well as FLT3 and CDX2 in 13q12. In conclusion, using high-resolution genome-wide screening tools such as array-CGH, a large number of high-level DNA amplifications were identified in AML with complex karyotype suggesting a more general role for protooncogene activation in this AML subset. This high-resolution technique allows the detection of complex amplicon structures with several distinct amplicon peaks pinpointing to selective candidate genes. In addition, correlation with GEP studies facilitates the delineation of overexpressed candidate genes within the amplified regions.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V108.11.1914.1914
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2006
    detail.hit.zdb_id: 1468538-3
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  • 5
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    A FLT3 Gene-Expression Signature Outperforms FLT3 Status in Predicting Clinical Outcome for Patients with Normal Karyotype AML.
    American Society of Hematology ; 2006
    In:  Blood Vol. 108, No. 11 ( 2006-11-01), p. 2311-2311
    Details
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-01), p. 2311-2311
    Abstract: In acute myeloid leukemia (AML), cyotgenetics is used to stratify cases for appropriate risk-adapted therapy. The largest subset of patients, those with normal karyotype AML (NK-AML), comprises a heterogeneous group with intermediate prognosis. To improve outcome prediction for this group, we carried out gene-expression profiling of a set of 65 clinically-annotated NK-AML cases. In exploratory studies, an outcome predictor derived from semi-supervised analysis comprised genes mainly correlated with the presence of FLT3 (fms-related tyrosine kinase 3) internal tandem duplication (ITD) activating mutation, itself a prognostic factor. We therefore sought to directly define and characterize a gene-expression predictor of FLT3-ITD mutation status. Using a supervised analysis (Prediction Analysis of Microarrays), we identified an optimal 25-gene FLT3 signature, which in an independent set of 73 NK-AML cases was a significant predictor of clinical outcome, notably outperforming FLT3-ITD mutation status itself. We speculate that the signature identifies cases with alternative genetic or epigenetic changes that phenocopy FLT3-ITD, and the signature genes provide a starting point to dissect these pathways. Our findings underscore the prognostic relevance of FLT3-ITD in NK-AML, and indicate the potential clinical utility of a gene-expression based measure of clinically-relevant FLT3 pathway activation.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V108.11.2311.2311
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2006
    detail.hit.zdb_id: 1468538-3
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  • 6
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    Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: interaction with other gene mutations
    American Society of Hematology ; 2005
    In:  Blood Vol. 106, No. 12 ( 2005-12-01), p. 3740-3746
    Details
    In: Blood, American Society of Hematology, Vol. 106, No. 12 ( 2005-12-01), p. 3740-3746
    Abstract: To assess the prognostic relevance of mutations in the NPM1 gene encoding a nucleocytoplasmic shuttle protein in younger adults with acute myeloid leukemia (AML) and normal cytogenetics, sequencing of NPM1 exon 12 was performed in diagnostic samples from 300 patients entered into 2 consecutive multicenter trials of the AML Study Group (AMLSG). Treatment included intensive double-induction therapy and consolidation therapy with high cumulative doses of high-dose cytarabine. NPM1 mutations were identified in 48% of the patients including 12 novel sequence variants, all leading to a frameshift in the C-terminus of the nucleophosmin 1 (NPM1) protein. Mutant NPM1 was associated with specific clinical, phenotypical, and genetic features. Statistical analysis revealed a significant interaction of NPM1 and FLT3 internal tandem duplications (ITDs). NPM1 mutations predicted for better response to induction therapy and for favorable overall survival (OS) only in the absence of FLT3 ITD. Multivariable analysis for OS revealed combined NPM1-mutated/FLT3 ITD–negative status, CEBPA mutation status, availability of a human leukocyte antigen (HLA)–compatible donor, secondary AML, and lactate dehydrogenase (LDH) as prognostic factors. In conclusion, NPM1 mutations in the absence of FLT3 ITD define a distinct molecular and prognostic subclass of young-adult AML patients with normal cytogenetics.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2005-05-2164
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
    detail.hit.zdb_id: 1468538-3
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  • 7
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    In Vitro and In Vivo Monitoring of Valproic Acid Effects on Gene Expression Signatures in Adult Acute Myeloid Leukemia.
    American Society of Hematology ; 2006
    In:  Blood Vol. 108, No. 11 ( 2006-11-16), p. 2605-2605
    Details
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 2605-2605
    Abstract: Inhibitors of histone deacetylases (HDACIs) like valproic acid (VPA) display activity in murine leukemia models, and induce tumor-selective cytoxicity against blasts from patients with acute myeloid leukemia (AML). However, despite of the existing knowledge of the potential function of HDACIs, there remain many unsolved questions especially regarding the factors that determine whether a cancer cell undergoes cell cycle arrest, differentiation, or death in response to HDACIs. Furthermore, there is still limited data on HDACIs effects in vivo, as well as HDACIs function in combination with standard induction chemotherapy, as most studies evaluated HDACIs as single agent in vitro. Thus, our first goal was to determine a VPA response signature in different myeloid leukemia cell lines in vitro, followed by an in vivo analysis of VPA effects in blasts from adult de novo AML patients entered within two randomized multicenter treatment trials of the German-Austrian AML Study Group. To define an VPA in vitro “response signature” we profiled gene expression in myeloid leukemia cell lines (HL-60, NB-4, HEL-1, CMK and K-562) following 48 hours of VPA treatment by using DNA Microarray technology. In accordance with previous studies in vitro VPA treatment of myeloid cell lines induced the expression of the cyclin-dependent kinase inhibitors CDKN1A and CDKN2D coding for p21 and p19, respectively. Supervised analyses revealed many genes known to be associated with a G1 arrest. In all cell lines except for CMK we examined an up-regulation of TNFSF10 coding for TRAIL, as well as differential regulation of other genes involved in apoptosis. Furthermore, gene set enrichment analyses showed a significant down-regulation of genes involved in DNA metabolism and DNA repair. Next, we evaluated the VPA effects on gene expression in AML samples collected within the AMLSG 07-04 trial for younger (age 〈 60yrs) and within the AMLSG 06-04 trial for older adults (age 〉 60yrs), in which patients are randomized to receive standard induction chemotherapy (idarubicine, cytarabine, and etoposide = ICE) with or without concomitant VPA. We profiled gene expression in diagnostic AML blasts and following 48 hours of treatment with ICE or ICE/VPA. First results from our ongoing analysis of in vivo VPA treated samples are in accordance with our cell line experiments as e.g. we also see an induction of CDKN1A expression. However, the picture observed is less homogenous as concomitant administration of ICE, as well as other factors, like e.g. VPA serum levels, might substantially influence the in vivo VPA response. Nevertheless, our data are likely to provide new insights into the VPA effect in vivo, and this study may proof to be useful to predict AML patients likely to benefit from VPA treatment. To achieve this goal, we are currently analyzing additional samples, and we are planning to correlate gene expression findings with histone acetylation status, VPA serum levels, cytogenetic, and molecular genetic data.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V108.11.2605.2605
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2006
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  • 8
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    Disclosure of Copy Number Alterations in AML with Normal Karyotype Using Matrix-Based Comparative Genomic Hybridization.
    American Society of Hematology ; 2005
    In:  Blood Vol. 106, No. 11 ( 2005-11-16), p. 759-759
    Details
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 759-759
    Abstract: Clonal chromosome abnormalities represent one of the most important prognostic factors in adult acute myeloid leukemia (AML), and cytogenetic data are used for risk-adapted treatment strategies. By conventional cytogenetic analysis, approximately 50% of patients lack clonal chromosome aberrations, and normal cytogenetics are associated with an intermediate clinical outcome. This clinically heterogeneous group seems to be in part characterized by molecular markers, such as MLL, FLT3, CEBPA, and NPM1 mutations. In order to identify novel candidate regions of genomic imbalances, we applied comparative genomic hybridization to microarrays (matrix-CGH). Using this high-resolution genome-wide screening approach we analyzed 49 normal karyotype AML cases characterized for the most common clinically relevant molecular markers (MLL-PTD n=13, FLT3-ITD n=7, FLT3-ITD/NPM1+ n=4, MLL-PTD/FLT3-ITD n=3, CEBPA+ n=12, CEBPA+/FLT3-ITD n=1; CEBPA+/NPM1+ n=1; no molecular markers n=8) with a microarray platform consisting of 2799 different BAC or PAC clones. A set of 1500 of these clones covers the whole human genome with a physical distance of approximately 2 Mb. The remaining 1299 clones either contiguously span genomic regions known to be frequently involved in hematologic malignancies (e.g., 1p, 2p, 3q, 7q, 9p, 11q, 12q, 13q, 17p, 18q) (n=600) or contain oncogenes or tumor suppressor genes (n=699). In addition to known copy number polymorphisms in 5q11, 7q22, 7q35, 14q32, and 15q11, the CLuster Along Chromosomes method (CLAC; http://www-stat.stanford.edu/~wp57/CGH-Miner) disclosed copy number alterations (CNAs) in terms of gains in 1p, 11q, 12q, and 17p. CNAs in terms of losses were identified in 9p, 11q, 12p, 12q, and 13q. Two-class supervised analyses using the significance analysis of microarrays (SAM) method identified for the MLL-PTD cases a gain of a single clone harboring the MLL gene. While the significance of these findings, which are currently validated using fluorescence in-situ hybridization (FISH), still remains to be determined, our preliminary results already demonstrate the power and reliablity of this microarray-based technique allowing genome-wide screens of genomic imbalances as the MLL aberration was detected in all cases known to have a MLL-PTD. Furthermore, ongoing correlation of high-resolution genomic profiling with global gene expression studies will help to disclose pathways underlying normal karyotype AML, thereby leading to new insights of leukemogenesis.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V106.11.759.759
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
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  • 9
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    Genetic and Epigenetic Profiling on 7q22 Identifies ATXN7L1 As Candidate Tumor Suppressor in Acute Myelogenous Leukemia
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 1408-1408
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 1408-1408
    Abstract: Abstract 1408 About 10 % of patients with acute myeloid leukemia (AML) present with either monosomy 7 or deletions on the long arm of chromosome 7. This chromosomal aberration is associated with poor prognosis and adverse therapeutic response. Following biallelic inactivation as proposed by Knudsen's hypothesis, a “second hit” of the remaining allele might be required for loss of gene function. So far, no consistent additional genetic hits could be identified in the minimally deleted regions. Thus, epigenetic silencing might display a local alternative mechanism ultimately causing silencing of a potential tumor suppressor. Based on cytogenetic data we defined a minimally deleted region on 7q22.2 of 2–3 Mb in size to narrow down the location of the putative tumor suppressor. It is flanked by the microsatellite markers D7S1503 and D7S1841. We utilized comprehensive DNA methylation profiling in the CpGrich areas of the minimal deleted regions by high resolution DNA methylation assessment by MassARRAY to identify aberrant epigenetic patterns in these regions. In this region we quantitatively analyzed CpG island methylation in a cohort of 64 AML patients with del(7q), 11 with monosomy 7, ten with normal karyotype and five CD34+ bone marrow cell DNA from healthy donors as controls. We identified four genes (PRES, LHFPL3, ATXN7L1, and CDH28) that are hypermethylated in their promoters in this region with significant mean methylation differences from 5 to 20 % comparing AML to healthy controls. Hypermethylation occurred both in patients with chromosome 7 aberrations and in patients with normal karyotypes. To narrow down aberrantly methylated genes to functional relevant candidates, we excluded those that were not expressed in healthy CD34+ cells. ATXN7L1, a gene located on 7q22.2 and coding for a potential subunit of the histone acetyl transferase (HAT) and deubiquitinase SAGA complex, was expressed in healthy CD34+ cells and granulocytes, but downregulated upon hypermethylation ( 〉 30%) in patients. To elucidate a potential functional role of ATXN7L1, we immunopurified SAGA from HeLa cells using antibodies against a SAGA subunit, GCN5,and analyzed the coimmunoprecipated proteins by subsequent mass spectrometry. Based on the identity of the co-precipitated proteins we demonstrate that ATXN7L1 is a bona fide component of the human SAGA complex. Thus our results suggest that ATXNL1 has a similar role as the closely related protein, ATXN7 that is known to be involved in transcription regulation via USP22 dependent deubiquitination of histones. Experiments to understand how ATXN7L1 silencing may affect the leukemic phenotype are in progress. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.1408.1408
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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    detail.hit.zdb_id: 80069-7
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  • 10
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    Analysis of Loss of Heterozygosity in Adult Patients with De Novo Acute Myeloid Leukemia and Normal Karyotype.
    American Society of Hematology ; 2006
    In:  Blood Vol. 108, No. 11 ( 2006-11-16), p. 806-806
    Details
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 806-806
    Abstract: A large proportion of acute myeloid leukemia (AML) exhibits a normal karyotype in which the underlying pathomechanisms still have to be determined. Novel techniques like arrayCGH or single nucleotide polymorphism (SNP) chip analysis allow the identification and characterization of molecular rearrangements at the sub-megabase level. Recently, the application of genome-wide SNP array technology revealed frequent uniparental disomy (UPD) in approximately 20% of AML suggesting that UPD represents a nonrandom event in leukemogenesis. Uniparental disomy is acquired by somatic recombination and therefore not accessible by conventional cytogenetic methods or arrayCGH. In this study we analyzed DNA from AML patients with normal karyotype for the presence of LOH. SNP analysis was performed on the Mapping 100k GeneChip (Affymetrix, Santa Clara, CA). DNA was extracted from paired samples of 56 de novo AML patients with normal karyotype at diagnosis and in complete remission, respectively. Signal intensity data were analyzed by the GCOS GeneChip analysis software and statistical analysis of SNP call data was performed by the dChipSNP software. In addition, standard mutation screening of the genes encoding NPM1, FLT3, CEBPA, MLL and NRAS was performed in all cases. Using the 100k SNP array, a mean SNP call rate of 98.2% was reached, resulting in & gt; 110,000 SNP genotype calls per sample. Signal intensity data analysis revealed submicroscopic chromosomal deletions resulting in hemizygosity in three patients. Patient 1 had a single 2 Mb deletion in chromosomal band 3p14.1, patient 2 had two small deletions affecting chromosome 12q23 and 12p13, the latter encompassing the ETV6 locus, and patient 3 had two small deletions within the long arm of chromosome 8. Besides these small chromosomal regions of copy number alterations, we found 4 large stretches of somatically acquired homozygosity without numeric alterations, affecting chromosome 6 (6p21 to 6 pter and 6q26 to 6 qter), chromosome 11 (11p12 to 11pter) and chromosome 13 (13q11 to 13qter). Noteworthy, in the case with uniparental disomy of chromosome 13, we could detect a homozygous FLT3-ITD mutation, supporting the findings that acquired isodisomy for chromosome 13 is common in AML, and associated with FLT3-ITD mutations (Griffiths et al., Leukemia, 2005). In summary, high resolution SNP assay technology in AML patients with normal karyotype allowed the identification of distinct chromosomal regions affected by UPD, supporting the postulated nonrandom mechanism of acquired mitotic recombination events in AML. Besides known chromosomal regions known to be affected by genomic aberrations in AML, we found additional submicroscopic chromosomal aberrations in cases with normal karyotype. Analysis of larger patient series will allow the identification of novel regions of interest harboring genes that might be involved in the pathogenesis of AML.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V108.11.806.806
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2006
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
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