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  • 1
    Keywords: RECEPTOR ; APOPTOSIS ; EXPRESSION ; SURVIVAL ; Germany ; DISTINCT ; GENE ; GENE-EXPRESSION ; GENES ; ANTIGEN ; cell cycle ; CYCLE ; PROGNOSTIC-FACTORS ; CD38 EXPRESSION ; SUBSET ; GENOMIC ABERRATIONS ; MUTATION STATUS ; ANTIGEN RECEPTORS ; B-CELL RECEPTOR ; EXPRESSION PATTERNS ; APOPTOSIS-ASSOCIATED GENES ; PATHOMECHANISMS
    Abstract: The mutation status and usage of specific VH genes such as V3-21 and V1-69 are potentially independent pathogenic and prognostic factors in chronic lymphocytic leukemia (CLL). To investigate the role of antigenic stimulation, we analyzed the expression of genes involved in B-cell receptor (BCR) signaling/activation, cell cycle, and apoptosis control in CLL using these specific VH genes compared to VH mutated (VH-MUT) and VH unmutated (VH-UM) CLL not using these VH genes. V3-21 cases showed characteristic expression differences compared to VH-MUT (up: ZAP70 [or ZAP-70]; down: CCND2, P27) and VH-UM (down: PI3K, CCND2, P27, CDK4, BAX) involving several BCR-related genes. Similarly, there was a marked difference between VH unmutated cases using the V1-69 gene and VH-UM (up: FOS; down: BLNK, SYK, CDK4, TP53). Therefore, usage of specific VH genes appears to have a strong influence on the gene expression pattern pointing to antigen recognition and ongoing BCR stimulation as a pathogenic factor in these CLL subgroups
    Type of Publication: Journal article published
    PubMed ID: 16322480
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  • 2
    Keywords: CANCER ; INHIBITOR ; SURVIVAL ; ACTIVATION ; MECHANISM ; MELANOMA ; GENOMIC ABERRATIONS ; RAF ; HAIRY-CELL LEUKEMIA ; PLX4032
    Abstract: BRAF mutations have been shown to occur at a high frequency in melanoma and thyroid cancer, but also at lower frequencies in hematological malignancies. To assess the potential role of BRAF, we have sequenced exons 11 and 15 of BRAF in 138 cases with chronic lymphocytic leukemia (CLL) and 32 cases of B-cell prolymphocytic leukemia (B-PLL). We found an incidence of BRAF mutations of 2.8% in CLL (4/138), while no cases with B-PLL showed BRAF mutations. The analysis of a cohort of patients with fludarabine-refractory disease (n = 87) showed no increase in the mutation incidence, suggesting that this mutation is not selected for during the disease progression. A limited analysis of the effect of BRAF inhibition in primary CLL cells showed no cell death induction in CLL samples with and without BRAF mutations. Our analysis suggests that BRAF mutations occur at a low frequency in CLL. The pharmacological inhibition of MEK/ERK signaling using the mutant BRAF inhibitor PLX4720 showed no effect on viability in vitro in CLL cases.
    Type of Publication: Journal article published
    PubMed ID: 23088640
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  • 3
    Keywords: EXPRESSION ; SURVIVAL ; BLOOD ; CELL ; Germany ; GENE ; GENES ; PATIENT ; recombination ; ANTIGEN ; ASSOCIATION ; LYMPHOMA ; DIFFERENCE ; MUTATION ; ABERRATIONS ; DELETIONS ; B-CELLS ; AGGRESSIVE VARIANTS ; ATM GENE ; CD38 EXPRESSION ; CENTROCYTIC LYMPHOMA ; CHROMOSOMAL IMBALANCES ; CHRONIC LYMPHOCYTIC-LEUKEMIA ; COMPLETE REMISSION ; IMMUNOGLOBULIN GENES ; MAJOR TRANSLOCATION CLUSTER ; SOMATIC HYPERMUTATION
    Abstract: Immunoglobulin variable heavy chain gene (V-H) mutation status and VDJ rearrangement structure were analyzed in 141 patients with mantle cell lymphoma (MCL) and correlated with biologic and clinical characteristics; 29% of the MCLs displayed mutated V-H using a 98% germline homology cutoff. Striking differences occurred in the VH mutation subgroups with respect to the use of specific V genes. Rearrangements involving V4-34 and V3-21 were almost exclusively unmutated, whereas rearrangements using V4-59 and V3-23 were typically mutated. Significant association occurred between mutated V-H with shorter CDR3 lengths and the use of J(H)4b. V3-21 and V4-59 were involved in highly characteristic rearrangements, implying that antigen specificity might have been involved in MCL development. There was no evidence for isotype switch recombination or Bcl-6 expression in any MCL. ZAP70 expression was not different in V-H-mutated or unmutated MCL. Although the deletions 11q- and 17p- showed a balanced distribution, an overrepresentation was observed for trisomies +3q, +8q, and tetraploidy in the V-H-unmutated subgroup and +12q in the V-H-mutated subgroup. Clinically, mutated V-H was associated with a higher rate of complete remission, but there was no correlation between VH mutation status and other clinical characteristics or overall survival. (Blood. 2003; 102:3003-3009) (C) 2003 by The American Society of Hematology
    Type of Publication: Journal article published
    PubMed ID: 12842981
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  • 4
    Keywords: EXPRESSION ; tumor ; Germany ; human ; MODEL ; neoplasms ; GENE ; GENE-EXPRESSION ; GENES ; TUMORS ; DNA ; MECHANISM ; DOWN-REGULATION ; MOUSE ; LESIONS ; CHROMATIN ; MUTATION ; leukemia ; DNA methylation ; TUMOR-SUPPRESSOR GENE ; REGION ; MUTATIONS ; REPLICATION ; METHYLATION ; CHRONIC LYMPHOCYTIC-LEUKEMIA ; TUMOR-SUPPRESSOR ; CANDIDATE GENES ; tumor suppressor gene ; LOCUS ; downregulation ; function ; LOSSES ; CANDIDATE ; packaging ; VARIETIES ; retinoblastoma ; TUMOR-SUPPRESSOR GENES ; EXCLUSION ; ASYNCHRONOUS REPLICATION ; CHROMOSOME 13Q14 ; MANTLE-CELL LYMPHOMA ; monoallelic expression ; replication timing
    Abstract: Genomic material from chromosome band 13q14.3 distal to the retinoblastoma locus is recurrently lost in a variety of human neoplasms, indicating an as-yet-unidentified tumor-suppressor mechanism. No pathogenic mutations have been found in the minimally deleted region until now. However, in B cell chronic lymphocytic leukemia tumors with loss of one copy of the critical region, respective candidate tumor-suppressor genes are down-regulated by a factor 〉 2, which would be expected by a normal gene-dosage effect. This finding points to an epigenetic pathomechanism. We find that the two copies of the critical region replicate asynchronously, suggesting differential chromatin packaging of the two copies of 13q14.3. Although we also detect monoallelic silencing of genes localized in the critical region, monoallelic expression originates from either the maternal or paternal copy, excluding an imprinting mechanism. DNA methylation analyses revealed one CpG island of the region to be methylated. DNA demethylation of this CpG island and global histone hyperacetylation induced biallelic expression, whereas replication timing was not affected. We propose that differential replication timing represents an early epigenetic mark that distinguishes the two copies of 13q14.3, resulting in differential chromatin packaging and monoallelic expression. Accordingly, deletion of the single active copy of 13q14.3 results in significant downregulation of the candidate genes and loss of function, providing a model for the interaction of genetic lesions and epigenetic silencing at 13q14.3 in B cell chronic lymphocytic leukemia
    Type of Publication: Journal article published
    PubMed ID: 16684883
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  • 5
    Abstract: Telomere shortening is of pathogenic and prognostic importance in cancers. In the present study, we analyzed telomere length in 73 mantle cell lymphoma (MCL), 55 chronic lymphocytic leukemia (CLL), and 20 normal B-cell samples using quantitative PCR (Q-PCR) to study its association with disease characteristics and outcome. Telomere length was found to be highly variable in MCL (range, 2.2-13.8 kb; median, 4.3 kb). Telomere dysfunction in MCL was evident from comparison with normal B cells (median, 7.5 kb), but had no significant association with any biologic or clinical feature. This was in contrast to CLL, in which a significant correlation of short telomeres with poor prognostic subgroups was confirmed. There was a trend toward an increased number of genomic aberrations with shortening of telomeres in MCL. No difference in survival was observed between the groups with short and long telomeres, indicating that, as opposed to CLL, telomere length is not of prognostic relevance in MCL.
    Type of Publication: Journal article published
    PubMed ID: 23243283
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  • 6
    Keywords: EXPRESSION ; SURVIVAL ; tumor ; Germany ; neoplasms ; GENE ; GENES ; GENOME ; HYBRIDIZATION ; microarray ; SAMPLE ; SAMPLES ; transcription ; ACTIVATION ; DNA ; mechanisms ; TARGET ; STAGE ; IN-SITU ; AMPLIFICATION ; COMPARATIVE GENOMIC HYBRIDIZATION ; LYMPHOMA ; DNA microarray ; microarrays ; ABERRATIONS ; DELETIONS ; POLYMERASE-CHAIN-REACTION ; DNA AMPLIFICATION ; FLUORESCENCE ; gene amplification ; IMBALANCES ; GAINS ; B-CELL LYMPHOMA ; CGH ; matrix-CGH ; DNA COPY-NUMBER
    Abstract: DNA amplifications are important mechanisms for protooncogene activation. Comparative genomic hybridization (CGH) to metaphase chromosome preparations has revealed amplifications in 10-20% of B-cell lymphomas (B-NHL). We analysed a series of 16 aggressive non-Hodgkin lymphomas by the new approach termed Matrix-CGH (M-CGH) using genomic DNA microarrays as hybridization target. For M-CGH, a dedicated B-cell lymphoma chip was constructed containing 496 genomic targets covering oncogenes, tumor suppressor genes as well as chromosome regions frequently altered in B-NHL. In 10 of 16 samples a total of 15 DNA amplifications were identified. The amplicons included BCL2, REL, CCND1, CCND2, JAK2, FGF4 and MDM2. Four of the 15 amplifications remained undetected by chromosomal CGH. The respective amplicons mapped to bands 2p13, 9p13-p21 and 12q24 and, were confirmed by fluorescence in situ hybridization. Furthermore, for four genomically amplified genes real-time quantitative reverse transcription polymerase chain reaction revealed elevated mRNA expression levels. These data show the superior diagnostic sensitivity of the newly developed diagnostic tool. As only a small portion of the genome (approximately 1.5%) has been analysed by the present DNA array, it is likely that gene amplifications are much more common in aggressive lymphomas than previously assumed
    Type of Publication: Journal article published
    PubMed ID: 12618769
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  • 7
    Keywords: SURVIVAL ; CELL ; evaluation ; Germany ; DISEASE ; incidence ; SAMPLE ; SAMPLES ; MOLECULAR CHARACTERIZATION ; TIME ; PATIENT ; INDEX ; prognosis ; DELETION ; NO ; TRIAL ; TRIALS ; IN-SITU ; LYMPHOMA ; DESIGN ; DELETIONS ; REGION ; REGIONS ; EVOLUTION ; INSIGHTS ; fluorescence in situ hybridization ; ATM GENE ; CHROMOSOMAL IMBALANCES ; CHRONIC LYMPHOCYTIC-LEUKEMIA ; MANTLE CELL LYMPHOMA ; HETEROGENEITY ; P53 GENE ; overall survival ; GENOMIC ABERRATIONS ; H MUTATION STATUS ; analysis ; methods ; LOSSES ; correlation ; BLASTOID VARIANTS ; SOMATIC MUTATIONS ; FOLLICLE MANTLE
    Abstract: Background The genetic hallmark of mantle cell lymphoma is a t(11;14)(q13;q32). However, additional genomic alterations are likely involved in the pathogenesis of this lymphoma. Design and Methods To determine the incidence and clinical relevance of these aberrations, we analyzed 103 well-characterized samples of mantle cell lymphoma by fluorescence in situ hybridization for the most common recurrent additional genomic findings. Results Screening 16 different regions we detected additional genomic aberrations in 92% of the cases of mantle cell lymphoma. Common gains included 3q26, 8q24, 15q23, 7p15, and common losses 13q14, 11q22-q23, 9p21, 1p22, 17p13, 6q27, and 8p22. Deletions 8p22, 9p21, 13q14, and gain of 7p15 were associated with evidence of clonal heterogeneity. While there was no correlation of additional genomic aberrations and VH-mutation status, gain of 15q23 and deletion 6q27 were associated with lower disease stage (p=0.01 and p=0.04, respectively). Patients with deletion 13q14 had shorter overall survival times (p=0.01), and there was a strong trend towards inferior outcome in patients with deletion 9p21 (p=0.07). In multivariable analysis, loss of 13q14 and an International Prognosis Index score ! 3 turned out to be significantly associated with inferior clinical outcome (p=0.002 and p〈0.001, respectively). Conclusions The comprehensive analysis of additional genomic aberrations in mantle cell lymphoma provided further evidence for the prognostic relevance of loss of 13q14, which warrants evaluation within prospective trials. Furthermore, our analysis gave novel insights into the pathogenesis of mantle cell lymphoma with regard to the detection of clonal heterogeneity, possibly indicating clonal evolution in this type of lymphoma
    Type of Publication: Journal article published
    PubMed ID: 18367489
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  • 8
    Keywords: CANCER ; Germany ; PATHWAY ; DISEASE ; RISK ; polymorphism ; single nucleotide polymorphism ; HUMANS ; PROMOTER ; leukemia ; NUCLEOTIDE
    Type of Publication: Journal article published
    PubMed ID: 18508789
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  • 9
    Keywords: APOPTOSIS ; CELLS ; EXPRESSION ; IRRADIATION ; CELL ; Germany ; NETWORK ; SUPPORT ; COHORT ; cohort studies ; DISEASE ; PATIENT ; DNA ; MECHANISM ; FAMILY ; INDUCTION ; mechanisms ; MEMBERS ; TARGET ; DELETION ; HUMANS ; resistance ; UP-REGULATION ; MUTATION ; chemotherapy ; leukemia ; inactivation ; p53 ; DAMAGE ; MUTATIONS ; DNA-DAMAGE ; BAX ; TARGETS ; TP53 ; ADULT ; FAMILIES ; CLL ; regulation ; LEVEL ; DNA damage ; female ; Male ; Aged ; Middle Aged ; Aged,80 and over ; TP53 mutation ; 17p deletion ; *Gene Expression Regulation,Leukemic ; Apoptosis Regulatory Proteins/genetics/metabolism ; Apoptosis/radiation effects ; bcl-2-Associated X Protein/genetics/metabolism ; Chromosome Deletion ; Chromosomes,Human,Pair 17/genetics/metabolism ; DNA Damage/radiation effects ; Leukemia,Lymphocytic,Chronic,B-Cell/genetics/*metabolism ; MicroRNAs/*biosynthesis/genetics ; Proto-Oncogene Proteins/genetics/metabolism ; RNA,Neoplasm/*biosynthesis/genetics ; Tumor Cells,Cultured ; Tumor Suppressor Protein p53/genetics/metabolism ; Up-Regulation/radiation effects
    Abstract: 17p (TP53) deletion identifies patients with chronic lymphocytic leukemia (CLL) who are resistant to chemotherapy. The members of the miR-34 family have been discovered to be direct p53 targets and mediate some of the p53-dependent effects. We studied miR-34a and miR-34b/c expression in a large cohort to define their potential role in refractory CLL. While no expression of miR-34b/c could be detected, we found variable expression levels of miR-34a. miR-34a levels were up-regulated after DNA damage in the presence of functional p53, but not in cases with 17p deletion (P 〈 .001). We found a strong correlation of low miR-34a levels with impaired DNA damage response, TP53 mutations (without 17p deletion), and fludarabine-refractory disease (also in the absence of 17p deletion). Up-regulation of miR-34a after irradiation was associated with induction of Bax and p21, but not Puma. CLL cells with reduced miR-34a expression showed increased viability after DNA damage independently of 17p status. Therefore, low expression of miR-34a in CLL is associated with p53 inactivation but also chemotherapy-refractory disease, impaired DNA damage response, and apoptosis resistance irrespective of 17p deletion/TP53 mutation. The elucidation of mechanisms underlying miR-34a regulation and overcoming its role in chemotherapy resistance warrant further study.
    Type of Publication: Journal article published
    PubMed ID: 18941118
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  • 10
    Abstract: Background In chronic lymphocytic leukemia (CLL), a variety of surrogate markers for genetic features and outcome have been described based on gene expression analyses. Previous studies mostly focused on individual markers and selected disease characteristics, which makes it difficult to estimate the relative value of the novel markers. Therefore, in the present study a comprehensive approach was chosen investigating eighteen promising, partly novel expression markers in a well characterized patient cohort with long clinical follow-up and full genetic information (IGHV status, genomic abnormalities). DESIGN AND METHODS: Expression markers were evaluated using real-time quantitative RT-PCR in CD19+ purified samples of 151 patients. Multivariate analyses were performed to test the markers; capability to identify patients at genetic risk and as prognostic markers in the context with established prognosis factors. RESULTS: Regarding individual markers, ZAP70 achieved the highest assignment rate (81%) for patients at genetic risk (IGHV unmutated, V3-21 usage, 11q- or 17p-), followed by LPL and TCF7 (76% both). This rate was improved to 88% by a 4-gene combination (ZAP70, TCF7, DMD, ATM). In multivariate analysis of treatment-free survival, IGHV mutation status and expression of ADAM29 were of independent prognostic value besides disease stage. Regarding overall survival, expression of ATM, ADAM29, TCL1, and SEPT10 provided prognostic information in addition to clinical and genetic factors. Conclusions Gene expression markers are suitable for screening but not as surrogate for genetic risk factors. While many individual markers may be associated with outcome, only few are of independent prognostic significance. Genetic prognostic factors cannot be substituted by the expression markers.
    Type of Publication: Journal article published
    PubMed ID: 19951976
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