GLORIA

GEOMAR Library Ocean Research Information Access

X

Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
  • 1
    Online Resource
    Online Resource
    High Expression of the Endoplasmic Reticulum Protein MZB1 predicts Inferior Prognosis in Chronic Lymphocytic Leukemia, Follicular Lymphoma and Diffuse Large B-Cell Lymphoma and Is Associated with a Unique Gene Expression Profile,
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 3657-3657
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 3657-3657
    Abstract: Abstract 3657 Introduction: The marginal zone B and B1 cell-specific protein (MZB1) was recently described as a key regulator of the secretion of IgM molecules, the control of calcium homeostasis and integrin-mediated adhesion in B-lymphocytes. We recently identified MZB1 gene expression as a novel prognostic factor being part of a highly significant 8 gene expression signature in chronic lymphocytic leukemia (CLL). Since several neoplasm's derive from mature B-lymphocytes and differ in clinical behavior and prognosis, but share unique functions like immunoglobulin production and secretion we asked whether these different diseases share common molecular mechanisms and prognostic factors. Here, we show that MZB1 expression is a novel, strong prognostic factor in a variety of B-cell neoplasm's. Methods: We analyzed 106 previously untreated and 33 relapsed CLL patients by quantitative PCR and correlated the MZB1 gene expression with overall survival (OS), time to treatment (TTT) and known risk factors of CLL. To expand the study on other hematological malignancies we additionally analyzed the public available gene expression data sets of follicular lymphoma (FL; GSE16131; n=184), diffuse large B-cell lymphoma (DLBCL; GSE10846; n=414), multiple myeloma (MM; GSE2658, n=559), and acute myeloid leukemia (AML; GSE12417; n=306). To adjust for clinical variables, multivariate Cox model were fitted to the respective data sets. To identify genes strongly correlated with MZB1 expression levels, we compared the CLL, DLBCL, FL and AML datasets and performed a multistep correlation analysis. Results: High MZB1 expression was a significant parameter of inferior prognosis in previously untreated (OS: HR: 1.63 (CI: 1.14–2.33), p=0.007; TTT: HR: 1.43 (CI: 1.13–1.81), p=0.003) and relapsed CLL patients (OS: not significant; TTT: HR: 1.48 (CI: 1.12–1.95), p=0.005) and was associated with known clinical and molecular parameters including unmutated IGVH status (p 〈 0.001) and advanced Binet stage (Binet A vs. C p=0.001). Thus, due to the high correlation with IGVH status, MZB1 expression remained not an independent factor in multivariate models including both factors. In addition, MZB1 expression was also a predictor of OS in FL (221286_s_at HR: 1.16 (CI: 0.98–1.37) p=0.086; 223565_at: HR: 1.3 (CI: 1.1–1.61) p=0.015) and DLBCL (221286_s_at: HR: 1.17 (CI: 1.06–1.3) p=0.003; 223565_at: HR: 1.21 (CI: 1.08–1.35) p=0.001) but not in other hematologic malignancies like MM or AML. Again, high MZB1 expression levels correlated with prognostic markers in both, FL and DLBCL. However, a multivariate analysis in DLBCL including the International Prognostic Index (IPI), the gene expression subtype of DLBCL and MZB1 expression (continuous) confirmed MZB1 as an independent predictor of OS. Similar results were obtained from a multivariate analysis in follicular lymphoma including MZB1 expression (continuous) and IPI. We also identified genes that closely correlated with MZB1 expression in CLL, FL, DLBCL and AML based on the multistep correlation analysis. We compared the four datasets using these genes and observed that FL, DLBCL, and CLL show stronger similarity to each other than to the AML group. Interestingly, the ratio of probesets positively correlated to MZB1 expression levels to negatively correlated probesets was the highest in the AML group (CLL=3.69; FL=3.4; DLBCL=0.60; AML=78.7). The similarity of the lymphoma subsets was further strengthened by the analysis of the deregulated pathways based on these genes. Among the top seven pathways deregulated only in CLL, FL, and DLBCL were protein processing in endoplasmic reticulum, endocytosis, MAPK signaling pathway and Fc gamma R-mediated phagocytosis. Discussion: In conclusion we discovered a novel prognostic marker that predicted OS in all analyzed malignancies of mature B-cell origin and showed additional prognostic value in multivariate analysis in both, FL and DLBCL. The differential analysis of genes co-expressed with MZB1 further strengthened the prognostic relevance of MZB1 across different mature B-cell diseases. Due to its biological function in neoplasm's of mature B-cell origin and the potential involvement in known oncogenic pathways MZB1 may represent a target for future therapeutic interventions. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.3657.3657
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 2
    Online Resource
    Online Resource
    Copy Number Alteration (CNA) Analysis in Targeted Sequencing Data from Acute Myeloid Leukemia (AML) Patients with Chromosome 9q Deletion
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 1058-1058
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 1058-1058
    Abstract: Whole exome sequencing (WES) or customized gene panel sequencing (GPS) in acute myeloid leukemia (AML) is commonly used to detect point mutations and small insertions/deletions that might contribute to leukemogenesis. Beyond sequence variant detection, targeted sequencing also allows to detect gain or loss of genomic material in tumor cells (i.e. copy number alteration; CNA) based on the comparison of sequence coverage in target regions between samples. This approach allows not only for the detection of whole chromosome aneuploidies but also submicroscopic deletions or amplifications affecting small regions of the genome. We selected cytogenetically well characterized AML patients with partial deletions of the long arm of chromosome 9 (AML del(9q), n=5) and performed WES at diagnosis and at complete remission (SureSelect, Agilent; Illumina paired-end sequencing). At least 75% of the target region was sequenced with coverage ≥ 10x. As state of the art method for CNA detection, we also performed SNP array profiling (Affymetrix) of the 5 diagnostic AML samples. In addition, we performed GPS of 140 genes (total target 492 kb; mean coverage 356x, range 112-995x; targets on chromosome 9 with mean coverage 275x, range 71-705x) in the diagnostic samples from 26 cases of AML del(9q) (including the 5 exome cases) and 21 AML patients without any detectable cytogenetic aberration on chromosome 9 (control cohort). Our custom gene panel (Haloplex, Agilent) included known mutational targets in AML and candidate genes located on 9q. We used a linear regression model to normalize the mean read count of exon regions for target enrichment efficiency and to model the test sample coverage as a linear function of the control sample coverage (Rigaill et al., 2012, Bioinformatics). This approach is able to deal with regions of zero coverage, monoallelic deletions and tolerates outliers. An exact segmentation algorithm was applied to each chromosome individually in order to separate regions of equivalent exon coverage from regions of different exon coverage between test and control samples. Thereby, regions of genomic alterations can be defined as well as ranges for the flanking breakpoints. We defined a maximum of 5 regions per chromosome and a minimum size of 2 exons per region. For WES analysis, diagnostic AML del(9q) data sets were used as test samples and matching remission data sets were used as control. The minimum mean exon coverage was set to 10x. For custom GPS analysis, the minimum coverage was set to 50x and each AML del(9q) patient was compared to each control patient. Only chromosome 9 was included in the analysis, as patients of the control cohort harbor additional alterations on other chromosomes. CNAs were defined as regions that differ from the majority of control samples. Overlapping CNAs of AML del(9q) patients were subsequently identified as common altered regions. CNA profiling based on WES data sets of AML del(9q) patients showed somatically acquired stretches of significantly reduced read counts for genes located on 9q in 2 of the 5 patients (Figure 1A), consistent with the corresponding SNP array results. CNA profiling based on GPS from 26 AML del(9q) patients and 21 control patients defined a common deleted region ranging from at least 79.2 Mb to 87.6 Mb (Figure 1B). The deletion was detected in 18 out of 26 (70%) of the AML del(9q) patients. Neither the comparison of the test samples to each other nor the comparison of the control samples to each other resulted in CNA calling. It is very likely that the varying clone size harboring the 9q deletion in the diagnostic samples is limiting for CNA detection. This is also supported by the observation that patients without detectable 9q deletion in our CNA analyses tended to have fewer metaphases with 9q deletion (median 27%, range 8-77%) compared to patient samples with detectable 9q deletion in the CNA analyses (median 95%, range 24-100%; p = 0.001), as reported by routine cytogenetics. Our study confirms that, despite the experimental variability of target enrichment, sequencing data can be efficiently used not only to identify somatic mutations with single nucleotide resolution, but also to detect recurring and/or somatic CNAs in AML. Similar to CNA detection by SNP array analysis, the clonal architecture of the tumor is limiting for sensitivity. However, this limitation might be overcome by increasing the read depth. Figure 1: Figure 1:. Detection of del(9q) in WES (A) and GPS data sets (B) Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.1058.1058
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 3
    Online Resource
    Online Resource
    PS29MRC - a Novel Predictive Score for Response to Therapy in Acute Myeloid Leukemia
    American Society of Hematology ; 2016
    In:  Blood Vol. 128, No. 22 ( 2016-12-02), p. 1209-1209
    Details
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 1209-1209
    Abstract: About 20-25% of patients with Acute Myeloid Leukemia (AML) have primary drug resistant disease and fail to achieve complete remission after induction therapy. These patients have an extremely poor prognosis and cannot reliably be identified prior to therapy with current methods. The aim of this work was to develop a predictive tool that can identify therapy resistant patients with high accuracy at the time of diagnosis. We used two independent Affymetrix gene expression (GE) data sets and standard molecular and clinical variables to develop a predictive score for response to cytarabine/anthracycline-based induction chemotherapy. The "training set 1" consisted of 407 adult AML patients enrolled in the AMLCG-1999 trial (GSE37642). Training set 2 included 449 adults treated in various HOVON trials (GSE6891). GE-based classifiers for primary treatment resistance were developed in training set 1 using a penalized logistic regression approach (Lasso). A cut off with a specificity of 90% was predefined in training set 1. Training set 2 was used to select the best classifier. The predictive score and cut off were then validated in a third, fully independent data set, comprising 260 patients enrolled in AMLCG-1999 and 2008 trials studied by RNA sequencing. Additionally, targeted amplicon sequencing data for 68 recurrently mutated genes in AML was available for training set 1 and the validation set. The final classifier (Predictive score 29 MRC - PS29MRC) consisted of 29 gene expression values and the cytogenetic risk group (defined according to the United Kingdom Medical Research Council (MRC) classification) and was calculated as a weighted sum of Lasso coefficients and predictor values. PS29MRC was a highly significant predictor of resistant disease in the validation set with an odds ratio of 2.32 (p=1.53x10-8, AUC: 0.75). We tested the signature in a multivariable model including all variables with univariate p-value & lt;0.05. TP53 mutations, age and PS29MRC (OR: 1.70; p=0.0020) were left significant in the validation set. In comparison to published predictive classifiers like the model by Walter et al. (integrating information on age, performance status, white blood cell count, platelet count, bone marrow blasts, gender, type of AML, cytogenetics and NPM1 and FLT3-ITD status; OR: 1.27; p=0.00083; AUC: 0.70) or the modified molecular version of this score (OR: 1.37; p=0.0027; AUC: 0.63) PS29MRC reached superior predictive accuracy. (Walter et al.; Leukemia 2015) Since we aimed to develop a clinically useful score, we categorized PS29MRC to distinguish between patients who have a high probability of refractory disease and those who are likely to benefit from induction therapy (complete remission or complete remission with incomplete hematologic recovery). By applying the predefined cut off, we were able to reach a specificity of 90% and sensitivity of 46% in the validation set (OR: 7.83; p=6.06x10-9). The accuracy of PS29MRC was 77%. In the multivariable model the categorized classifier was highly significant (OR: 4.45; p=0.00040) and only age and TP53 mutations were left as significant variables again. Within the cytogenetic subgroups favorable (n=14; refractory: n=0; responders: n=13), intermediate (n=189; refractory: n=43; responders: n=136) and adverse (n=49; refractory: n=29; responders: n=15) the classifier showed an accuracy of 100%, 78% and 66%, respectively. Furthermore, the classifier predicted survival and was able to unravel the intermediate MRC subgroup (Figure). Additionally, genes included in our predictive signature seem to be involved in AML pathogenesis and potentially actively contribute to mechanisms responsible for primary therapeutic resistance. For example MIR-155HG, an already known parameter of inferior outcome in AML, contributed significantly to PS29MRC. There are currently ongoing trials with the novel inhibitor Pevonedistat that aim to modulate this target in AML. In summary we were able to develop a predictive risk classifier summarizing 29 gene expression values and the MRC classification that outperformed all currently used methods to predict refractory disease in intensively treated adult AML patients. PS29MRC demonstrates that it is possible to identify patients at risk of treatment failure in AML at diagnosis with high specificity. Figure 1. Kaplan-Meier estimates showing overall survival of AML patients in the validation set according to PS29MRC Figure 1. Kaplan-Meier estimates showing overall survival of AML patients in the validation set according to PS29MRC Figure 2. Figure 2. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V128.22.1209.1209
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 4
    Online Resource
    Online Resource
    An 86-Probe Gene Expression Signature Can Predict Survival in AML with Normal Karyotype Independently of FLT3 ITD and NPM1 Mutation Status - A Collaborative Study from the AMLCG and CALGB Study Groups.
    American Society of Hematology ; 2007
    In:  Blood Vol. 110, No. 11 ( 2007-11-16), p. 596-596
    Details
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 596-596
    Abstract: Patients with acute myeloid leukemia and a normal karyotype (NK AML) comprise 50% of all AML cases and show heterogeneous treatment outcomes and survival. We used gene expression profiling to develop a prognostic gene signature that predicts survival in this clinically relevant AML subgroup. Our analysis was based on data from 163 patients with newly diagnosed NK AML treated in the German multicenter AMLCG 2000 trial, for whom pretreatment gene expression profiles were obtained using Affymetrix HG-U133 microarrays. We used supervised principal component analysis to identify 86 oligonucleotide probesets (corresponding to 66 different genes and ESTs) that were correlated with overall survival (OS), and to define a prognostic score based on these probesets. When applied to an independent test cohort of 79 NK AML cases from the same AMLCG trial, the continuous prognostic score was predictive of OS (P=0.002, hazard ratio [HR] for a change in prognostic score equal to the difference between the 75th and 25th percentiles of the score = 1.94) and event-free survival (EFS) (P = 0.001, HR=1.70). The score based on our gene signature showed a strong correlation with the presence of the FLT3 internal tandem duplication (ITD), but retained its prognostic value for OS in the test cohort even after adjustment for FLT3 ITD, NPM1 status and age (P=0.037, HR=1.65). When we defined a cut-off value in the training population and used it to dichotomize the gene expression score values in the test cohort, the resulting two subgroups had significantly different OS (median, 259 days vs. not reached, P=0.002) and event-free survival (EFS) (median, 72 vs. 300 days, P = 0.015). We subsequently confirmed our findings in a group of 64 NK AML patients (Blood2006;108:1677–83) treated on CALGB 9621. In this validation cohort, our continuous gene expression score was predictive of OS (P 〈 0.001, HR=4.11) and EFS (P 〈 0.001, HR=2.90). In multivariate analyses that adjusted for age, NPM1 and FLT3 ITD status, the gene expression score remained significant for OS (P = 0.007, HR=3.40). When we used the prognostic score to split the CALGB validation cohort into two groups, based on the same cut-off value as in the AMLCG test population, the two resulting subgroups differed in their OS (median, 375 days vs. not reached, P 〈 0.001) and EFS (median, 258 vs. 728 days, P = 0.027). In summary, we present a novel and robust gene expression signature that offers independent prognostic information for patients with normal karyotype AML.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V110.11.596.596
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 5
    Online Resource
    Online Resource
    Detection of Chromosomal Aberrations in Acute Myeloid Leukemia By Copy Number Alteration Analysis of Exome Sequencing Data
    American Society of Hematology ; 2015
    In:  Blood Vol. 126, No. 23 ( 2015-12-03), p. 3859-3859
    Details
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 3859-3859
    Abstract: Exome sequencing is widely used and established to detect tumor-specific sequence variants such as point mutations and small insertions/deletions. Beyond single nucleotide resolution, sequencing data can also be used to identify changes in sequence coverage between samples enabling the detection of copy number alterations (CNAs). Somatic CNAs represent gain or loss of genomic material in tumor cells like aneuploidies (e.g. monosomies and trisomies), duplications, or deletions. In order to test the feasibility of somatic CNA detection from exome data, we analyzed 13 acute myeloid leukemia (AML) patients with known cytogenetic alterations detected at diagnosis (n=8) and/or at relapse (n=11). Corresponding remission exomes from all patients were available as germline controls resulting in 19 comparisons of paired leukemia and remission exome data sets. Exome sequencing was performed on a HiSeq 2500 instrument (Illumina) with mean target coverage of 〉 100x. Exons with divergent coverage were detected using a linear regression model on mean exon coverage, and CNAs were called by an exact segmentation algorithm (Rigaill et al. 2012, Bioinformatics). For all samples, cytogenetic information was available either form routine chromosomal analysis or fluorescent in situ hybridization (FISH). Blast count were known for all but one AML sample (n=19). Copy number-neutral cytogenetic alterations such as balanced translocations were excluded from the comparative analysis. By CNA-analysis of exomes we were able to detect chromosomal aberrations consistent with routine cytogenetics in 18 out of 19 (95%) AML samples. In particular, we confirmed 2 out of 2 monosomies (both -7), and 9 out of 10 trisomies (+4, n=1; +8, n=8; +21, n=1), e.g. trisomy 8 in figure 1A. Partial amplifications or deletions of chromosomes were confirmed in 10 out of 10 AML samples (dup(1q), n=3; dup(8q), n=1; del(5q), n=3; del(17p), n=1; del(20q), n=2), e.g. del(5q) in figure 1B. In the one case with inconsistent findings of chromosomal aberrations between exome and cytogenetic data there was a small subclone harboring the alteration described in only 4 out of 21 metaphases (19%). To assess the specificity of our CNA approach, we analyzed the exomes of 44 cytogenetically normal (CN) AML samples. Here we did not detect any CNAs larger than 5 Mb in the vast majority of these samples (43/44, 98%), only one large CNA was detected indicating a trisomy 8. Estimates of the clone size were highly correlated between CNA-analysis of exomes and the parameters from cytogenetics and cytomorphology (p=0.0076, Fisher's exact test, Figure 1C). In CNA-analysis of exomes, we defined the clone size based on the coverage ratio: . Clone size estimation by cytogenetics and cytomorphology was performed by calculating the mean of blast count and abnormal metaphase/interphase count. Of note, clones estimated by CNA-analysis of exomes tended to be slightly larger. This may result from purification by Ficoll gradient centrifugation prior to DNA extraction for sequencing and/or the fact that the fraction of cells analyzed by cytogenetics does not represent the true size of the malignant clone accurately because of differences in the mitotic index between normal and malignant cells. Overall, there was a high correlation between our CNA analysis of exome sequencing data and routine cytogenetics including limitations in the detection of small subclones. Our results confirm that high throughput sequencing is a versatile, valuable, and robust method to detect chromosomal changes resulting in copy number alterations in AML with high specificity and sensitivity (98% and 95%, respectively). Figure 1. (A) Detection of trisomy 8 with an estimated clone size of 100% (B) Detection of deletion on chromosome 5q with an estimated clone size of 90% (C) Correlation of clone size estimation by routine diagnostics and exome sequencing (p=0.0076) Figure 1. (A) Detection of trisomy 8 with an estimated clone size of 100%. / (B) Detection of deletion on chromosome 5q with an estimated clone size of 90%. / (C) Correlation of clone size estimation by routine diagnostics and exome sequencing (p=0.0076) Figure 2. Figure 2. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V126.23.3859.3859
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 6
    Online Resource
    Online Resource
    BCR-ABL1-like Acute Lymphoblastic Leukemia Is Associated with IKZF1 and JAK2 Alterations and inferior Outcome in Adults
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 3787-3787
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 3787-3787
    Abstract: Background: BCR-ABL1-like (Ph-like) B-precursor acute lymphoblastic leukemia (ALL) displays a gene expression profile closely related to B-precursor ALL with t(9;22)(q34;q11). In addition, Ph-like ALL patients (pts) are characterized by distinct genetic alterations and inferior prognosis in pediatric trials. The purpose of this study was the genetic and clinical characterization of Ph-like ALL in adults. Methods: Affymetrix gene expression profiles (GEP) generated from diagnostic bone marrow samples of 306 adult B-precursor and T-ALL pts (median age 41 years, range 16-84 years) were classified as Ph-like ALL according to published algorithms (Roberts et al., Cancer Cell 2012) and separated from BCR-ABL1-positive and B-other ALL pts (BCR-ABL1-negative; non Ph-like). The incidence and genetic characteristics of the Ph-like subset were analyzed in the overall cohort, whereas clinical and outcome analysis were restricted to B-precursor ALL pts treated within GMALL trials 06/99 and 07/03 (n=107). The median age of this population was 30 (16-64) years. The routine diagnostic work-up included immunophenotyping, fluorescent in situ hybridization (FISH) for BCR-ABL1 and KMT2A (MLL) rearrangements, cytogenetics and molecular analyses of BCR-ABL1 translocations and MLL rearrangements. A subgroup of pts with B-precursor ALL was analyzed for CRLF2 alterations by FISH (n=88) and by RT-PCR for the P2RY8-CRLF2 translocation (n=117). Multiplex ligation-dependent probe amplification (MLPA) for common copy number variations (SALSA MLPA probemix P335-B1) and targeted amplicon sequencing of 131 genes recurrently mutated in ALL were performed in BCR-ABL1 positive (n=30), Ph-like (n=16) and B-other ALL pts (n=23). Results: Of the 306 pts, we classified 26 pts (9%) as Ph-like ALL based on their GEP and the absence of the BCR-ABL1 translocation, corresponding to an incidence of 13% (26/207) in B-precursor ALL and 24% (26/110) among BCR-ABL1-negative B-precursor ALL. Nineteen of 107 B-precursor ALL pts treated within the GMALL trials displayed a Ph-like phenotype. There were no significant differences in baseline characteristics like age, sex, white-cell count, hemoglobin or platelet count and risk group in comparison to the B-other subgroup (n=51). All 19 Ph-like pts showed no MLL rearrangement and 58% belonged to the standard risk group. The complete remission rate after induction was similar for Ph-like and B-other pts (96% vs 100%; p 〉 0.05). At 5 years, the Ph-like ALL subgroup had a lower probability of continuous complete remission (RD: 24% vs 63%; p=0.004) and overall survival (OS: 22% vs 56%; p=0.05) compared to B-other ALL pts. After exclusion of pts with MLL rearrangement from the B-other group (n=11), these differences remained significant (RD: 24% vs 62%; p 〈 0.001; OS: 22% vs 64%; p=0.006). MLPA and amplicon sequencing revealed specific genetic alterations associated with the Ph-like ALL subgroup (Figure 1). All pts with IGH-CRLF2 (n=6) were identified in the Ph-like subgroup, whereas all pts with P2RY8-CRLF2 (n=2) were found in the B-other group (p 〈 0.001 and p 〉 0.05, respectively). Additionally, most pts with high CRLF2 expression clustered in the Ph-like ALL subgroup (13/26, 50% vs 8/79, 10% of B-other; p 〈 0.001). Deletions of IKZF1 were significantly more common in Ph-like ALL (13/16, 81%; p=0.003) and in BCR-ABL1 positive ALL (21/30, 70%; p=0.005) in contrast to B-other ALL (7/21, 30%). Mutations in JAK2 were exclusively found in the Ph-like subgroup (0/53, 0% vs 7/16, 44%; p 〈 0.001). In our data set, FISH for IGH-CRLF2 and sequencing of JAK2 was sufficient to identify Ph-like cases with a sensitivity and specificity of 59% and 100%, respectively. Conclusion: Ph-like ALL in adults is associated with inferior survival in a homogenously treated group of pts. Additionally, molecular analysis revealed distinct genetic alterations identifying this specific ALL subtype. Since gene expression analysis could be difficult to be implemented in routine diagnostics our data suggest, that testing for JAK2 mutations and the IGH-CRLF2 translocation could be options for the diagnosis of the Ph-like subtype. Future treatment strategies should be explored to improve the dismal prognosis for these high risk pts. Figure 1: Distribution of common mutations and deletions in adult B-precursor ALL Figure 1:. Distribution of common mutations and deletions in adult B-precursor ALL Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.3787.3787
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 7
    Online Resource
    Online Resource
    An 86-probe-set gene-expression signature predicts survival in cytogenetically normal acute myeloid leukemia
    American Society of Hematology ; 2008
    In:  Blood Vol. 112, No. 10 ( 2008-11-15), p. 4193-4201
    Details
    In: Blood, American Society of Hematology, Vol. 112, No. 10 ( 2008-11-15), p. 4193-4201
    Abstract: Patients with cytogenetically normal acute myeloid leukemia (CN-AML) show heterogeneous treatment outcomes. We used gene-expression profiling to develop a gene signature that predicts overall survival (OS) in CN-AML. Based on data from 163 patients treated in the German AMLCG 1999 trial and analyzed on oligonucleotide microarrays, we used supervised principal component analysis to identify 86 probe sets (representing 66 different genes), which correlated with OS, and defined a prognostic score based on this signature. When applied to an independent cohort of 79 CN-AML patients, this continuous score remained a significant predictor for OS (hazard ratio [HR] , 1.85; P = .002), event-free survival (HR = 1.73; P = .001), and relapse-free survival (HR = 1.76; P = .025). It kept its prognostic value in multivariate analyses adjusting for age, FLT3 ITD, and NPM1 status. In a validation cohort of 64 CN-AML patients treated on CALGB study 9621, the score also predicted OS (HR = 4.11; P 〈 .001), event-free survival (HR = 2.90; P 〈 .001), and relapse-free survival (HR = 3.14, P 〈 .001) and retained its significance in a multivariate model for OS. In summary, we present a novel gene-expression signature that offers additional prognostic information for patients with CN-AML.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2008-02-134411
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 8
    Online Resource
    Online Resource
    Acute Myeloid Leukemia With Isolated Trisomy 13 Is a Genetically Homogenous Entity With a High Frequency Of Mutations In Genes Encoding Components Of The Splicing Machinery and Extremely Poor Prognosis
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 608-608
    Details
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 608-608
    Abstract: Acute myeloid leukemia (AML) with isolated trisomy 13 (AML+13) is rare and frequently associated with FAB M0 morphology. The clinical course is not well characterized but according to the ELN classification of intermediate prognosis. Eighty to one-hundred percent of patients (pts) with AML+13 carry mutations in the RUNX1 gene. Over-expression of FLT3 (located on chromosome 13 [chr 13]) due to the additional gene copy on the third chr 13 was proposed as a mechanism of leukemogenesis in AML+13 (gene dosage hypothesis). We set out to characterize the clinical course of AML+13 pts and elucidate their molecular background using whole exome sequencing, targeted resequencing and gene expression profiling. We identified 23 pts with AML+13 enrolled in a multicenter trial of the German AML Cooperative Group (AMLCG-1999) and compared this group to 386 pts without +13 who were classified in the ELN Intermediate-II genetic category. All pts received intensive induction chemotherapy. There was no significant difference in age, white blood cell or platelet count between the two groups. However, LDH levels were significantly (p=.01) lower in the AML+13 group while bone marrow blast percentage was significantly higher (p=.04). Twelve AML+13 pts (52%) reached complete remission, but all relapsed. Relapse-free and overall survival were inferior in the AML+13 group compared to other ELN Intermediate-II pts (median RFS, 9 vs 15 months, p=.01; median OS, 7 vs. 13 months, p=.03). Remission samples from two AML+13 pts were available as normal control for exome sequencing. Using SureSelect human all exon target enrichment (Agilent) followed by 80bp paired-end sequencing on an Illumina GAIIx platform, we were able to identify non-synonymous leukemia-specific mutations affecting, among others, RUNX1, ASXL1, PTPN11 and CEBPZ. Genes identified by exome sequencing and a panel of genes recurringly mutated in AML were studied by targeted amplicon resequencing in all AML+13 pts with available material (16/23; Figure). As described before, a high incidence of RUNX1 mutations (75%) was identified. In addition, we detected mutations in spliceosome components in 14/16 (88%) of AML+13 pts, including SRSF2 codon 95 mutations in 13/16 pts (81%). One patient without SRSF2 mutation showed a mutation in SF3B1. Moreover, recurring mutations were found in ASXL1 (44%) and BCOR (25%), and were associated with RUNX1 and SRSF2 mutations. Interestingly, both pts without mutations in the splicing machinery had mutations in DNMT3A, which were also mutually exclusive with mutations in RUNX1 or ASXL1. Two pts carried mutations in CEBPZ suggesting that CEBPZ is a novel recurringly mutated gene in AML.FigureMutation frequencies in 16 patients with AML+13Figure. Mutation frequencies in 16 patients with AML+13 To further characterize this genetically homogenous subgroup, we compared gene expression profiles of 9 pts with AML+13 with 509 AML pts without +13. We identified 678 (up-regulated 492; down-regulated 186) probe sets as significantly deregulated. Only 59 (8.7%) of these probe sets were localized on chr 13, but of those, 55 were up-regulated and only 4 were down-regulated. Up-regulated probe sets on chr 13 included FOXO1, FLT3 and RB1. The strongest down-regulated probe set on chr 13 belonged to the tumor suppressor gene SPRY2, which is a negative regulator of receptor tyrosine kinases. Gene set enrichment analysis showed significant deregulation of gene sets associated with regulation of transcription and nuclear transport. In summary, our study is the first to show that AML+13 is significantly associated with inferior OS and RFS compared to other intermediate-risk cytogenetic abnormalities in a homogeneously treated cohort. Furthermore, we present evidence that AML+13 leukemias are a genetically quite homogenous subgroup. AML+13 is not only associated with a high rate of RUNX1 mutations but also with mutations in SRFS2, ASXL1 and BCOR. The incidence of mutations in SRSF2 in AML+13 is the highest of any AML subgroup reported so far. In addition, our gene expression data show a homogenous expression profile associated with AML+13. The striking association of a few recurring mutations in AML+13 suggests a biological relationship with synergistic lesions during leukemogenesis. While mutations in RUNX1, ASXL1 and up-regulation of FLT3 were previously reported as markers of poor prognosis in AML, the combination of these lesions might be responsible for the extremely poor outcome of AML+13. Disclosures: Krebs: Illumina: Honoraria. Greif:Illumina: Honoraria.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.608.608
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 9
    Online Resource
    Online Resource
    Isolated trisomy 13 defines a homogeneous AML subgroup with high frequency of mutations in spliceosome genes and poor prognosis
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 8 ( 2014-08-21), p. 1304-1311
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 8 ( 2014-08-21), p. 1304-1311
    Abstract: AML patients with isolated trisomy 13 have a very poor clinical outcome Isolated trisomy 13 in AML is associated with a high frequency of mutations in SRSF2 (81%) and RUNX1 (75%)
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2013-12-540716
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 10
    Online Resource
    Online Resource
    A clinically applicable gene expression–based score predicts resistance to induction treatment in acute myeloid leukemia
    American Society of Hematology ; 2021
    In:  Blood Advances Vol. 5, No. 22 ( 2021-11-23), p. 4752-4761
    Details
    In: Blood Advances, American Society of Hematology, Vol. 5, No. 22 ( 2021-11-23), p. 4752-4761
    Abstract: Prediction of resistant disease at initial diagnosis of acute myeloid leukemia (AML) can be achieved with high accuracy using cytogenetic data and 29 gene expression markers (Predictive Score 29 Medical Research Council; PS29MRC). Our aim was to establish PS29MRC as a clinically usable assay by using the widely implemented NanoString platform and further validate the classifier in a more recently treated patient cohort. Analyses were performed on 351 patients with newly diagnosed AML intensively treated within the German AML Cooperative Group registry. As a continuous variable, PS29MRC performed best in predicting induction failure in comparison with previously published risk models. The classifier was strongly associated with overall survival. We were able to establish a previously defined cutoff that allows classifier dichotomization (PS29MRCdic). PS29MRCdic significantly identified induction failure with 59% sensitivity, 77% specificity, and 72% overall accuracy (odds ratio, 4.81; P = 4.15 × 10−10). PS29MRCdic was able to improve the European Leukemia Network 2017 (ELN-2017) risk classification within every category. The median overall survival with high PS29MRCdic was 1.8 years compared with 4.3 years for low-risk patients. In multivariate analysis including ELN-2017 and clinical and genetic markers, only age and PS29MRCdic were independent predictors of refractory disease. In patients aged ≥60 years, only PS29MRCdic remained as a significant variable. In summary, we confirmed PS29MRC as a valuable classifier to identify high-risk patients with AML. Risk classification can still be refined beyond ELN-2017, and predictive classifiers might facilitate clinical trials focusing on these high-risk patients with AML.
    Type of Medium: Online Resource
    ISSN: 2473-9529 , 2473-9537
    URL: Article
    DOI: 10.1182/bloodadvances.2021004814
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2021
    detail.hit.zdb_id: 2876449-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...