Jürgen Krauter
Research interests
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InterestsLeukemia, AML, Hematopoietic Stem Cells
Publications
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4.60Impact points
ID1 expression associates with other molecular markers and is not an independent prognostic factor in cytogenetically normal acute myeloid leukaemia.
British journal of haematology. 05/2012;
In acute myeloid leukaemia with normal karyotype (CN-AML), gene mutations (e.g. NPM1, FLT3, CEBPA ) as well as deregulated gene expression affect outcome. High expression of ID1 was described as a negative prognostic factor. We have shown that CEBPA regulates ID1 expression. Therefore, we analysed t... [more] In acute myeloid leukaemia with normal karyotype (CN-AML), gene mutations (e.g. NPM1, FLT3, CEBPA ) as well as deregulated gene expression affect outcome. High expression of ID1 was described as a negative prognostic factor. We have shown that CEBPA regulates ID1 expression. Therefore, we analysed the prognostic impact of ID1 expression in 269 patients (aged 16-60 years) with CN-AML in the context of other molecular markers, particularly CEBPA mutations. ID1 (high) status was an independent negative prognostic factor for overall survival (OS) in multivariate analysis when analysed together with age, extramedullary disease, platelets, expression of BAALC and WT1, FLT3-internal tandem duplication, NPM1, WT1 single nucleotide polymorphism rs16754 and IDH1. ID1 expression was higher in CEBPA wildtype patients than in patients with monoallelic CEBPA mutations and these patients showed higher ID1 expression compared to patients with biallelic CEBPA mutations. Thus, when CEBPA mutations were considered, ID1 expression lost its prognostic impact. Likewise, the negative impact of ID1 (high) status on relapse-free survival (RFS) was lost when CEBPA mutations were included in the analysis. In CEBPA wildtype patients, ID1 expression had no impact on complete remission-rate, OS or RFS. In conclusion, CEBPA mutations seem to deregulate ID1 expression. Therefore, ID1 expression is not an independent prognostic factor in CN-AML.
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2.92Impact points
Prognostic significance of combined MN1, ERG, BAALC, and EVI1 (MEBE) expression in patients with myelodysplastic syndromes.
Annals of hematology. 04/2012;
Overexpression of MN1, ERG, BAALC, and EVI1 (MEBE) genes in cytogenetically normal acute myeloid leukemia (AML) patients is associated with poor prognosis, but their prognostic effect in patients with myelodysplastic syndromes (MDS) has not been studied systematically. Expression data of the four ge... [more] Overexpression of MN1, ERG, BAALC, and EVI1 (MEBE) genes in cytogenetically normal acute myeloid leukemia (AML) patients is associated with poor prognosis, but their prognostic effect in patients with myelodysplastic syndromes (MDS) has not been studied systematically. Expression data of the four genes from 140 MDS patients were combined in an additive score, which was validated in an independent patient cohort of 110 MDS patients. A high MEBE score, defined as high expression of at least two of the four genes, predicted a significantly shorter overall survival (OS) (HR 2.29, 95 % CI 1.3-4.09, P = .005) and time to AML progression (HR 4.83, 95 % CI 2.01-11.57, P < .001) compared to a low MEBE score in multivariate analysis independent of karyotype, percentage of bone marrow blasts, transfusion dependence, ASXL1, and IDH1 mutation status. In a validation cohort of 110 MDS patients, a high MEBE score predicted shorter OS (HR 1.77; 95 % CI 1.04-3.0, P = .034) and time to AML progression (HR 3.0, 95 % CI 1.17-7.65, P = .022). A high MEBE expression score is an unfavorable prognostic marker in MDS and is associated with an increased risk for progression to AML. Expression of the MEBE genes is regulated by FLI1 and c-MYC, which are potential upstream targets of the MEBE signature.
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3.86Impact points
Next-generation sequencing for minimal residual disease monitoring in acute myeloid leukemia patients with FLT3-ITD or NPM1 mutations.
Genes, chromosomes & cancer. 03/2012;
Systematic assessment of minimal residual disease (MRD) in acute myeloid leukemia (AML) patients has been hampered by lack of a reliable, uniform MRD marker applicable to all patients. We evaluated next-generation sequencing (NGS) for MRD assessment in AML patients (n = 80 samples). The ability of N... [more] Systematic assessment of minimal residual disease (MRD) in acute myeloid leukemia (AML) patients has been hampered by lack of a reliable, uniform MRD marker applicable to all patients. We evaluated next-generation sequencing (NGS) for MRD assessment in AML patients (n = 80 samples). The ability of NGS technologies to generate thousands of clonal sequences makes it possible to determine the allelic ratio of sequence variants. Using NGS, we were able to determine the allelic ratio of different FLT3-internal tandem duplication (ITD) clones within one patient sample, in addition to resolution of FLT3-ITD insertion site, length, and sequence in a single analysis. Furthermore, NGS allowed us to study emergence of clonal dominance. Parallel assessment of MRD by NGS and quantitative real-time polymerase chain reaction in NPM1 mutated patients was concordant in 95% of analyzed samples (n = 38). The frequency of mutated alleles was linearly quantified by NGS. As NGS sensitivity is scalable depending on sequence coverage, it reflects a highly flexible and reliable tool to assess MRD in leukemia patients. © 2012 Wiley Periodicals, Inc.
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10.56Impact points
High-resolution genomic profiling of adult and pediatric core-binding factor acute myeloid leukemia reveals new recurrent genomic alterations.
Blood. 03/2012; 119(10):e67-75.
To identify cooperating lesions in core-binding factor acute myeloid leukemia, we performed single-nucleotide polymorphism-array analysis on 300 diagnostic and 41 relapse adult and pediatric leukemia samples. We identified a mean of 1.28 copy number alterations per case at diagnosis in both patient ... [more] To identify cooperating lesions in core-binding factor acute myeloid leukemia, we performed single-nucleotide polymorphism-array analysis on 300 diagnostic and 41 relapse adult and pediatric leukemia samples. We identified a mean of 1.28 copy number alterations per case at diagnosis in both patient populations. Recurrent minimally deleted regions (MDRs) were identified at 7q36.1 (7.7%), 9q21.32 (5%), 11p13 (2.3%), and 17q11.2 (2%). Approximately one-half of the 7q deletions were detectable only by single-nucleotide polymorphism-array analysis because of their limited size. Sequence analysis of MLL3, contained within the 7q36.1 MDR, in 46 diagnostic samples revealed one truncating mutation in a leukemia lacking a 7q deletion. Recurrent focal gains were identified at 8q24.21 (4.7%) and 11q25 (1.7%), both containing a single noncoding RNA. Recurrent regions of copy-neutral loss-of-heterozygosity were identified at 1p (1%), 4q (0.7%), and 19p (0.7%), with known mutated cancer genes present in the minimally altered region of 1p (NRAS) and 4q (TET2). Analysis of relapse samples identified recurrent MDRs at 3q13.31 (12.2%), 5q (4.9%), and 17p (4.9%), with the 3q13.31 region containing only LSAMP, a putative tumor suppressor. Determining the role of these lesions in leukemogenesis and drug resistance should provide important insights into core-binding factor acute myeloid leukemia.
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10.56Impact points
Frequency and prognostic impact of mutations in SRSF2, U2AF1, and ZRSR2 in patients with myelodysplastic syndromes.
Blood. 03/2012;
Mutations in genes of the splicing machinery have recently been described in MDS. In this study, we examined a cohort of 193 MDS patients for mutations in SRSF2, U2AF1 (synonym U2AF35), ZRSR2, and, as previously reported, SF3B1 in the context of other molecular markers including mutations in ASXL1, ... [more] Mutations in genes of the splicing machinery have recently been described in MDS. In this study, we examined a cohort of 193 MDS patients for mutations in SRSF2, U2AF1 (synonym U2AF35), ZRSR2, and, as previously reported, SF3B1 in the context of other molecular markers including mutations in ASXL1, RUNX1, NRAS, TP53, IDH1, IDH2, NPM1 and DNMT3A. Mutations in SRSF2, U2AF1, ZRSR2, and SF3B1 were found in 24 (12.4%), 14 (7.3%), 6 (3.1%), and 28 (14.5%) patients, respectively, corresponding to a total of 67 of 193 MDS patients (34.7%). SRSF2 mutations were associated with RUNX1 (P<.001) and IDH1 mutations (P=.013), while U2AF1 mutations were associated with ASXL1 (P=.005) and DNMT3A (P=.004) mutations. In univariate analysis, mutated SRSF2 predicted shorter overall survival (OS) and more frequent AML progression compared to wildtype SRSF2, whereas mutated U2AF1, ZRSR2, and SF3B1 had no impact on patient outcome. In multivariate analysis, SRSF2 remained an independent poor risk marker for OS (HR 2.3; 95%CI 1.28-4.13; P=.017) and AML progression (HR 2.83; 95%CI 1.31-6.12; P=.008). These results show a negative prognostic impact of SRSF2 mutations in MDS. SRSF2 mutations may become useful for clinical risk stratification and treatment decisions in the future.
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10.56Impact points
TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome.
Blood. 12/2011; 119(9):2114-21.
To assess the frequency of TP53 alterations and their correlation with other genetic changes and outcome in acute myeloid leukemia with complex karyotype (CK-AML), we performed integrative analysis using TP53 mutational screening and array-based genomic profiling in 234 CK-AMLs. TP53 mutations were ... [more] To assess the frequency of TP53 alterations and their correlation with other genetic changes and outcome in acute myeloid leukemia with complex karyotype (CK-AML), we performed integrative analysis using TP53 mutational screening and array-based genomic profiling in 234 CK-AMLs. TP53 mutations were found in 141 of 234 (60%) and TP53 losses were identified in 94 of 234 (40%) CK-AMLs; in total, 164 of 234 (70%) cases had TP53 alterations. TP53-altered CK-AML were characterized by a higher degree of genomic complexity (aberrations per case, 14.30 vs 6.16; P < .0001) and by a higher frequency of specific copy number alterations, such as -5/5q-, -7/7q-, -16/16q-, -18/18q-, +1/+1p, and +11/+11q/amp11q13∼25; among CK-AMLs, TP53-altered more frequently exhibited a monosomal karyotype (MK). Patients with TP53 alterations were older and had significantly lower complete remission rates, inferior event-free, relapse-free, and overall survival. In multivariable analysis for overall survival, TP53 alterations, white blood cell counts, and age were the only significant factors. In conclusion, TP53 is the most frequently known altered gene in CK-AML. TP53 alterations are associated with older age, genomic complexity, specific DNA copy number alterations, MK, and dismal outcome. In multivariable analysis, TP53 alteration is the most important prognostic factor in CK-AML, outweighing all other variables, including the MK category.
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10.56Impact points
Monosomal karyotype in adult acute myeloid leukemia: prognostic impact and outcome after different treatment strategies.
Blood. 11/2011; 119(2):551-8.
We aimed to determine the prognostic impact of monosomal karyotype (MK) in acute myeloid leukemia (AML) in the context of the current World Health Organization (WHO) classification and to evaluate the outcome of MK(+) patients after allogeneic HSCT. Of 1058 patients with abnormal cytogenetics, 319 (... [more] We aimed to determine the prognostic impact of monosomal karyotype (MK) in acute myeloid leukemia (AML) in the context of the current World Health Organization (WHO) classification and to evaluate the outcome of MK(+) patients after allogeneic HSCT. Of 1058 patients with abnormal cytogenetics, 319 (30%) were MK MK(+). MK(+) patients were significantly older (P = .0001), had lower white blood counts (P = .0006), and lower percentages of BM blasts (P = .0004); MK was associated with the presence of -5/5q-, -7, 7q-, abnl(12p), abnl(17p), -18/18q-, -20/20q-, inv(3)/t(3;3), complex karyotype (CK), and myelodysplasia (MDS)-related cytogenetic abnormalities (P < .0001, each); and NPM1 mutations (P < .0001), FLT3 internal tandem duplications (P < .0001), and tyrosine kinase domain mutations (P = .02) were less frequent in MK(+). Response to induction therapy and overall survival in MK(+) patients were dismal with a complete remission rate of 32.5% and a 4-year survival of 9%. MK retained its prognostic impact in AML with CK, AML with MDS-related cytogenetic abnormalities, and in a revised definition (MK-R) excluding cases with recurrent genetic abnormalities according to WHO classification and those with derivative chromosomes not leading to true monosomies. In younger patients, allogeneic HSCT from matched related and unrelated donors resulted in a limited improvement of overall survival.
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6.42Impact points
Rare occurrence of DNMT3A mutations in myelodysplastic syndromes.
Haematologica. 08/2011; 96(12):1870-3.
Gene mutations and epigenetic changes have been shown to play significant roles in the pathogenesis of myelodysplastic syndromes. Recently, mutations in DNMT3A were identified in 22.1% of patients with acute myeloid leukemia. In this study, we analyzed the frequency and clinical impact of DNMT3A mut... [more] Gene mutations and epigenetic changes have been shown to play significant roles in the pathogenesis of myelodysplastic syndromes. Recently, mutations in DNMT3A were identified in 22.1% of patients with acute myeloid leukemia. In this study, we analyzed the frequency and clinical impact of DNMT3A mutations in a cohort of 193 patients with myelodysplastic syndromes. Mutations in DNMT3A were found in 2.6% of patients. The majority of mutations were heterozygous missense mutations affecting codon R882. Patients with DNMT3A mutations were found to have a higher rate of transformation to acute myeloid leukemia. When assessing the global methylation levels in patients with mutated versus unmutated DNMT3A and healthy controls no difference in global DNA methylation levels between the two groups was seen. Our data show that in patients with myelodysplastic syndromes, DNMT3A mutations occur at a low frequency and may be a risk factor for leukemia progression.
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2.35Impact points
Cytoreductive treatment with clofarabine/ara-C combined with reduced-intensity conditioning and allogeneic stem cell transplantation in patients with high-risk, relapsed, or refractory acute myeloid leukemia and advanced myelodysplastic syndrome.
European journal of haematology. 08/2011; 88(1):52-60.
The combination of cytoreductive chemotherapy with reduced-intensity conditioning (RIC) is a highly effective antileukemic therapy. Purpose of this retrospective analysis was to evaluate the antileukemic efficacy and toxicity of clofarabine-based chemotherapy followed by RIC and allogeneic stem cell... [more] The combination of cytoreductive chemotherapy with reduced-intensity conditioning (RIC) is a highly effective antileukemic therapy. Purpose of this retrospective analysis was to evaluate the antileukemic efficacy and toxicity of clofarabine-based chemotherapy followed by RIC and allogeneic stem cell transplantation (SCT) for high-risk, relapsed, or refractory acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). From May 2007 until October 2009, a total of 27 patients underwent allogeneic SCT after treatment with clofarabine and ara-C for 5d and RIC (4Gy TBI/cyclophosphamide/ATG). Prophylaxis of graft-versus-host disease (GvHD) consisted of cyclosporine and mycophenolate mofetil. Unmanipulated G-CSF mobilized PBSC (n=26) or bone marrow cells (n=1) were transplanted from unrelated (n=21) or matched related (n=6) donors. Non-hematological toxicities of this regimen mainly affected liver and skin and were all reversible. Seven patients relapsed within a median time of 5.7 months. The overall survival (OS) and relapse-free survival rates were 56% and 52% at 2 yr, respectively. In this cohort of patients, cytoreduction with clofarabine/ara-C (ClAraC) followed by RIC allogeneic SCT was well tolerated and showed good antileukemic efficacy even in patients with high-risk AML or MDS, with engraftment and GvHD-incidence comparable to other RIC regimens.
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8.30Impact points
Functional role of BAALC in leukemogenesis.
Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 08/2011; 26(3):532-6.
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8.30Impact points
Prognostic implications and molecular associations of NADH dehydrogenase subunit 4 (ND4) mutations in acute myeloid leukemia.
Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 08/2011; 26(2):289-95.
To study the prevalence and prognostic importance of mutations in NADH dehydrogenase subunit 4 (ND4), a mitochondrial encoded transmembrane component of the electron transport chain respiratory Complex I, 452 AML patients were examined for ND4 mutations by direct sequencing. The prognostic impact of... [more] To study the prevalence and prognostic importance of mutations in NADH dehydrogenase subunit 4 (ND4), a mitochondrial encoded transmembrane component of the electron transport chain respiratory Complex I, 452 AML patients were examined for ND4 mutations by direct sequencing. The prognostic impact of ND4 mutations was evaluated in the context of other clinical prognostic markers and genetic risk factors. In all, 29 of 452 patients (6.4%) had either somatic (n=12) or germline (n=17) ND4 mutations predicted to affect translation. Somatic mutations were more likely to be heteroplasmic (P<0.001), to occur in predicted transmembrane domains (P<0.001) and were predicted to have damaging effects upon translation (P<0.001). Patients with somatically acquired ND4 mutations had significantly longer relapse-free survival (P=0.017) and overall survival (OS) (P=0.021) than ND4(wildtype) patients. Multivariate analysis also demonstrated a tendency for increased survival in patients with somatic ND4 mutations (RFS: hazard ratio (HR) 0.25, confidence interval (CI) 0.06-1.01, P=0.052; OS: HR 0.29, CI 0.74-1.20, P=0.089). Somatic ND4(mutated) patients had a higher prevalence of concomitant DNMT3A mutations (P=0.023) and a higher percentage of the NPM1/FLT3-ITD low-risk genotype (P=0.021). Germline affected cases showed higher BAALC (P=0.036) and MLL5 (P=0.051) expression levels. Further studies are warranted to validate the favorable prognostic influence of acquired ND4 mutations in AML.
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17.79Impact points
Prognostic significance of ASXL1 mutations in patients with myelodysplastic syndromes.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 06/2011; 29(18):2499-506.
To study the incidence and prognostic impact of mutations in Additional sex comb-like 1 (ASXL1) in a large cohort of patients with myelodysplastic syndrome (MDS). PATIENTS, MATERIALS, AND METHODS: Overall, 193 patients with MDS and 65 healthy volunteers were examined for ASXL1 mutations by direct se... [more] To study the incidence and prognostic impact of mutations in Additional sex comb-like 1 (ASXL1) in a large cohort of patients with myelodysplastic syndrome (MDS). PATIENTS, MATERIALS, AND METHODS: Overall, 193 patients with MDS and 65 healthy volunteers were examined for ASXL1 mutations by direct sequencing and for expression levels of ASXL1. The prognostic impact of ASXL1 mutation and expression levels was evaluated in the context of other clinical and molecular prognostic markers. Mutations in ASXL1 occurred with a frequency of 20.7% in MDS (n = 40 of 193) with 70% (n = 28) of mutations being frameshift mutations and 30% (n = 12) being heterozygous point mutations leading to translational changes. ASXL1 mutations were correlated with an intermediate-risk karyotype (P = .002) but not with other clinical parameters. The presence of ASXL1 mutations was associated with a shorter overall survival for frameshift and point mutations combined (hazard ratio [HR], 1.744; 95% CI, 1.08 to 2.82; P = .024) and for frameshift mutations only (HR, 2.06; 95% CI, 1.21 to 3.50; P = .008). ASXL1 frameshift mutations were associated with a reduced time to progression of acute myeloid leukemia (AML; HR 2.35; 95% CI, 1.17 to 4.74; P = .017). In multivariate analysis, when considering karyotype, transfusion dependence, and IDH1 mutation status, ASXL1 frameshift mutations remained an independent prognostic marker in MDS (overall survival: HR, 1.85; 95% CI, 1.03 to 3.34; P = .040; time to AML progression: HR, 2.39; 95% CI, 1.12 to 5.09; P = .024). These results suggest that ASXL1 mutations are frequent molecular aberrations in MDS that predict an adverse prognostic outcome. Screening of patients for ASXL1 mutations might be useful for clinical risk stratification and treatment decisions in the future.
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17.79Impact points
Incidence and prognostic influence of DNMT3A mutations in acute myeloid leukemia.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 06/2011; 29(21):2889-96.
To study the incidence and prognostic impact of mutations in DNA methyltransferase 3A (DNMT3A) in patients with acute myeloid leukemia. A total of 489 patients with AML were examined for mutations in DNMT3A by direct sequencing. The prognostic impact of DNMT3A mutations was evaluated in the context ... [more] To study the incidence and prognostic impact of mutations in DNA methyltransferase 3A (DNMT3A) in patients with acute myeloid leukemia. A total of 489 patients with AML were examined for mutations in DNMT3A by direct sequencing. The prognostic impact of DNMT3A mutations was evaluated in the context of other clinical prognostic markers and genetic risk factors (cytogenetic risk group; mutations in NPM1, FLT3, CEBPA, IDH1, IDH2, MLL1, NRAS, WT1, and WT1 SNPrs16754; expression levels of BAALC, ERG, EVI1, MLL5, MN1, and WT1). DNMT3A mutations were found in 87 (17.8%) of 489 patients with AML who were younger than 60 years of age. Patients with DNMT3A mutations were older, had higher WBC and platelet counts, more often had a normal karyotype and mutations in NPM1, FLT3, and IDH1 genes, and had higher MLL5 expression levels as compared with patients with wild-type DNMT3A. Mutations in DNMT3A independently predicted a shorter overall survival (OS; hazard ratio [HR], 1.59; 95% CI, 1.15 to 2.21; P = .005) by multivariate analysis, but were not associated with relapse-free survival (RFS) or complete remission (CR) rate when the entire patient cohort was considered. In cytogenetically normal (CN) AML, 27.2% harbored DNMT3A mutations that independently predicted shorter OS (HR = 2.46; 95% CI, 1.58 to 3.83; P < .001) and lower CR rate (OR, 0.42; 95% CI, 0.21 to 0.84; P = .015), but not RFS (P = .32). Within patients with CN-AML, DNMT3A mutations had an unfavorable effect on OS, RFS, and CR rate in NPM1/FLT3-ITD high-risk but not in low-risk patients. DNMT3A mutations are frequent in younger patients with AML and are associated with an unfavorable prognosis.
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8.30Impact points
Prevalence and prognostic value of IDH1 and IDH2 mutations in childhood AML: a study of the AML-BFM and DCOG study groups.
Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 06/2011; 25(11):1704-10.
Mutations in the NADP(+)-dependent isocitrate dehydrogenase genes 1 and 2 (IDH1 and IDH2) have recently been found in adult acute myeloid leukemia (AML) patients with a prevalence rising up to 33%. To investigate the frequency of IDH1/2 mutations in pediatric AML, we characterized the mutational hot... [more] Mutations in the NADP(+)-dependent isocitrate dehydrogenase genes 1 and 2 (IDH1 and IDH2) have recently been found in adult acute myeloid leukemia (AML) patients with a prevalence rising up to 33%. To investigate the frequency of IDH1/2 mutations in pediatric AML, we characterized the mutational hotspot (exon 4) of these genes in diagnostic samples from 460 pediatric AML patients. Our analysis identified somatic IDH1/2 mutations in 4% of cases (IDH1 R132 n=8; IDH2 R140 n=10) and the minor allele of single-nucleotide polymorphism (SNP) rs11554137 in 47 children (10.2%). IDH mutations were associated with an intermediate age (P=0.008), FAB M1/M2 (P=0.013) and nucleophosmin1 mutations (P=0.001). In univariate analysis, IDH(mutated) compared with IDH(wildtype) patients showed a significantly improved overall survival (OS; P=0.032) but not event-free survival (EFS; P=0.14). However, multivariate analysis did not show independent prognostic significance. Children with at least one minor allele of IDH1 SNP rs11554137 had similar EFS (P=0.27) and OS (P=0.62) compared with major allele patients. Gene expression profiles of 12 IDH(mutated) were compared with 201 IDH(wildtype) patients to identify differentially expressed genes and pathways. Although only a small number of discriminating genes were identified, analysis revealed a deregulated tryptophan metabolism, and a significant downregulation of KYNU expression in IDH(mutated) cases.
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10.56Impact points
Comprehensive analysis of mammalian miRNA* species and their role in myeloid cells.
Blood. 05/2011; 118(12):3350-8.
Processing of pre-miRNA through Dicer1 generates an miRNA duplex that consists of an miRNA and miRNA* strand. Despite the general view that miRNA*s have no functional role, we further investigated miRNA* species in 10 deep-sequencing libraries from mouse and human tissue. Comparisons of miRNA/miRNA*... [more] Processing of pre-miRNA through Dicer1 generates an miRNA duplex that consists of an miRNA and miRNA* strand. Despite the general view that miRNA*s have no functional role, we further investigated miRNA* species in 10 deep-sequencing libraries from mouse and human tissue. Comparisons of miRNA/miRNA* ratios across the miRNA sequence libraries revealed that 50% of the investigated miRNA duplexes exhibited a highly dominant strand. Conversely, 10% of miRNA duplexes showed a comparable expression of both strands, whereas the remaining 40% exhibited variable ratios across the examined libraries, as exemplified by miR-223/miR-223* in murine and human cell lines. Functional analyses revealed a regulatory role for miR-223* in myeloid progenitor cells, which implies an active role for both arms of the miR-223 duplex. This was further underscored by the demonstration that miR-223 and miR-223* targeted the insulin-like growth factor 1 receptor/phosphatidylinositol 3-kinase axis and that high miR-223* levels were associated with increased overall survival in patients with acute myeloid leukemia. Thus, we found a supporting role for miR-223* in differentiating myeloid cells in normal and leukemic cell states. The fact that the miR-223 duplex acts through both arms extends the complexity of miRNA-directed gene regulation of this myeloid key miRNA.
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17.79Impact points
Monitoring of minimal residual disease in NPM1-mutated acute myeloid leukemia: a study from the German-Austrian acute myeloid leukemia study group.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 05/2011; 29(19):2709-16.
To evaluate the prognostic value of minimal residual disease (MRD) in patients with acute myeloid leukemia (AML) with NPM1 mutation (NPM1(mut)). RNA-based real-time quantitative polymerase chain reaction (RQ-PCR) specific for the detection of six different NPM1(mut) types was applied to 1,682 sample... [more] To evaluate the prognostic value of minimal residual disease (MRD) in patients with acute myeloid leukemia (AML) with NPM1 mutation (NPM1(mut)). RNA-based real-time quantitative polymerase chain reaction (RQ-PCR) specific for the detection of six different NPM1(mut) types was applied to 1,682 samples (bone marrow, n = 1,272; blood, n = 410) serially obtained from 245 intensively treated younger adult patients who were 16 to 60 years old. NPM1(mut) transcript levels as a continuous variable were significantly associated with prognosis after each treatment cycle. Achievement of RQ-PCR negativity after double induction therapy identified patients with a low cumulative incidence of relapse (CIR; 6.5% after 4 years) compared with RQ-PCR-positive patients (53.0%; P < .001); this translated into significant differences in overall survival (90% v 51%, respectively; P = .001). After completion of therapy, CIR was 15.7% in RQ-PCR-negative patients compared with 66.5% in RQ-PCR-positive patients (P < .001). Multivariable analyses after double induction and after completion of consolidation therapy revealed higher NPM1(mut) transcript levels as a significant factor for a higher risk of relapse and death. Serial post-treatment assessment of MRD allowed early detection of relapse in patients exceeding more than 200 NPM1(mut)/10(4) ABL copies. We defined clinically relevant time points for NPM1(mut) MRD assessment that allow for the identification of patients with AML who are at high risk of relapse. Monitoring of NPM1(mut) transcript levels should be incorporated in future clinical trials to guide therapeutic decisions.
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2.92Impact points
Elevated frequencies of leukemic myeloid and plasmacytoid dendritic cells in acute myeloid leukemia with the FLT3 internal tandem duplication.
Annals of hematology. 04/2011; 90(9):1047-58.
Some 30% of acute myeloid leukemia (AML) patients display an internal tandem duplication (ITD) mutation in the FMS-like tyrosine kinase 3 (FLT3) gene. FLT3-ITDs are known to drive hematopoietic stem cells towards FLT3 ligand independent growth, but the effects on dendritic cell (DC) differentiation ... [more] Some 30% of acute myeloid leukemia (AML) patients display an internal tandem duplication (ITD) mutation in the FMS-like tyrosine kinase 3 (FLT3) gene. FLT3-ITDs are known to drive hematopoietic stem cells towards FLT3 ligand independent growth, but the effects on dendritic cell (DC) differentiation during leukemogenesis are not clear. We compared the frequency of cells with immunophenotype of myeloid DC (mDC: Lin(-), HLA-DR(+), CD11c(+), CD86(+)) and plasmacytoid DC (pDC: Lin(-), HLA-DR(+), CD123(+), CD86(+)) in diagnostic samples of 47 FLT3-ITD(-) and 40 FLT3-ITD(+) AML patients. The majority of ITD(+) AML samples showed high frequencies of mDCs or pDCs, with significantly decreased HLA-DR expression compared with DCs detectable in ITD(-) AML samples. Interestingly, mDCs and pDCs sorted out from ITD(+) AML samples contained the ITD insert revealing their leukemic origin and, upon ex vivo culture with cytokines, they acquired DC morphology. Notably, mDC/pDCs were detectable concurrently with single lineage mDCs and pDCs in all ITD(+) AML (n = 11) and ITD(-) AML (n = 12) samples analyzed for mixed lineage DCs (Lin(-), HLA-DR(+), CD11c(+), CD123(+)). ITD(+) AML mDCs/pDCs could be only partially activated with CD40L and CpG for production of IFN-α, TNF-α, and IL-1α, which may affect the anti-leukemia immune surveillance in the course of disease progression.
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3.00Impact points
Prognostic factors in allo-SCT of elderly patients with AML.
Bone marrow transplantation. 04/2011; 46(4):545-51.
The prognosis of elderly patients with AML after chemotherapy is poor. Allo-SCT is feasible in these patients, but data on prognostic factors and outcome are limited. We analyzed all 102 AML patients ≥55 years, who underwent allo-SCT at our institution from 1997 to 2008. OS and relapse-free survival... [more] The prognosis of elderly patients with AML after chemotherapy is poor. Allo-SCT is feasible in these patients, but data on prognostic factors and outcome are limited. We analyzed all 102 AML patients ≥55 years, who underwent allo-SCT at our institution from 1997 to 2008. OS and relapse-free survival (RFS) rates at 3 years are 39 and 37%, respectively. Multivariate analysis for OS revealed age ≥60 years and active (refractory or untreated before allo-SCT) or advanced (>CR1) disease as adverse prognostic factors. Patients transplanted in CR1 had a 3-year OS of 67 vs 27% for patients with active/advanced disease. Multivariate analysis for RFS revealed active/advanced disease as the only adverse factor. Patients transplanted in CR1 had a 3-year RFS of 70 vs 22% for patients with active/advanced disease. In all, 17% of patients suffered from acute GVHD ≥grade II. The risk for severe acute GVHD was increased after allo-SCT from mismatched donors. Nonrelapse mortality (NRM) was 23% at 1 year. The only risk factor for NRM was active/advanced disease. In conclusion, allo-SCT from related or unrelated donors yields very good results in elderly AML patients transplanted in CR1. Disease status at transplantation is the most important prognostic factor for transplantation success.
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10.56Impact points
Integrative prognostic risk score in acute myeloid leukemia with normal karyotype.
Blood. 03/2011; 117(17):4561-8.
To integrate available clinical and molecular information for cytogenetically normal acute myeloid leukemia (CN-AML) patients into one risk score, 275 CN-AML patients from multicenter treatment trials AML SHG Hannover 0199 and 0295 and 131 patients from HOVON/SAKK protocols as external controls were... [more] To integrate available clinical and molecular information for cytogenetically normal acute myeloid leukemia (CN-AML) patients into one risk score, 275 CN-AML patients from multicenter treatment trials AML SHG Hannover 0199 and 0295 and 131 patients from HOVON/SAKK protocols as external controls were evaluated for mutations/polymorphisms in NPM1, FLT3, CEBPA, MLL, NRAS, IDH1/2, and WT1. Transcript levels were quantified for BAALC, ERG, EVI1, ID1, MN1, PRAME, and WT1. Integrative prognostic risk score (IPRS) was modeled in 181 patients based on age, white blood cell count, mutation status of NPM1, FLT3-ITD, CEBPA, single nucleotide polymorphism rs16754, and expression levels of BAALC, ERG, MN1, and WT1 to represent low, intermediate, and high risk of death. Complete remission (P = .005), relapse-free survival (RFS, P < .001), and overall survival (OS, P < .001) were significantly different for the 3 risk groups. In 2 independent validation cohorts of 94 and 131 patients, the IPRS predicted different OS (P < .001) and RFS (P < .001). High-risk patients with related donors had longer OS (P = .016) and RFS (P = .026) compared with patients without related donors. In contrast, intermediate-risk group patients with related donors had shorter OS (P = .003) and RFS (P = .05). Donor availability had no impact on outcome of patients in the low-risk group. Thus, the IPRS may improve consolidation treatment stratification in CN-AML patients. Study registered at www.clinicaltrials.gov as #NCT00209833.
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2.92Impact points
Myeloid growth factors in acute myeloid leukemia: systematic review of randomized controlled trials.
Annals of hematology. 03/2011; 90(3):273-81.
Randomized controlled trials (RCT) investigating administration of colony-stimulating factors (CSF) during or after chemotherapy in acute myeloid leukemia (AML) patients have not been systematically reviewed. We performed a meta-analysis of all reported RCTs comparing prophylactic or concurrent use ... [more] Randomized controlled trials (RCT) investigating administration of colony-stimulating factors (CSF) during or after chemotherapy in acute myeloid leukemia (AML) patients have not been systematically reviewed. We performed a meta-analysis of all reported RCTs comparing prophylactic or concurrent use of CSFs in adult AML patients. Two reviewers extracted data independently. Summary estimates with 95% confidence intervals (CIs) were calculated using a fixed effects model. Fourteen RCTs (n = 4,069 patients) were identified investigating prophylactic CSF administration. Time to neutrophil recovery (>500/μl) was significantly reduced in the CSF group (-4.13 days; 95% CI, -4.23 to -4.04) as was the length of hospitalization (-2.06 days; 95% CI, -2.36 to -1.76). However, no significant reduction in infection-related mortality was observed in CSF-treated compared with control patients (odds ratio (OR) 0.94; 95% CI, 0.8 to 1.1). Prophylactic CSF administration did not impact complete remission (CR) rate or survival. Fourteen RCTs (n = 4,518 patients) were identified investigating administration of CSFs during chemotherapy. Summary estimates of CR, disease/event-free, or overall survival were not significantly different for CSF versus control patients. Prophylactic CSF administration reduces the time to neutrophil recovery and length of hospitalization, but has no impact on documented infections or outcome. Economic analyses of prophylactic CSF administration in AML patients are warranted.
Following (13)
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Jorge Sierra
Hospital de la Santa Creu i Sant Pau -
Michael A Morgan
Medizinische Hochschule Hannover -
Zhang Jie
Aarhus Business School -
Christian Thiede
University Hospital Carl Gustav Carus Dresden -
Wolfram Brugger
Schwarzwald-Baar Clinic, Acad. Teaching Hospital, University of Freiburg
Topics (2)
