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Ommen H.B.,Aarhus University Hospital | Schnittger S.,Munich Leukemia Laboratory | Jovanovic J.V.,King's College London | Ommen I.B.,Aarhus University Hospital | And 4 more authors.
Blood | Year: 2010

Early relapse detection in acute myeloid leukemia is possible using standardized real-time quantitative polymerase chain reaction (RQ-PCR) protocols. However, optimal sampling intervals have not been defined and are likely to vary according to the underlying molecular lesion. In 74 patients experiencing hematologic relapse and harboring aberrations amenable to RQ-PCR (mutated NPM1 [designated NPM1c], PML-RARA, RUNX1-RUNX1T1, and CBFB-MYH11), we observed strikingly different relapse kinetics. The median doubling time of the CBFB-MYH11 leukemic clone was significantly longer (36 days) than that of clones harboring other markers (RUNX1-RUNX1T1, 14 days; PML-RARA, 12 days; and NPM1c, 11 days; P < .001). Furthermore, we used a mathematical model to determine frequency of relapse detection and median time from detection of minimal residual disease to hematologic relapse as a function of sampling interval length. For example, to obtain a relapse detection fraction of 90% and a median time of 60 days, blood sampling every sixth month should be performed for CBFB-MYH11 leukemias. By contrast, in NPM1c+/FLT3-ITD-, NPM1c+/FLT3-ITD+, RUNX1-RUNX1T1, and PMLRARA leukemias, bone marrow sampling is necessary every sixth, fourth, and fourth and second month, respectively. These data carry important implications for the development of optimal RQ-PCR monitoring schedules suitable for evaluation of minimal residual disease-directed therapies in future clinical trials. © 2010 by The American Society of Hematology.


Elmaagacli A.H.,University of Duisburg - Essen | Steckel N.K.,University of Duisburg - Essen | Koldehoff M.,University of Duisburg - Essen | Hegerfeldt Y.,University of Duisburg - Essen | And 10 more authors.
Blood | Year: 2011

The impact of early human cytomegalovirus (HCMV) replication on leukemic recurrence was evaluated in 266 consecutive adult (median age, 47 years; range, 18-73 years) acute myeloid leukemia patients, who underwent allogeneic stem cell transplantation (alloSCT) from 10 of 10 high-resolution human leukocyte Ag-identical unrelated (n = 148) or sibling (n = 118) donors. A total of 63% of patients (n = 167) were at risk for HCMV reactivation by patient and donor pretransplantation HCMV serostatus. In 77 patients, first HCMV replication as detected by pp65-antigenemia assay developed at a median of 46 days (range, 25-108 days) after alloSCT. Taking all relevant competing risk factors into account, the cumulative incidence of hematologic relapse at 10 years after alloSCT was 42% (95% confidence interval [CI], 35%-51%) in patients without opposed to 9% (95% CI, 4%-19%) in patients with early pp65-antigenemia (P < .0001). A substantial and independent reduction of the relapse risk associated with early HCMV replication was confirmed by multivariate analysis using time-dependent covariate functions for grades II to IV acute and chronic graft-versus-host disease, and pp65-antigenemia (hazard ratio = 0.2; 95% CI, 0.1-0.4, P < .0001). This is the first report that demonstrates an independent and substantial reduction of the leukemic relapse risk after early replicative HCMV infection in a homogeneous population of adult acute myeloid leukemia patients. © 2011 by The American Society of Hematology.


Paulsson K.,Lund University | Haferlach C.,Munich Leukemia Laboratory | Fonatsch C.,Medical University of Vienna | Hagemeijer A.,Catholic University of Leuven | And 4 more authors.
Human Molecular Genetics | Year: 2010

Myelodysplastic syndromes and acute myeloid leukemia with an isodicentric X chromosome [idic(X)(q13)] occur in elderly women and frequently display ringed sideroblasts. Because of the rarity of idic(X)(q13), little is known about its formation, whether a fusion gene is generated, and patterns of additional aberrations. We here present an SNP array study of 14 idic(X)-positive myeloid malignancies, collected through an international collaborative effort. The breakpoints clustered in two regions of segmental duplications and were not in a gene, making dosage effects from the concurrent gain of Xpter-q13 and loss of Xq13-qter, rather than a fusion gene, the most likely pathogenetic outcome. Methylation analysis revealed involvement of the inactive X chromosomes in five cases and of the active in two. The ABCB7 gene, mutated in X-linked sideroblastic anemia and spinocerebellar ataxia, is in the deleted region, suggesting that loss of this gene underlies the frequent presence of ringed sideroblasts. Additional genetic abnormalities were present in 12/14 (86%), including partial uniparental disomies for 9p (one case) and 4q (two cases) associated with homozygous mutations of JAK2 and TET2, respectively. In total, TET2 mutations were seen in 4/11 (36%) analyzed cases, thus constituting a common secondary event in idic(X)-positive malignancies. © The Author 2010. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org.


Kleppe M.,Vlaams Institute for Biotechnology | Kleppe M.,Catholic University of Leuven | Lahortiga I.,Vlaams Institute for Biotechnology | Lahortiga I.,Catholic University of Leuven | And 19 more authors.
Nature Genetics | Year: 2010

PTPN2 (protein tyrosine phosphatase non-receptor type 2, also known as TC-PTP) is a cytosolic tyrosine phosphatase that functions as a negative regulator of a variety of tyrosine kinases and other signaling proteins 1-3. In agreement with its role in the regulation of the immune system, PTPN2 was identified as a susceptibility locus for autoimmune diseases4,5. In this work, we describe the identification of focal deletions of PTPN2 in human T-cell acute lymphoblastic leukemia (T-ALL). Deletion of PTPN2 was specifically found in T-ALLs with aberrant expression of the TLX1 transcription factor oncogene, including four cases also expressing the NUP214-ABL1 tyrosine kinase. Knockdown of PTPN2 increased the proliferation and cytokine sensitivity of T-ALL cells. In addition, PTPN2 was identified as a negative regulator of NUP214-ABL1 kinase activity. Our study provides genetic and functional evidence for a tumor suppressor role of PTPN2 and suggests that expression of PTPN2 may modulate response to treatment. © 2010 Nature America, Inc. All rights reserved.


Rapin N.,Copenhagen University | Bagger F.O.,Copenhagen University | Jendholm J.,Copenhagen University | Mora-Jensen H.,Copenhagen University | And 10 more authors.
Blood | Year: 2014

Gene expression profiling has been used extensively to characterize cancer, identify novel subtypes, and improve patient stratification. However, it has largely failed to identify transcriptional programs that differ between cancer and corresponding normal cells and has not been efficient in identifying expression changes fundamental to disease etiology. Here we present a method that facilitates the comparison of any cancer sample to its nearest normal cellular counterpart, using acute myeloid leukemia (AML) as a model. We first generated a gene expression-based landscape of the normal hematopoietic hierarchy, using expression profiles from normal stem/progenitor cells, and next mapped the AML patient samples to this landscape. This allowed us to identify the closest normal counterpart of individual AML samples and determine gene expression changes between cancer and normal. We find the cancer vs normal method (CvN method) to be superior to conventional methods in stratifying AML patients with aberrant karyotype and in identifying common aberrant transcriptional programs with potential importance for AML etiology. Moreover, the CvN method uncovered a novel poor-outcome subtype of normal-karyotype AML, which allowed for the generation of a highly prognostic survival signature. Collectively, our CvN method holds great potential as a tool for the analysis of gene expression profiles of cancer patients. © 2014 by The American Society of Hematology.


Stengel A.,Munich Leukemia Laboratory | Schnittger S.,Munich Leukemia Laboratory | Weissmann S.,Munich Leukemia Laboratory | Kuznia S.,Munich Leukemia Laboratory | And 4 more authors.
Blood | Year: 2014

TP53 is the most extensively studied gene in cancer. However, data on frequency and the prognostic impact of TP53 mutations in acute lymphoblastic leukemia (ALL) remain scarce. Thus, we aimed at identifying the mutation frequency of TP53, its association with cytogenetic subgroups, and its impact on survival in a large cohort of 625 patients with ALL. Our data revealed an overall mutation incidence of 15.7%, which increases with age. Correlation with cytogenetic subgroups showed that mutations were most frequent in ALL with low hypodiploidy or MYC-rearrangements. Furthermore, for a large number of patients, both TP53 alleles were altered, either by 2 TP53 mutations (12%) or by a TP53 mutation and a TP53 deletion in the second allele (39%). A high TP53 mutation load was correlated to low hypodiploidy, high hyperdiploidy, and a complex karyotype. Moreover, a higher mutation load was found in B-lineage ALL compared with T-lineage ALL. Similar to other cancers, the median overall survival was significantly shorter in patients with TP53 mutation compared with patients with wild-type TP53. This effect was especially pronounced when both TP53 alleles were affected, either by 2 TP53 mutations or by both a mutation and an accompanying TP53 deletion. © 2014 by The American Society of Hematology.


Haferlach C.,Munich Leukemia Laboratory | Bacher U.,University of Hamburg | Kohlmann A.,Munich Leukemia Laboratory | Schindela S.,Munich Leukemia Laboratory | And 4 more authors.
Haematologica | Year: 2011

Background Alterations of the short arm of chromosome 12 (12p) occur in various hematologic malignancies and ETV6 and CDKN1B, which are located on 12p, have been implicated as leukemogenic genes of interest. Design and Methods We selected seven patients with myeloid malignancies and small 12p deletions detected by fluorescence in situ hybridization encompassing only the region centromeric of ETV6 and further evaluated them by single nucleotide polymorphism microarrays. Results The minimally deleted region contained only nine genes. These genes were subsequently analyzed by microarray expression profiling in an independent cohort of 781 patients, most, but not all, of whom had different hematologic malignancies CREBL2, MANSC1, and CDKN1B were expressed in more than 25% of cases, while the other six genes were expressed in only a minority of cases. As CDKN1B is a cell cycle regulator and functions as a tumor suppressor gene, this gene was selected for further expression studies in 286 patients with acute myeloid leukemia. When comparing patients with low CDKN1B expression (expression level <1,160; 1st quartile) with those with intermediate or high expression (2nd-4th quartiles), certain mutations were observed more frequently in the former: RUNX1-RUNX1T1 (11/83, 13.3% versus 5/203; 2.5%; P=0.001), PML-RARA rearrangements (11/83, 13.3% versus 4/203, 2.0%; P<0.001), 11q23/MLL rearrangements (6/83, 7.2% versus 4/203, 2.0%; P=0.038), and FLT3-TKD mutations (7/63, 11.1% versus 6/167, 3.6%; P=0.047). The median overall survival of patients with low CDKN1B expression was longer than that of patients with intermediate/high expression (not reached versus 14.9 months; P=0.005). Likewise, patients with low CDKN1B expression had a longer event-free survival than those with intermediate/high expression (31.0 versus 9.7 months; P=0.013). Conclusions CDKN1B is an interesting candidate gene as a potential biomarker for prognostication in acute myeloid leukemia. ©2011 Ferrata Storti Foundation.


Schnittger S.,Munich Leukemia Laboratory | Haferlach C.,Munich Leukemia Laboratory | Ulke M.,Munich Leukemia Laboratory | Alpermann T.,Munich Leukemia Laboratory | And 2 more authors.
Blood | Year: 2010

Mutations in the IDH1 gene at position R132 coding for the enzyme cytosolic isocitrate dehydrogenase are known in glioma and have recently been detected also in acute myeloid leukemia (AML). These mutations result in an accumulation of α-ketoglutarate to R (2)-2-hydroxyglutarate (2HG). To further clarify the role of this mutation in AML, we have analyzed IDH1R132 in 1414 AML patients. We detected IDH1R132 mutations in 93 of 1414 patients (6.6%) with a clear prevalence in intermediate risk karyotype group (10.4%, P < .001). Although IDH1R132 mutations can incidentally occur together with all other molecular markers, there were strong associations with NPM1 mutations (14.2% vs 5.4% in NPM1wt, P < .001) and MLL-PTD (18.2% vs 7.0% in MLLwt, P = .020). IDH1-mutated cases more often had AML without maturation/French-American-British M1 (P < .001), an immature immunophenotype, and female sex (8.7% vs 4.7% in male, P = .003) compared with IDH1wt cases. Prognosis was adversely affected by IDH1 mutations with trend for shorter overall survival (P = .110), a shorter event-free survival (P < .003) and a higher cumulative risk for relapse (P = .001). IDH1 mutations were of independent prognostic relevance for eventfree survival (P = .039) especially in the age group < 60 years (P = .028). In conclusion, these data show that IDH1R132 may significantly add information regarding characterization and prognostication in AML. © 2010 by The American Society of Hematology.


Kohlmann A.,Munich Leukemia Laboratory | Nadarajah N.,Munich Leukemia Laboratory | Alpermann T.,Munich Leukemia Laboratory | Grossmann V.,Munich Leukemia Laboratory | And 7 more authors.
Leukemia | Year: 2014

We studied the utility and clinical relevance of RUNX1 (runt-related transcription factor 1) mutations and their application as residual disease detection markers using next-generation deep-sequencing. Mutation screening was prospectively performed in 814 acute myeloid leukemia patients. At diagnosis, 211/814 (25.9%) patients harbored mutations with a median clone size of 39% (range: 2-96%). Furthermore, in 57 patients paired samples from diagnosis and relapse were analyzed. In 47/57 (82.5%) cases the same alterations detected at diagnosis were present at relapse, whereas in 1/57 (1.8%) cases the mutation from the diagnostic sample was no longer detectable. Discrepancies were observed in 9/57 (15.8%) cases, also including the occurrence of novel RUNX1 mutations not restricted to those regions affected at diagnosis. Moreover, in 103 patients the prognostic impact of residual levels of RUNX1 mutations during complete remission was studied. Separation of patients according to median residual mutation burden into 'good responders' and 'poor responders' (median: 3.61%; range: 0.03-48.0%) resulted in significant differences of both event-free (median 21.0 vs 5.7 months, P<0.001) and overall survival (OS; median 56.9 vs 32.0 months, P=0.002). In conclusion, deep-sequencing revealed that RUNX1 mutations qualify as patient-specific markers for individualized disease monitoring. The measurement of mutation load may refine the assignment into distinct risk categories and treatment strategies. © 2014 Macmillan Publishers Limited.


Klein H.-U.,University of Munster | Bartenhagen C.,University of Munster | Kohlmann A.,Munich Leukemia Laboratory | Grossmann V.,Munich Leukemia Laboratory | And 3 more authors.
Bioinformatics | Year: 2011

The R453Plus1Toolbox is an R/Bioconductor package for the analysis of 454 Sequencing data. Projects generated with Roche's data analysis software can be imported into R allowing advanced and customized analyses within the R/Bioconductor environment for sequencing data. Several methods were implemented extending the current functionality of Roche's software. These extensions include methods for quality assurance and annotation of detected variants. Further, a pipeline for the detection of structural variants, e.g. balanced chromosomal translocations, is provided. © The Author 2011. Published by Oxford University Press. All rights reserved.

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