Papers by Torsten Haferlach
Accurate diagnosis and classification of leukemias are the bases for the appropri- ate management... more Accurate diagnosis and classification of leukemias are the bases for the appropri- ate management of patients. The diagnos- tic accuracy and efficiency of present methods may be improved by the use of microarrays for gene expression profil- ing. We analyzed gene expression pro- files in 937 bone marrow and peripheral blood samples from 892 patients with all clinically relevant leukemia
Risk assessment in acute myeloid leuke- mia (AML) using pretreatment character- istics may be imp... more Risk assessment in acute myeloid leuke- mia (AML) using pretreatment character- istics may be improved by incorporat- ing parameters of early response to therapy. In the 1992 trial of the German AML Cooperative Group (AMLCG), the amount of residual leukemic blasts in bone marrow was assessed one week after the first induction course (day 16 blasts). A total of 449
British Journal of Haematology, 1996
British Journal of Haematology, 2001
We analyzed 2502 patients with acute myeloid leukemia at diagnosis for NRAS mutations around the ... more We analyzed 2502 patients with acute myeloid leukemia at diagnosis for NRAS mutations around the hot spots at codons 12, 13, and 61 and correlated the results to cytomorphology, cytogenetics, other molecular markers, and prognostic rel- evance of these mutations. Two hundred fifty-seven (10.3%) of 2502 patients had NRAS mutations (NRASmut). Most muta- tions (112 of 257; 43.6%) were found
Haematologica-the Hematology Journal, 2008
Acute myeloid leukemia with mutated NPM1 gene and aberrant cytoplasmic expression of nucleophosmi... more Acute myeloid leukemia with mutated NPM1 gene and aberrant cytoplasmic expression of nucleophosmin (NPMc+acute myeloid leukemia) shows distinctive biological and clinical features. Experimental evidence of the oncogenic potential of the nucleophosmin mutant is, however, still lacking, and it is unclear whether other genetic lesion(s), e.g. FLT3 internal tandem duplication, cooperate with NPM1 mutations in acute myeloid leukemia development. An analysis
Haematologica, Jan 22, 2015
Next generation sequencing technologies have provided insights into the molecular heterogeneity o... more Next generation sequencing technologies have provided insights into the molecular heterogeneity of various myeloid neoplasms, revealing previously unknown somatic genetic events. In our cohort of 1444 cases analyzed by next generation sequencing, somatic mutations in the gene BRCA1-BRCA2-containing complex 3 (BRCC3) were identified in 28 cases (1.9%). BRCC3 is a member of the JAMM/MPN+ family of zinc metalloproteases capable of cleaving Lys-63 linked polyubiquitin chains, and is implicated in DNA repair. The mutations were located throughout its coding region. The average variant allelic frequency of BRCC3 mutations was 30.1%, and by a serial sample analysis at two different time points a BRCC3 mutation was already identified in the initial stage of a myelodysplastic syndrome. BRCC3 mutations commonly occurred in nonsense (n=12), frameshift (n=4), and splice site (n=5) configurations. Due to the marginal male dominance (odds ratio; 2.00, 0.84-4.73) of BRCC3 mutations, the majority o...
Nature communications, 2015
Clonal proliferation in myeloproliferative neoplasms (MPN) is driven by somatic mutations in JAK2... more Clonal proliferation in myeloproliferative neoplasms (MPN) is driven by somatic mutations in JAK2, CALR or MPL, but the contribution of inherited factors is poorly characterized. Using a three-stage genome-wide association study of 3,437 MPN cases and 10,083 controls, we identify two SNPs with genome-wide significance in JAK2(V617F)-negative MPN: rs12339666 (JAK2; meta-analysis P=1.27 × 10(-10)) and rs2201862 (MECOM; meta-analysis P=1.96 × 10(-9)). Two additional SNPs, rs2736100 (TERT) and rs9376092 (HBS1L/MYB), achieve genome-wide significance when including JAK2(V617F)-positive cases. rs9376092 has a stronger effect in JAK2(V617F)-negative cases with CALR and/or MPL mutations (Breslow-Day P=4.5 × 10(-7)), whereas in JAK2(V617F)-positive cases rs9376092 associates with essential thrombocythemia (ET) rather than polycythemia vera (allelic χ(2) P=7.3 × 10(-7)). Reduced MYB expression, previously linked to development of an ET-like disease in model systems, associates with rs9376092 i...
Haematologica, 2015
ABSTRACT - Copyright © 2014, Ferrata Storti Foundation.
Blood, Jan 10, 2014
TP53 is the most extensively studied gene in cancer. However, data on frequency and the prognosti... more 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 surviv...
Leukemia, 2002
For the diagnosis of CML and for monitoring of treatment response the detection of the t(9;22)(q3... more For the diagnosis of CML and for monitoring of treatment response the detection of the t(9;22)(q34;q11) or the BCR-ABL rearrangement is necessary. Chromosome banding analysis (CA) is still the gold standard but other techniques like Southern blot, fluorescence in situ hybridization (FISH) and polymerase chain reaction (PCR) are available. We analyzed 350 CML patients at different stages of disease in parallel with CA, interphase-FISH (IP-FISH), hypermetaphase-FISH (HM-FISH) and RT-PCR. In 20 cases with no Ph(+) metaphases in CA, HM-FISH detected 0.2 to 10% BCR-ABL(+)metaphases. After IP-FISH 107 samples were judged as negative. However, in 17 of these samples HM-FISH detected BCR-ABL(+) metaphases (0.3-11%), and in eight cases CA detected Ph(+) metaphases (2.5-25%). A comparison of IP-FISH performed on uncultivated cells vs cells cultivated for 48 h in 70 cases revealed a higher proportion of BCR-ABL+ cells in the cultivated samples. If nested PCR was negative, all other methods wer...
Leukemia, 2000
Partial tandem duplications of the MLL gene have been associated with trisomy 11 in acute myeloid... more Partial tandem duplications of the MLL gene have been associated with trisomy 11 in acute myeloid leukemia (AML) and recently, have also been reported for karyotypically normal AML. In order to test the incidence and prognostic importance of this molecular marker, we have analyzed eight cases of AML with trisomy 11 and 387 unselected consecutive cases with AML for partial duplications of the MLL gene. Patients with normal karyotypes and those with various chromosome aberrations were included. De novo as well as secondary leukemias including all FAB subtypes were analyzed. Performing a one-step RT-PCR with 35 cycles using an exon 9 forward primer and an exon 3 reverse primer partial tandem duplications of the MLL gene were demonstrated in 3/8 (37.5%) patients with trisomy 11. In addition, 13/387 (3.4%) of unselected cases revealed a tandem duplication. Ten of these 13 cases were cytogenetically normal, the other three cases had < or =2 additional chromosomal alterations. Sequencin...
The Hematology Journal, 2002
Introduction: Acute promyelocytic leukemia (APL) is a distinct entity characterized by a speci®c ... more Introduction: Acute promyelocytic leukemia (APL) is a distinct entity characterized by a speci®c bone marrow morphology and a rearrangement of the PML-and the RARa-gene mostly due to a balanced translocation between the long arm of chromosome 15 with a breakpoint in 15q22 and the long arm of chromosome 17 with a breakpoint in 17q12-21. The introduction of all trans retinoic acid (ATRA) into treatment protocols has improved the outcome of APL dramatically. Therefore, it is essential to establish the diagnosis of APL as quickly and as reliably as possible. Materials and methods: We investigated 1714 newly diagnosed AML. In 92 cases an AML M3 (n=67) or M3v (n=25) was diagnosed using cytomorphology. In all these cases chromosome banding analysis and molecular studies were performed. Results: In 3/92 APL cases (3.2%) normal chromosomes 15 and 17 in chromosome banding analysis were observed. In these cases either an insertion of parts of the PML-gene into the RARalocus or an insertion of parts of the RARa-gene into the PML-locus was detected by FISH analysis. In all three patients a PML-RARa-rearrangement was also observed by RT ± PCR. Conclusion: A small subgroup of APL shows cryptic rearrangements of the PML-and RARa-gene that are undetectable by cytogenetics. This is analogous to Ph-negative, BCR-ABL-positive CML cases. FISH and RT ± PCR have to be performed in all cases that show the typical characteristics of AML M3 or M3v in cytomorphology in addition to chromosome banding analysis. The Hematology Journal t(15;17)-negative, PML-RARa-positive APL C Schoch et al 262 The Hematology Journal t(15;17)-negative, PML-RARa-positive APL C Schoch et al
Haematologica, 2015
ABSTRACT Current strategies for the treatment of acute myeloid leukemia (AML) focus on the induct... more ABSTRACT Current strategies for the treatment of acute myeloid leukemia (AML) focus on the induction of cell death by chemotherapy or targeted therapy. In elderly patients with chemorefractory disease the prognosis is still poor. We herein present a novel biomodulatory therapy consisting of low-dose 5-azacytidine (AZA) in combination with pioglitazone (PGZ) and all-trans retinoic acid (ATRA). Five elderly patients with AML primary refractory to standard induction therapies received AZA, PGZ, and ATRA (APA) on a compassionate-use basis outside a clinical trial. APA treatment induced ongoing morphologic complete remission (CR) in three of five, including two molecular CRs. Early increases of granulocytes during biomodulatory treatment indicated a differentiation inducing effect of APA. In conclusion, this study suggests that low-toxic salvage therapy with APA is clinically active in elderly AML patients who are refractory to standard induction chemotherapy.
Haematologica, 2003
Detection of minimal residual disease (MRD) by multiparameter flow cytometry is an emerging progn... more Detection of minimal residual disease (MRD) by multiparameter flow cytometry is an emerging prognostic factor in patients with acute myeloid leukemia (AML). The present analysis aimed at improving the applicability of this approach to more patients with AML. Bone marrow samples from unselected patients with AML at diagnosis and from healthy volunteers were immunophenotyped applying triple-stainings of 31 antigens. Leukemia-associated immunophenotypes were defined by gating on populations displaying an aberrant or infrequent immunophenotype and by applying Boolean algebra. The combination of gates obtained was applied to list mode data files containing measurements of normal bone marrow samples. Dilution experiments of AML samples in normal bone marrow were performed to test the linearity of measurements. At least one aberrant/infrequent immunophenotype was identified (median, 2; range, 1-5) in all of 68 analyzed AML patients. The median frequencies of cells displaying an aberrant/in...
UTOLOGOUS peripheral blood progenitor cells (PBPCs) mobilized by hematopoietic growth factors suc... more UTOLOGOUS peripheral blood progenitor cells (PBPCs) mobilized by hematopoietic growth factors such as granulocyte or granulocyte-macrophage colony- stimulating factor (G-CSF or GM-CSF) are increasingly be- ing used instead of bone marrow (BM) to allow hematopoi- etic recovery after myeloablative therapy for leukemia, lymphoma, and a variety of solid tumors. Although the re- sults of randomised trials comparing the kinetics of
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Papers by Torsten Haferlach