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Hanfstein B.,University of Heidelberg | Muller M.C.,University of Heidelberg | Hehlmann R.,University of Heidelberg | Erben P.,University of Heidelberg | And 29 more authors.
Leukemia | Year: 2012

In the face of competing first-line treatment options for CML, early prediction of prognosis on imatinib is desirable to assure favorable survival or otherwise consider the use of a second-generation tyrosine kinase inhibitor (TKI). A total of 1303 newly diagnosed imatinib-treated patients (pts) were investigated to correlate molecular and cytogenetic response at 3 and 6 months with progression-free and overall survival (PFS, OS). The persistence of BCR-ABL transcript levels > 10% according to the international scale (BCR-ABL IS) at 3 months separated a high-risk group (28% of pts; 5-year OS: 87%) from a group with 1-10% BCR-ABL IS (41% of pts; 5-year OS: 94%; P0.012) and from a group with 1% BCR-ABL IS (31% of pts; 5-year OS: 97%; P0.004). Cytogenetics identified high-risk pts by 35% Philadelphia chromosome-positive metaphases (Ph, 27% of pts; 5-year OS: 87%) compared with 35% Ph (73% of pts; 5-year OS: 95%; P0.036). At 6 months, 1% BCR-ABL IS (37% of pts; 5-year OS: 89%) was associated with inferior survival compared with 1% (63% of pts; 5-year OS: 97%; P0.001) and correspondingly 0% Ph (34% of pts; 5-year OS: 91%) compared with 0% Ph (66% of pts; 5-year OS: 97%; P0.015). Treatment optimization is recommended for pts missing these landmarks. © 2012 Macmillan Publishers Limited All rights reserved.


PubMed | Medizinische Klinik 5, Universitatsklinikum Cologne, Universitatsklinikum Bonn, Klinik fur Hamatologie and 34 more.
Type: Comparative Study | Journal: Leukemia | Year: 2016

Tyrosine kinase inhibitors represent todays treatment of choice in chronic myeloid leukemia (CML). Allogeneic hematopoietic stem cell transplantation (HSCT) is regarded as salvage therapy. This prospective randomized CML-study IIIA recruited 669 patients with newly diagnosed CML between July 1997 and January 2004 from 143 centers. Of these, 427 patients were considered eligible for HSCT and were randomized by availability of a matched family donor between primary HSCT (group A; N=166 patients) and best available drug treatment (group B; N=261). Primary end point was long-term survival. Survival probabilities were not different between groups A and B (10-year survival: 0.76 (95% confidence interval (CI): 0.69-0.82) vs 0.69 (95% CI: 0.61-0.76)), but influenced by disease and transplant risk. Patients with a low transplant risk showed superior survival compared with patients with high- (P<0.001) and non-high-risk disease (P=0.047) in group B; after entering blast crisis, survival was not different with or without HSCT. Significantly more patients in group A were in molecular remission (56% vs 39%; P=0.005) and free of drug treatment (56% vs 6%; P<0.001). Differences in symptoms and Karnofsky score were not significant. In the era of tyrosine kinase inhibitors, HSCT remains a valid option when both disease and transplant risk are considered.


Hnisz D.,Christian Doppler Laboratory | Bardet A.F.,Institute of Molecular Pathology IMP | Nobile C.J.,University of California at San Francisco | Petryshyn A.,Christian Doppler Laboratory | And 5 more authors.
PLoS Genetics | Year: 2012

Despite their classical role as transcriptional repressors, several histone deacetylases, including the baker's yeast Set3/Hos2 complex (Set3C), facilitate gene expression. In the dimorphic human pathogen Candida albicans, the homologue of the Set3C inhibits the yeast-to-filament transition, but the precise molecular details of this function have remained elusive. Here, we use a combination of ChIP-Seq and RNA-Seq to show that the Set3C acts as a transcriptional co-factor of metabolic and morphogenesis-related genes in C. albicans. Binding of the Set3C correlates with gene expression during fungal morphogenesis; yet, surprisingly, deletion of SET3 leaves the steady-state expression level of most genes unchanged, both during exponential yeast-phase growth and during the yeast-filament transition. Fine temporal resolution of transcription in cells undergoing this transition revealed that the Set3C modulates transient expression changes of key morphogenesis-related genes. These include a transcription factor cluster comprising of NRG1, EFG1, BRG1, and TEC1, which form a regulatory circuit controlling hyphal differentiation. Set3C appears to restrict the factors by modulating their transcription kinetics, and the hyperfilamentous phenotype of SET3-deficient cells can be reverted by mutating the circuit factors. These results indicate that the chromatin status at coding regions represents a dynamic platform influencing transcription kinetics. Moreover, we suggest that transcription at the coding sequence can be transiently decoupled from potentially conflicting promoter information in dynamic environments. © 2012 Hnisz et al.


PubMed | Wessex Regional Genetics Laboratory, Medizinische Klinik V, Institute For Humangenetik, MLL Munchner Leukamielabor GmbH and 3 more.
Type: Case Reports | Journal: Genes, chromosomes & cancer | Year: 2015

In eosinophilia-associated myeloproliferative neoplasms (MPN-eo), constitutive activation of protein tyrosine kinases (TK) as consequence of translocations, inversions, or insertions and creation of TK fusion genes is recurrently observed. The most commonly involved TK and their potential TK inhibitors include PDGFRA at 4q12 or PDGFRB at 5q33 (imatinib), FGFR1 at 8p11 (ponatinib), and JAK2 at 9p24 (ruxolitinib). We here report the identification of three new PDGFRB fusion genes in three male MPN-eo patients: MPRIP-PDGFRB in a case with t(5;17)(q33;p11), CPSF6-PDGFRB in a case with t(5;12)(q33;q15), and GOLGB1-PDGFRB in a case with t(3;5)(q13;q33). The fusion proteins identified by 5-rapid amplification of cDNA ends polymerase chain reaction (PCR) or DNA-based long distance inverse PCR are predicted to contain the TK domain of PDGFRB. The partner genes contain domains like coiled-coil structures, which are likely to cause dimerization and activation of the TK. In all patients, imatinib induced rapid and durable complete remissions.


Giehl M.,University of Heidelberg | Leitner A.,University of Heidelberg | Haferlach C.,MLL Munchner Leukamielabor GmbH | Duesberg P.,University of Heidelberg | And 5 more authors.
European Journal of Haematology | Year: 2010

Objectives: Tyrosine kinase inhibitors (TKIs) target various pathways associated with proliferation of aberrant clones in malignant diseases. Despite good response and acceptable tolerability, little is known concerning long-term toxicity. Furthermore, the influence of these inhibitors on disease-unrelated cells is not investigated yet. Methods: Centrosome aberrations are hallmarks of various cancers. We sought to evaluate the effect of TKIs on centrosomes of disease-unrelated cells. We examined cells of the oral mucosa (OM) and fibroblasts of patients with chronic myeloid leukemia (CML) treated with dasatinib and bosutinib. Results were compared with data from patients with CML treated with imatinib or nilotinib and with data from patients suffering from renal and hepatocellular carcinomas (RCC/HCC) treated with sorafenib or sunitinib. Cells of healthy donors served as controls. Results: OM cells (n = 12) and fibroblasts (n = 7) of patients with CML treated with dasatinib and OM cells of three patients with CML treated with bosutinib showed centrosomal alterations (mean, 14%) compared with 16 (10 OM and 6 fibroblasts) controls (mean, 3%). OM cells of five patients with CML and one patient with systemic mastocytosis treated with imatinib or nilotinib and of eight patients with RCC or HCC treated with sorafenib or sunitinib showed centrosome defects in a mean of 15%. Conclusions: Our data have shown that TKI treatment of tumor patients may influence centrosomes in disease-unrelated cells or tissues. This may be important with regard to various observed side effects. © 2010 John Wiley & Sons A/S.


Grant
Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2012.1.2-1 | Award Amount: 7.62M | Year: 2012

Hematological diseases are highly heterogeneous malignancies in the matter of the molecular mechanisms related to their development and progression. A considerable heterogeneity can be further observed within the same hematological disease at the inter-individual level, being reflected by different clinical outcomes and responses to treatment in different patients. Nowadays, the advent of high-throughput next generation sequencing (NGS) technologies that are revolutionizing genomics and transcriptomics by providing a single base resolution tool for a unified deep analysis of diseases complexity allows a fast and cost-efficient fine-scale assessment of the genetic variability hidden within cohorts of patients affected by the same leukemia. That being so, by potentially highlighting inter-individual differences that may play a role in the differential success of diverse therapeutic interventions, they promise to be crucial for selecting the most appropriate medical treatments. This project aims at developing a European Hematological/NGS platform of scientists for improving outcomes for therapeutic interventions on acute and chronic leukemias and at developing strategies to personalize treatments and tailor therapies to different stratified groups of leukemia patients, with the goal of optimizing their efficacy and safety through a deeper and deeper understanding of the influence of genetic alterations on leukemias pathogenesis and treatment response (i.e. personalized therapy). Moreover, the final aim will be the identification of novel prognostic biomarkers for acute and chronic leukemias, as well as of molecular biomarkers and/or genome-wide profiles for the assessment of minimal residual disease. The originality of this project is to perform systematic deep whole exome/transcriptome studies on well-clinically-characterized leukemia patients, by exploiting NGS technologies able to quickly produce data with a good cost-effectiveness and an unprecedented resolution.


Germing U.,Heinrich Heine University Düsseldorf | Haferlach T.,MLL Munchner Leukamie Labor GmbH
LaboratoriumsMedizin | Year: 2015

Myelodysplastic syndromes (MDS) are clonal malignant diseases of the hematopoietic stem cell. They are diagnosed mainly in elderly cytopenic patients and are characterized by a heterogeneous course of the disease. The diagnosis is based on blood and marrow cytology, chromosomal examination, and histology of the marrow, taking into account the degree of dysplasia, peripheral and medullary blast count, and cytogenetic findings according to the proposals of the World Health Organisation classification. The assessment of cytologic findings is important because the different types of MDS differ in terms of prognosis and therapeutic considerations. Acute myeloid leukemias are discriminated from MDS according to the blast counts in the bone marrow or peripheral blood (≥20%). Diagnosis is based on morphology and cytogenetics, and histology is also important. In addition, immunophenotyping and molecular investigations are needed. Information derived from cytogenetics and molecular markers play an important role for prognostication. Minimal residual disease can be best investigated using immunophenotyping and measurement of molecular markers. © 2015 by De Gruyter.

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