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Julia Richter,
Matthias Schlesner,
Steve Hoffmann,
Markus Kreuz,
Ellen Leich,
Birgit Burkhardt,
Maciej Rosolowski,
Ole Ammerpohl,
Rabea Wagener,
Stephan H Bernhart, [......],
Peter F Stadler,
Peter Lichter,
Roland Eils,
Ralf Küppers,
Michael Hummel,
Wolfram Klapper,
Philip Rosenstiel,
Andreas Rosenwald,
Benedikt Brors,
Reiner Siebert
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ABSTRACT: Burkitt lymphoma is a mature aggressive B-cell lymphoma derived from germinal center B cells. Its cytogenetic hallmark is the Burkitt translocation t(8;14)(q24;q32) and its variants, which juxtapose the MYC oncogene with one of the three immunoglobulin loci. Consequently, MYC is deregulated, resulting in massive perturbation of gene expression. Nevertheless, MYC deregulation alone seems not to be sufficient to drive Burkitt lymphomagenesis. By whole-genome, whole-exome and transcriptome sequencing of four prototypical Burkitt lymphomas with immunoglobulin gene (IG)-MYC translocation, we identified seven recurrently mutated genes. One of these genes, ID3, mapped to a region of focal homozygous loss in Burkitt lymphoma. In an extended cohort, 36 of 53 molecularly defined Burkitt lymphomas (68%) carried potentially damaging mutations of ID3. These were strongly enriched at somatic hypermutation motifs. Only 6 of 47 other B-cell lymphomas with the IG-MYC translocation (13%) carried ID3 mutations. These findings suggest that cooperation between ID3 inactivation and IG-MYC translocation is a hallmark of Burkitt lymphomagenesis.
Nature Genetics 11/2012; · 35.53 Impact Factor
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Nicola Gökbuget,
Michael Kneba,
Thorsten Raff, Heiko Trautmann,
Claus-Rainer Bartram,
Renate Arnold,
Rainer Fietkau,
Mathias Freund,
Arnold Ganser,
Wolf-Dieter Ludwig,
Georg Maschmeyer,
Harald Rieder,
Stefan Schwartz,
Hubert Serve,
Eckhard Thiel,
Monika Brüggemann,
Dieter Hoelzer
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ABSTRACT: Quantification of minimal residual disease (MRD) by real-time PCR directed to TCR and Ig gene rearrangements allows a refined evaluation of response in acute lymphoblastic leukemia (ALL). The German Multicenter Study Group for Adult ALL prospectively evaluated molecular response after induction/consolidation chemotherapy according to standardized methods and terminology in patients with Philadelphia chromosome-negative ALL. The cytologic complete response (CR) rate was 89% after induction phases 1 and 2. At this time point the molecular CR rate was 70% in 580 patients with cytologic CR and evaluable MRD. Patients with molecular CR after consolidation had a significantly higher probability of continuous complete remission (CCR; 74% vs 35%; P < .0001) and of overall survival (80% vs 42%; P = .0001) compared with patients with molecular failure. Patients with molecular failure without stem cell transplantation (SCT) in first CR relapsed after a median time of 7.6 months; CCR and survival at 5 years only reached 12% and 33%, respectively. Quantitative MRD assessment identified patients with molecular failure as a new high-risk group. These patients display resistance to conventional drugs and are candidates for treatment with targeted, experimental drugs and allogeneic SCT. Molecular response was shown to be highly predictive for outcome and therefore constitutes a relevant study end point. The studies are registered at www.clinicaltrials.gov as NCT00199056 and NCT00198991.
Blood 03/2012; 120(9):1868-76. · 9.90 Impact Factor
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Itziar Salaverria,
Claudia Philipp,
Ilske Oschlies,
Christian W Kohler,
Markus Kreuz,
Monika Szczepanowski,
Birgit Burkhardt, Heiko Trautmann,
Stefan Gesk,
Miroslaw Andrusiewicz, [......],
Julia Richter,
Maciej Rosolowski,
Carsten Schwaenen,
Harald Stein,
Lorenz Trümper,
Swen Wessendorf,
Rainer Spang,
Ralf Küppers,
Wolfram Klapper,
Reiner Siebert
[show abstract]
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ABSTRACT: The prognosis of germinal center-derived B-cell (GCB) lymphomas, including follicular lymphoma and diffuse large-B-cell lymphoma (DLBCL), strongly depends on age. Children have a more favorable outcome than adults. It is not known whether this is because of differences in host characteristics, treatment protocols, or tumor biology, including the presence of chromosomal alterations. By screening for novel IGH translocation partners in pediatric and adult lymphomas, we identified chromosomal translocations juxtaposing the IRF4 oncogene next to one of the immunoglobulin (IG) loci as a novel recurrent aberration in mature B-cell lymphoma. FISH revealed 20 of 427 lymphomas to carry an IG/IRF4-fusion. Those were predominantly GCB-type DLBCL or follicular lymphoma grade 3, shared strong expression of IRF4/MUM1 and BCL6, and lacked PRDM1/BLIMP1 expression and t(14;18)/BCL2 breaks. BCL6 aberrations were common. The gene expression profile of IG/IRF4-positive lymphomas differed from other subtypes of DLBCL. A classifier for IG/IRF4 positivity containing 27 genes allowed accurate prediction. IG/IRF4 positivity was associated with young age and a favorable outcome. Our results suggest IRF4 translocations to be primary alterations in a molecularly defined subset of GCB-derived lymphomas. The probability for this subtype of lymphoma significantly decreases with age, suggesting that diversity in tumor biology might contribute to the age-dependent differences in prognosis of lymphoma.
Blood 04/2011; 118(1):139-47. · 9.90 Impact Factor
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Blood 12/2009; 114(26):5400-1; author reply 5401-2. · 9.90 Impact Factor
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Michael Hummel,
Stefan Bentink,
Hilmar Berger,
Wolfram Klapper,
Swen Wessendorf,
Thomas F E Barth,
Heinz-Wolfram Bernd,
Sergio B Cogliatti,
Judith Dierlamm,
Alfred C Feller, [......],
Carsten Schwaenen,
Benjamin Stürzenhofecker,
Monika Szczepanowski, Heiko Trautmann,
Hans-Heinrich Wacker,
Rainer Spang,
Markus Loeffler,
Lorenz Trümper,
Harald Stein,
Reiner Siebert
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ABSTRACT: The distinction between Burkitt's lymphoma and diffuse large-B-cell lymphoma is unclear. We used transcriptional and genomic profiling to define Burkitt's lymphoma more precisely and to distinguish subgroups in other types of mature aggressive B-cell lymphomas.
We performed gene-expression profiling using Affymetrix U133A GeneChips with RNA from 220 mature aggressive B-cell lymphomas, including a core group of 8 Burkitt's lymphomas that met all World Health Organization (WHO) criteria. A molecular signature for Burkitt's lymphoma was generated, and chromosomal abnormalities were detected with interphase fluorescence in situ hybridization and array-based comparative genomic hybridization.
We used the molecular signature for Burkitt's lymphoma to identify 44 cases: 11 had the morphologic features of diffuse large-B-cell lymphomas, 4 were unclassifiable mature aggressive B-cell lymphomas, and 29 had a classic or atypical Burkitt's morphologic appearance. Also, five did not have a detectable IG-myc Burkitt's translocation, whereas the others contained an IG-myc fusion, mostly in simple karyotypes. Of the 176 lymphomas without the molecular signature for Burkitt's lymphoma, 155 were diffuse large-B-cell lymphomas. Of these 155 cases, 21 percent had a chromosomal breakpoint at the myc locus associated with complex chromosomal changes and an unfavorable clinical course.
Our molecular definition of Burkitt's lymphoma clarifies and extends the spectrum of the WHO criteria for Burkitt's lymphoma. In mature aggressive B-cell lymphomas without a gene signature for Burkitt's lymphoma, chromosomal breakpoints at the myc locus were associated with an adverse clinical outcome.
New England Journal of Medicine 07/2006; 354(23):2419-30. · 53.30 Impact Factor
