Michael Hummel

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Genomic and transcriptomic changes complement each other in the pathogenesis of sporadic Burkitt lymphoma.
MMML - Molecular mechanisms in malignant lymphoma

Abstract (Expand)

Burkitt lymphoma (BL) is the most common B-cell lymphoma in children. Within the International Cancer Genome Consortium (ICGC), we performed whole genome and transcriptome sequencing of 39 sporadic BL. … Here, we unravel interaction of structural, mutational, and transcriptional changes, which contribute to MYC oncogene dysregulation together with the pathognomonic IG-MYC translocation. Moreover, by mapping IGH translocation breakpoints, we provide evidence that the precursor of at least a subset of BL is a B-cell poised to express IGHA. We describe the landscape of mutations, structural variants, and mutational processes, and identified a series of driver genes in the pathogenesis of BL, which can be targeted by various mechanisms, including IG-non MYC translocations, germline and somatic mutations, fusion transcripts, and alternative splicing.

Authors: C. Lopez, K. Kleinheinz, S. M. Aukema, M. Rohde, S. H. Bernhart, D. Hubschmann, R. Wagener, U. H. Toprak, F. Raimondi, M. Kreuz, S. M. Waszak, Z. Huang, L. Sieverling, N. Paramasivam, J. Seufert, S. Sungalee, R. B. Russell, J. Bausinger, H. Kretzmer, O. Ammerpohl, A. K. Bergmann, H. Binder, A. Borkhardt, B. Brors, A. Claviez, G. Doose, L. Feuerbach, A. Haake, M. L. Hansmann, J. Hoell, M. Hummel, J. O. Korbel, C. Lawerenz, D. Lenze, B. Radlwimmer, J. Richter, P. Rosenstiel, A. Rosenwald, M. B. Schilhabel, H. Stein, S. Stilgenbauer, P. F. Stadler, M. Szczepanowski, M. A. Weniger, M. Zapatka, R. Eils, P. Lichter, M. Loeffler, P. Moller, L. Trumper, W. Klapper, S. Hoffmann, R. Kuppers, B. Burkhardt, M. Schlesner, R. Siebert

Date Published: 29th Mar 2019

Publication Type: Not specified

Human Diseases: lymphoma, Burkitt lymphoma

Clinical Impact of the Cell-of-Origin Classification and the MYC/ BCL2 Dual Expresser Status in Diffuse Large B-Cell Lymphoma Treated Within Prospective Clinical Trials of the German High-Grade Non-Hodgkin's Lymphoma Study Group.
GLA - German Lymphoma Alliance

Abstract (Expand)

Purpose To explore the prognostic impact and interdependence of the cell-of-origin (COO) classification, dual expression (DE) of MYC and BCL2 proteins, and MYC, BCL2, and BCL6 translocations in two … prospectively randomized clinical trials of patients with diffuse large B-cell lymphoma (DLBCL). Patients and Methods Overall, 452 formalin-fixed paraffin-embedded samples from two prospective, randomized DLBCL trials (RICOVER-60, prospective, randomized study for patients > 60 years, all IPI groups; and R-MegaCHOEP, prospective, randomized study for patients </= 60 years with age-adjusted IPI 2,3) of the German High-Grade Non-Hodgkin Lymphoma Study Group were analyzed with the Lymph2Cx assay for COO classification, with immunohistochemistry for MYC and BCL2, and with fluorescent in situ hybridization for MYC, BCL2, and BCL6 rearrangements. Results COO classification was successful in 414 of 452 samples. No significant differences with respect to COO (activated B-cell [ABC]-like DLBCL v germinal center B-cell [GCB]-like DLBCL) were observed in event-free survival, progression-free survival, and overall survival in patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in the RICOVER-60 trial. Also, no differences with respect to COO were observed in multivariable analyses adjusted for International Prognostic Index factors in event-free survival (hazard ratio [HR] of ABC-like disease v GCB-like disease, 1.0; 95% CI, 0.6 to 1.6; P = .93), progression-free survival (HR, 1.1; 95% CI, 0.6 to 1.8; P = .82), and overall survival (HR, 1.0; 95% CI, 0.6 to 1.8; P = .96). Similar results were observed in the R-MegaCHOEP trial. In patients treated with R-CHOP, DE status was associated with significantly inferior survival compared with nonDE within the GCB, but not within the ABC subgroup. DE status was associated with significantly inferior outcome compared with patients with ABC-like DLBCL without DE (5-year PFS rate, 39% [95% CI,19% to 59%] v 68% [95% CI, 52% to 85%]; P = .03) and compared with patients with GCB-like DLBCL without DE. When data from patients with nonDE were analyzed separately, the outcome of patients in the ABC subgroup was inferior to that of patients in the GCB subgroup (5-year PFS rate, 68% [95% CI, 52% to 85%] v 85% [95% CI, 74% to 96%]; P = .04). Conclusion COO profiling in two prospective randomized DLBCL trials failed to identify prognostic subgroups, whereas dual expression of MYC and BCL2 was predictive of poor survival. Evaluation of prognostic or predictive biomarkers in the management of DLBCL, such as the COO, within prospective clinical trials will be important in the future.

Authors: A. M. Staiger, M. Ziepert, H. Horn, D. W. Scott, T. F. E. Barth, H. W. Bernd, A. C. Feller, W. Klapper, M. Szczepanowski, M. Hummel, H. Stein, D. Lenze, M. L. Hansmann, S. Hartmann, P. Moller, S. Cogliatti, G. Lenz, L. Trumper, M. Loffler, N. Schmitz, M. Pfreundschuh, A. Rosenwald, G. Ott

Date Published: 1st Aug 2017

Publication Type: Not specified

Human Diseases: diffuse large B-cell lymphoma

Frequent NFKBIE deletions are associated with poor outcome in primary mediastinal B-cell lymphoma.
GLA - German Lymphoma Alliance

Abstract (Expand)

We recently reported a truncating deletion in the NFKBIE gene, which encodes IkappaBepsilon, a negative feedback regulator of NF-kappaB, in clinically aggressive chronic lymphocytic leukemia (CLL). … Because preliminary data indicate enrichment of NFKBIE aberrations in other lymphoid malignancies, we screened a large patient cohort (n = 1460) diagnosed with different lymphoid neoplasms. While NFKBIE deletions were infrequent in follicular lymphoma, splenic marginal zone lymphoma, and T-cell acute lymphoblastic leukemia (<2%), slightly higher frequencies were seen in diffuse large B-cell lymphoma, mantle cell lymphoma, and primary central nervous system lymphoma (3% to 4%). In contrast, a remarkably high frequency of NFKBIE aberrations (46/203 cases [22.7%]) was observed in primary mediastinal B-cell lymphoma (PMBL) and Hodgkin lymphoma (3/11 cases [27.3%]). NFKBIE-deleted PMBL patients were more often therapy refractory (P = .022) and displayed inferior outcome compared with wild-type patients (5-year survival, 59% vs 78%; P = .034); however, they appeared to benefit from radiotherapy (P =022) and rituximab-containing regimens (P = .074). NFKBIE aberrations remained an independent factor in multivariate analysis (P = .003) and when restricting the analysis to immunochemotherapy-treated patients (P = .008). Whole-exome sequencing and gene expression profiling verified the importance of NF-kappaB deregulation in PMBL. In summary, we identify NFKBIE aberrations as a common genetic event across B-cell malignancies and highlight NFKBIE deletions as a novel poor-prognostic marker in PMBL.

Authors: L. Mansouri, D. Noerenberg, E. Young, E. Mylonas, M. Abdulla, M. Frick, F. Asmar, V. Ljungstrom, M. Schneider, K. Yoshida, A. Skaftason, T. Pandzic, B. Gonzalez, A. Tasidou, N. Waldhueter, A. Rivas-Delgado, M. Angelopoulou, M. Ziepert, C. M. Arends, L. Couronne, D. Lenze, C. D. Baldus, C. Bastard, J. Okosun, J. Fitzgibbon, B. Dorken, H. G. Drexler, D. Roos-Weil, C. A. Schmitt, H. D. Munch-Petersen, T. Zenz, M. L. Hansmann, J. C. Strefford, G. Enblad, O. A. Bernard, E. Ralfkiaer, M. Erlanson, P. Korkolopoulou, M. Hultdin, T. Papadaki, K. Gronbaek, A. Lopez-Guillermo, S. Ogawa, R. Kuppers, K. Stamatopoulos, N. Stavroyianni, G. Kanellis, A. Rosenwald, E. Campo, R. M. Amini, G. Ott, T. P. Vassilakopoulos, M. Hummel, R. Rosenquist, F. Damm

Date Published: 8th Dec 2016

Publication Type: Not specified

Human Diseases: B-cell lymphoma

Novel IGH and MYC Translocation Partners in Diffuse Large B-Cell Lymphomas.
MMML - Molecular mechanisms in malignant lymphoma

Abstract (Expand)

Chromosomal translocations involving an immunoglobulin (IG) locus and a proto-oncogene play a major role in diffuse large B-cell lymphoma (DLBCL) pathogenesis. Recurrent IG translocation partners in … DLBCL are the BCL6, BCL2, and MYC genes, but other rare translocation partners are also known. We studied 20 DLBCL with fluorescence in situ hybridization-based evidence for IG heavy chain (IGH) locus-associated translocations not involving BCL6, BCL2, MALT1, or MYC by long distance inverse PCR to identify the translocation partners. Moreover, we studied eight DLBCL with MYC translocations not involving IG or known non-IG loci as translocation partner to search for novel MYC translocations. We identified three novel IGH-associated translocations. Chromosomal breakpoints involved the IMMP2L gene in 7q31, the BCAS2 gene in 1p13, and the PVRL2 gene in 19q13. The latter gene, which is recurrently translocated in T-cell lymphomas, is significantly higher expressed in the biopsy with the translocation compared to cases without this genetic aberration, indicating a pathogenetic role of PVRL2 also in DLBCL. In one case with a MYC break we obtained a novel MYC-SOCS1 translocation representing an unusual translocation of a proto-oncogene with a tumor suppressor gene. Indeed, we demonstrate that the oncogene was deregulated and the tumor suppressor gene inactivated. As both genes undergo aberrant somatic hypermutation in the region of the chromosomal breakpoints, this translocation likely happened as a byproduct of the hypermutation process. Overall, our study suggests that chromosomal translocations in DLBCL are more heterogeneous than previously known. (c) 2016 Wiley Periodicals, Inc.

Authors: C. Otto, R. Scholtysik, R. Schmitz, M. Kreuz, C. Becher, M. Hummel, A. Rosenwald, L. Trumper, W. Klapper, R. Siebert, R. Kuppers

Date Published: 30th Jun 2016

Publication Type: Journal article

Human Diseases: diffuse large B-cell lymphoma

Age and cellular composition influence overall survival in a collective of non-immunocompromised patients with EBV-positive diffuse large B-cell lymphoma from a German lymphoma center.
GLA - German Lymphoma Alliance

Abstract (Expand)

We investigated 41 diffuse large B-cell lymphomas (DLBCL) diagnosed at one center harboring >/=50% of latently Epstein-Barr virus (EBV)-infected neoplastic cells occurring in 34 patients aged >/=50 … years and in 7 patients younger than 50 years in the absence of any known immunodeficiency for the expression patterns of EBV latent and immediate-early proteins, for the differentiation stage of the neoplastic cells, the presence of cytogenetic alterations and a possible co-infection with the human herpes virus (HHV)-8. Here, we show that EBV-positive DLBCLs rarely arise from naive and more frequently from post-germinal center B-cells that often contain crippling immunoglobulin gene mutations. Most of the lymphomas did not exhibit breaks in the BCL2, BCL6, and MYC genes and none of the cases investigated contained HHV-8 sequences. Patients aged <50 years performed better than older ones while in patients aged >/=50 years only the cellular composition had an impact on overall survival.

Authors: K. Johrens, R. U. Trappe, D. Lenze, M. Pfreundschuh, M. Ziepert, M. Hummel, I. Anagnostopoulos

Date Published: 29th Apr 2016

Publication Type: Not specified

Human Diseases: diffuse large B-cell lymphoma

The PCBP1 gene encoding poly(rC) binding protein I is recurrently mutated in Burkitt lymphoma.
LIFE - Leipzig Research Center for Civilization Diseases

Abstract (Expand)

The genetic hallmark of Burkitt lymphoma is the translocation t(8;14)(q24;q32), or one of its light chain variants, resulting in IG-MYC juxtaposition. However, these translocations alone are insufficient … to drive lymphomagenesis, which requires additional genetic changes for malignant transformation. Recent studies of Burkitt lymphoma using next generation sequencing approaches have identified various recurrently mutated genes including ID3, TCF3, CCND3, and TP53. Here, by using similar approaches, we show that PCBP1 is a recurrently mutated gene in Burkitt lymphoma. By whole-genome sequencing, we identified somatic mutations in PCBP1 in 3/17 (18%) Burkitt lymphomas. We confirmed the recurrence of PCBP1 mutations by Sanger sequencing in an independent validation cohort, finding mutations in 3/28 (11%) Burkitt lymphomas and in 6/16 (38%) Burkitt lymphoma cell lines. PCBP1 is an intron-less gene encoding the 356 amino acid poly(rC) binding protein 1, which contains three K-Homology (KH) domains and two nuclear localization signals. The mutations predominantly (10/12, 83%) affect the KH III domain, either by complete domain loss or amino acid changes. Thus, these changes are predicted to alter the various functions of PCBP1, including nuclear trafficking and pre-mRNA splicing. Remarkably, all six primary Burkitt lymphomas with a PCBP1 mutation expressed MUM1/IRF4, which is otherwise detected in around 20-40% of Burkitt lymphomas. We conclude that PCBP1 mutations are recurrent in Burkitt lymphomas and might contribute, in cooperation with other mutations, to its pathogenesis.

Authors: R. Wagener, S. M. Aukema, M. Schlesner, A. Haake, B. Burkhardt, A. Claviez, H. G. Drexler, M. Hummel, M. Kreuz, M. Loeffler, M. Rosolowski, C. Lopez, P. Moller, J. Richter, M. Rohde, M. J. Betts, R. B. Russell, S. H. Bernhart, S. Hoffmann, P. Rosenstiel, M. Schilhabel, M. Szczepanowski, L. Trumper, W. Klapper, R. Siebert

Date Published: 16th Jul 2015

Publication Type: Not specified

Human Diseases: lymphoma

Characterization of genomic imbalances in diffuse large B-cell lymphoma by detailed SNP-chip analysis.
MMML - Molecular mechanisms in malignant lymphoma

Abstract (Expand)

The pathogenesis of diffuse large B-cell lymphomas (DLBCL) is only partly understood. We analyzed 148 DLBCL by single nucleotide polymorphism (SNP)-chips to characterize genomic imbalances. Seventy-nine … cases were of the germinal center B-cell like (GCB) type of DLBCL, 49 of the activated B-cell like (ABC) subtype and 20 were unclassified DLBCL. Twenty-four regions of recurrent genomic gains and 38 regions of recurrent genomic losses were identified over the whole cohort, with a median of 25 imbalances per case for ABC-DLBCL and 19 per case for GCB-DLBCL. Several recurrent copy number changes showed differential frequencies in the GCB- and ABC-DLBCL subgroups, including gains of HDAC7A predominantly in GCB-DLBCL (38% of cases) and losses of BACH2 and CASP8AP2 predominantly in ABC-DLBCL (35%), hinting at disparate pathogenetic mechanisms in these entities. Correlating gene expression and copy number revealed a strong gene dosage effect in all tumors, with 34% of probesets showing a concordant expression change in affected regions. Two new potential tumor suppressor genes emerging from the analysis, CASP3 and IL5RA, were sequenced in ten and 16 candidate cases, respectively. However, no mutations were found, pointing to a potential haploinsufficiency effect of these genes, considering their reduced expression in cases with deletions. Our study thus describes differences and similarities in the landscape of genomic aberrations in the DLBCL subgroups in a large collection of cases, confirming already known targets, but also discovering novel copy number changes with possible pathogenetic relevance.

Authors: R. Scholtysik, M. Kreuz, M. Hummel, M. Rosolowski, M. Szczepanowski, W. Klapper, M. Loeffler, L. Trumper, R. Siebert, R. Kuppers

Date Published: 1st Mar 2015

Publication Type: Not specified

Human Diseases: diffuse large B-cell lymphoma

Different biological risk factors in young poor-prognosis and elderly patients with diffuse large B-cell lymphoma.
GLA - German Lymphoma Alliance

Abstract (Expand)

Prognostically relevant risk factors in patients with diffuse large B-cell lymphoma (DLBCL) have predominantly been evaluated in elderly populations. We tested whether previously described risk factors … are also valid in younger, poor-prognosis DLBCL patients. Paraffin-embedded samples from 112 patients with de novo DLBCL, enrolled in the R-MegaCHOEP trial of the German High Grade Non-Hodgkin Lymphoma Study Group (DSHNHL) were investigated using immunohistochemistry (MYC, FOXP1, LMO2, GCET1, CD5, CD10, BCL2, BCL6, IRF4/MUM1) and fluorescence in situ hybridization (MYC, BCL2, BCL6). MYC, BCL2 and BCL6 breaks occurred in 14, 21 and 31%, respectively. In the majority of cases, MYC was simultaneously rearranged with BCL2 and/or BCL6. The adverse impact of MYC rearrangements was confirmed, but the sole presence of BCL2 breaks emerged as a novel prognostic marker associated with inferior overall survival (OS) (P=0.002). Combined overexpression of MYC and BCL2 showed only limited association with inferior OS. All immunohistochemical cell of origin classifiers applied failed to predict survival time. DLBCL tumors with significant proportion of immunoblastic and/or immunoblastic-plasmacytoid cells had inferior OS, independently from from BCL2 break. Younger, poor-prognosis DLBCL patients, therefore, display different biological risk factors compared with an elderly population, with BCL2 translocations emerging as a powerful negative prognostic marker.

Authors: H. Horn, M. Ziepert, M. Wartenberg, A. M. Staiger, T. F. Barth, H. W. Bernd, A. C. Feller, W. Klapper, C. Stuhlmann-Laeisz, M. Hummel, H. Stein, D. Lenze, S. Hartmann, M. L. Hansmann, P. Moller, S. Cogliatti, M. Pfreundschuh, L. Trumper, M. Loeffler, B. Glass, N. Schmitz, G. Ott, A. Rosenwald

Date Published: 18th Feb 2015

Publication Type: Not specified

Human Diseases: diffuse large B-cell lymphoma

Massive transcriptional perturbation in subgroups of diffuse large B-cell lymphomas.
MMML - Molecular mechanisms in malignant lymphoma

Abstract (Expand)

Based on the assumption that molecular mechanisms involved in cancerogenesis are characterized by groups of coordinately expressed genes, we developed and validated a novel method for analyzing … transcriptional data called Correlated Gene Set Analysis (CGSA). Using 50 extracted gene sets we identified three different profiles of tumors in a cohort of 364 Diffuse large B-cell (DLBCL) and related mature aggressive B-cell lymphomas other than Burkitt lymphoma. The first profile had high level of expression of genes related to proliferation whereas the second profile exhibited a stromal and immune response phenotype. These two profiles were characterized by a large scale gene activation affecting genes which were recently shown to be epigenetically regulated, and which were enriched in oxidative phosphorylation, energy metabolism and nucleoside biosynthesis. The third and novel profile showed only low global gene activation similar to that found in normal B cells but not cell lines. Our study indicates novel levels of complexity of DLBCL with low or high large scale gene activation related to metabolism and biosynthesis and, within the group of highly activated DLBCLs, differential behavior leading to either a proliferative or a stromal and immune response phenotype.

Authors: M. Rosolowski, J. Lauter, D. Abramov, H. G. Drexler, M. Hummel, W. Klapper, R. A. Macleod, S. Pellissery, F. Horn, R. Siebert, M. Loeffler

Date Published: 14th Nov 2013

Publication Type: Not specified

Human Diseases: diffuse large B-cell lymphoma

Biological characterization of adult MYC-translocation-positive mature B-cell lymphomas other than molecular Burkitt lymphoma.
MMML - Molecular mechanisms in malignant lymphoma

Abstract (Expand)

Chromosomal translocations affecting the MYC oncogene are the biological hallmark of Burkitt lymphomas but also occur in a subset of other mature B-cell lymphomas. If accompanied by a chromosomal break … targeting the BCL2 and/or BCL6 oncogene these MYC translocation-positive (MYC(+)) lymphomas are called double-hit lymphomas, otherwise the term single-hit lymphomas is applied. In order to characterize the biological features of these MYC(+) lymphomas other than Burkitt lymphoma we explored, after exclusion of molecular Burkitt lymphoma as defined by gene expression profiling, the molecular, pathological and clinical aspects of 80 MYC-translocation-positive lymphomas (31 single-hit, 46 double-hit and 3 MYC(+)-lymphomas with unknown BCL6 status). Comparison of single-hit and double-hit lymphomas revealed no difference in MYC partner (IG/non-IG), genomic complexity, MYC expression or gene expression profile. Double-hit lymphomas more frequently showed a germinal center B-cell-like gene expression profile and had higher IGH and MYC mutation frequencies. Gene expression profiling revealed 130 differentially expressed genes between BCL6(+)/MYC(+) and BCL2(+)/MYC(+) double-hit lymphomas. BCL2(+)/MYC(+) double-hit lymphomas more frequently showed a germinal center B-like gene expression profile. Analysis of all lymphomas according to MYC partner (IG/non-IG) revealed no substantial differences. In this series of lymphomas, in which immunochemotherapy was administered in only a minority of cases, single-hit and double-hit lymphomas had a similar poor outcome in contrast to the outcome of molecular Burkitt lymphoma and lymphomas without the MYC break. Our data suggest that, after excluding molecular Burkitt lymphoma and pediatric cases, MYC(+) lymphomas are biologically quite homogeneous with single-hit and double-hit lymphomas as well as IG-MYC and non-IG-MYC(+) lymphomas sharing various molecular characteristics.

Authors: S. M. Aukema, M. Kreuz, C. W. Kohler, M. Rosolowski, D. Hasenclever, M. Hummel, R. Kuppers, D. Lenze, G. Ott, C. Pott, J. Richter, A. Rosenwald, M. Szczepanowski, C. Schwaenen, H. Stein, H. Trautmann, S. Wessendorf, L. Trumper, M. Loeffler, R. Spang, P. M. Kluin, W. Klapper, R. Siebert

Date Published: 2nd Nov 2013

Publication Type: Not specified

Human Diseases: non-Hodgkin lymphoma, diffuse large B-cell lymphoma

Expression Data from Malignant Lymphoma
MMML-MYC-SYS

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.

Creator: Michael Hummel

Submitter: Christoph Beger

Data file type: Genomic Data

Human Diseases: B-cell lymphoma

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