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Articles by Wolfram Klapper
A TBK1/ULK1 signalling axis couples lysosomal stress to TFEB activation
Abstract Lysosomal adaptation to environmental changes is critical for cellular and metabolic homeostasis and requires coordination by the mTORC1 kinase, which conveys nutritional and stress signals into distinct, substrate-specific outputs1,2. The FLCN–FNIP complex (FLCN:FNIP) serves as a crucial regulator of lysosomal function by selectively controlling the ability of mTORC1 to inhibit transcription factor EB (TFEB), a master regulator of catabolic programs and a known oncogene3.
Mantle cell lymphoma artificial intelligence prognostic index using hematoxylin and eosin histology
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Abstract The clinical course of Mantle Cell Lymphoma (MCL) varies between individual patients. Early detection of risk is crucial to assign MCL patients to novel treatment strategies. Most of the established biomarkers of outcome require specifically trained pathologists or molecular analysis.
By Sarah Reinke, Karoline Koch, Ilske Oschlies, Stefan Schrod, Paul Huttl, Michael Huttner, Sílvia Beà, Elias Campo, Marco Ladetto, Sergio Cogliatti, Mats Ehinger, Grzegorz Rymkiewicz, Valentina Tabanelli, Hilka Rauert-Wunderlich, Andreas Rosenwald, Eva Hoster, Martin Dreyling, Michael Christoph Altenbuchinger, Wolfram Klapper, Jonas Lippl, Lukas Wolfseher, Rainer Spang
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Nature
Verified
KMT2A-rearranged B-lymphoblastic lymphomas are skewed towards a more mature developmental stage
To the Editor In both B-lymphoblastic leukemia (B-ALL) and Acute Myeloid Leukemia (AML), rearrangements of the KMT2A gene (KMT2Ar) are associated with unfavourable outcome. In contrast, in B-lymphoblastic lymphoma (B-LBL), the non-leukemic counterpart of B-ALL, no significant difference in progression-free and overall survival associated with KMT2Ar were observed in our previous study focused on a pediatric patients’ cohort [1].
Common origin and somatic mutation patterns of composite lymphomas and leukemias - Leukemia
Abstract When two lymphomas occur concurrently or sequentially in a patient, it is a major question whether they derive from the same lymphocyte or hematopoietic precursor cell or developed independently. We studied four composite classic Hodgkin lymphomas (HL) and other mature B-cell lymphomas, and two composite mature B- and T-cell neoplasias by whole exome sequencing (WES).
Refining histopathological growth pattern-based risk group discrimination in nodular lymphocyte-predominant Hodgkin lymphoma: an analysis from the German Hodgkin Study Group | Leukemia
Abstract Histopathological growth patterns (GP) in nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) have previously been divided into GP AB (typical) vs CDEF (variant). However, it is unclear whether this division is optimal. We thus investigated alternative GP grouping approaches (GP ABC vs DEF; GP ABCF vs DE). Overall, 583 NLPHL patients who had first-line treatment within GHSG trials were included in the analysis.
Subgrouping germinal center-derived B-cell lymphomas based on machine learning-deduced DNA methylation modules - Leukemia
To the Editor: Follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) are the most common lymphomas, both exhibiting features of germinal center-derived B-cells (gcBCs). DLBCL can arise de novo or through transformation of a low-grade lymphoma like FL. FL and DLBCL are heterogeneous with regard to clinical outcome as well as morphologic, immunophenotypic, genetic, transcriptomic and other biological aspects [1].
T-cell diversity and exclusion of blood-derived T-cells in the tumor microenvironment of classical Hodgkin Lymphoma - Leukemia
Abstract The Tumor Microenvironment (TME) in classical Hodgkin Lymphoma (HL) contains abundant immune cells and only few neoplastic Hodgkin and Reed-Sternberg cells (HRSC). We analyzed the T-cell receptor (TCR) repertoire to detect T-cell expansion in the TME and blood. In contrast to solid cancer tissue, T-cells in the TME of HL are highly polyclonal at first diagnosis and show only minor clonal expansion during anti-PD1 immune checkpoint blockade (ICB).
Lack of SMARCB1 expression characterizes a subset of human and murine peripheral T-cell lymphomas - Nature Communications
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Abstract Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is a heterogeneous group of malignancies with poor outcome. Here, we identify a subgroup, PTCL-NOSSMARCB1-, which is characterized by the lack of the SMARCB1 protein and occurs more frequently in young patients. Human and murine PTCL-NOSSMARCB1- show similar DNA methylation profiles, with hypermethylation of T-cell-related genes and hypomethylation of genes involved in myeloid development.
By Anja Fischer, Thomas Albert, Mathis Richter, Sebastian T. Balbach, Susanne Bens, Carolin Göbel, Daniel Münter, Alexander Chan, Ahmet Dogan, Jonathan Bush, Wolfgang Hartmann, Martin Dugas, Sarah Sandmann, Julian Varghese, Ulrich Schüller, Alexandar Tzankov, Francesco A. D’Amore, Karin Mellgren, Udo Kontny, Birgit Burkhardt, Oliver Soehnlein, Wolfram Klapper, Laurence de Leval
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Nature
Verified
Comprehensive genetic analysis by targeted sequencing identifies risk factors and predicts patient outcome in Mantle Cell Lymphoma: results from the EU-MCL network trials | Leukemia
Abstract Recent studies highlighted genetic aberrations associated with prognosis in Mantle Cell lymphoma (MCL), yet comprehensive testing is not implemented in clinical routine. We conducted a comprehensive genomic characterization of 180 patients from the European MCL network trials by targeted sequencing of peripheral blood DNA using the EuroClonality(EC)-NDC assay.
Identification, risk factors, and clinical course of CNS relapse in DLBCL patients across 19 prospective phase 2 and 3 trials-a LYSA and GLA/ DSHNHL collaboration | Leukemia
Abstract Progression or relapse in the central nervous system (CNS) remains a rare but mostly fatal event for patients with diffuse large B-cell lymphoma (DLBCL). In a retrospective analysis of 5189 patients treated within 19 prospective German and French phase 2/3 trials, we identified 159 patients experiencing a CNS event (relapse: 62%, progression: 38%). Intracerebral, meningeal, intraspinal, or combined involvement was reported in 44%, 31%, 3%, and 22% of patients, respectively.
Novel insights into the pathogenesis of follicular lymphoma by molecular profiling of localized and systemic disease forms - Leukemia
Abstract Knowledge on the pathogenesis of FL is mainly based on data derived from advanced/systemic stages of FL (sFL) and only small cohorts of localized FL (lFL) have been characterized intensively so far. Comprehensive analysis with profiling of somatic copy number alterations (SCNA) and whole exome sequencing (WES) was performed in 147 lFL and 122 sFL. Putative targets were analyzed for gene and protein expression.
Clinical outcome of Mantle Cell Lymphoma patients with high-risk disease (high-risk MIPI-c or high p53 expression) - Leukemia
Patients A total of 1183 MCL patients with confirmed MCL and Ann Arbor stage II to IV were registered in the MCL Younger [14] (NCT00209222) and MCL-Elderly trial [15] (NCT00209209) of the European MCL Network from 2004–2010 serving as training cohort. Patients without available Ki-67 and p53 data were excluded from this analysis. All patients gave written informed consent to participation in the trials.
Correction: “The 5th edition of The World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms” Leukemia. 2022 Jul;36(7):1720-1748 | Leukemia
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Correction to: Leukemia https://doi.org/10.1038/s41375-022-01620-2, published online 22 June 2022 At the time of original publication, there was an incomplete listing of contributing authors and their institutions. This revision corrects those omissions. 1. Dr Ritsuro Suzuki, Department of Hematology & Oncology, Shimane University School of Medicine, Shimane, Japan, was regrettably omitted from the main author list; 2.
By Rita Alaggio, Catalina Amador, Ioannis Anagnostopoulos, Ayoma D Attygalle, Emilio Berti, Govind Bhagat, Mariarita Calaminici, Amy Chadburn, Wah Cheuk, Wee-Joo Chng, John Choi, Shih-Sung Chuang, Sarah E. Coupland, Magdalena Czader, Sandeep Dave, Daphne de Jong, Ming-Qing Du, Kojo Elenitoba-Johnson, Judith A. Ferry, Julia T. Geyer, Dita A Gratzinger, Joan Guitart, Sumeet Gujral, Marian Harris, Christine Harrison, Sylvia Hartmann, Andreas Hochhaus Verified, Patty Jansen, Werner Kempf, Joseph Khoury, Hiroshi Kimura, Wolfram Klapper, Alexandra E. Kovach, Shaji Kumar Verified, Alexander J. Lazar, Stefano Lazzi, Lorenzo Leoncini, Nelson W. Y. Leung, Vasiliki Leventaki, Xiao-Qiu Li, Megan Lim Verified, Wei-ping Liu, Abner Louissaint Jr., Andrea Marcogliese, L. Jeffrey Medeiros, Michael Michal, Roberto N. Miranda, Christina Mitteldorf, Santiago Montes-Moreno, William Morice, Valentina Nardi, Kikkeri N. Naresh, Yasodha Natkunam, Siok-Bian Ng, Ilske Oschlies, German Ott, Marie Parrens, Melissa Pulitzer, S. Vincent Rajkumar, Andrew Rawstron, Karen L. Rech, Andreas Rosenwald, Clémentine Sarkozy, Caner Saygin, Anna Schuh, William Sewell, Reiner Siebert, Aliyah R. Sohani, Reuben M. Tooze, Alexandra Traverse-Glehen, Francisco Vega, Beatrice Vergier, Ashutosh D Wechalekar, Luc Xerri, Wenbin Xiao
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Nature
Verified
PARP14 is a novel target in STAT6 mutant follicular lymphoma - Leukemia
Abstract The variable clinical course of follicular lymphoma (FL) is determined by the molecular heterogeneity of tumor cells and complex interactions within the tumor microenvironment (TME). IL-4 producing follicular helper T cells (TFH) are critical components of the FL TME. Binding of IL-4 to IL-4R on FL cells activates JAK/STAT signaling. We identified STAT6 mutations (STAT6MUT) in 13% of FL (N = 33/258), all clustered within the DNA binding domain.
Characterization of IG-MYC-breakpoints and their application for quantitative minimal disease monitoring in high-risk pediatric Burkitt-lymphoma and -leukemia | Leukemia
To the Editor: The cure rate of children with Burkitt lymphoma (BL) and -leukemia (B-AL) reaches 90% with NHL-BFM-type chemotherapy. Only children with clinical high-risk disease (stage III or IV, LDH > 500U/l and/or CNS-involvement, risk groups R3 and R4; supplementary table 1) have a relapse rate exceeding 15% and their survival at relapse is 20% [1,2,3,4].
The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms - Leukemia
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Abstract We herein present an overview of the upcoming 5th edition of the World Health Organization Classification of Haematolymphoid Tumours focussing on lymphoid neoplasms. Myeloid and histiocytic neoplasms will be presented in a separate accompanying article. Besides listing the entities of the classification, we highlight and explain changes from the revised 4th edition.
By Rita Alaggio, Catalina Amador, Ioannis Anagnostopoulos, Ayoma D Attygalle, Emilio Berti, Govind Bhagat, Mariarita Calaminici, Amy Chadburn, Wah Cheuk, Wee-Joo Chng, John Choi, Shih-Sung Chuang, Sarah E. Coupland, Magdalena Czader, Sandeep Dave, Daphne de Jong, Ming-Qing Du, Kojo Elenitoba-Johnson, Judith A. Ferry, Julia T. Geyer, Dita A Gratzinger, Joan Guitart, Sumeet Gujral, Marian Harris, Christine Harrison, Sylvia Hartmann, Andreas Hochhaus Verified, Patty Jansen, Werner Kempf, Joseph Khoury, Hiroshi Kimura, Wolfram Klapper, Alexandra E. Kovach, Shaji Kumar Verified, Alexander J. Lazar, Stefano Lazzi, Lorenzo Leoncini, Nelson W. Y. Leung, Vasiliki Leventaki, Xiao-Qiu Li, Megan Lim Verified, Wei-ping Liu, Abner Louissaint Jr., Andrea Marcogliese, L. Jeffrey Medeiros, Michael Michal, Roberto N. Miranda, Christina Mitteldorf, Santiago Montes-Moreno, William Morice, Valentina Nardi, Kikkeri N. Naresh, Yasodha Natkunam, Siok-Bian Ng, Ilske Oschlies, German Ott, Marie Parrens, Melissa Pulitzer, S. Vincent Rajkumar, Andrew Rawstron, Karen L. Rech, Andreas Rosenwald, Clémentine Sarkozy, Caner Saygin, Anna Schuh, William Sewell, Reiner Siebert, Aliyah R. Sohani, Reuben M. Tooze, Alexandra Traverse-Glehen, Francisco Vega, Beatrice Vergier, Ashutosh D Wechalekar, Luc Xerri
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Nature
Verified
Rare haematologic and neurologic drug reactions from immune checkpoint inhibition in a responding patient with metastatic anorectal mucosal melanoma
Immune checkpoint inhibitors (ICIs) blocking engagement with the cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) or the programmed death 1 (PD-1) receptors have emerged to dramatically improve the treatment outcome of various advanced cancer types. In melanoma, the combination of nivolumab (anti-PD-1) with ipilimumab (anti-CTLA-4) has demonstrated significantly improved long-term survival [ [1] Larkin J. Chiarion-Sileni V. Gonzalez R. Grob J.J. Rutkowski P. Lao C.D. et al.
Gene expression-based outcome prediction in advanced stage classical Hodgkin lymphoma treated with BEACOPP
To the Editor: Classical Hodgkin Lymphoma (cHL) is a B cell-derived lymphoid malignancy, affecting 2.5–3/100,000 people per year. To date, in patients diagnosed with advanced cHL no reliable tool is able to—a priori—distinguish the subset of patients at high risk for relapse or refractory disease. Clinical risk indices for cHL, such as the International Prognostic Score (IPS), have not been successfully applied as a treatment decision tool in advanced stage cHL [1].
Longevity of lobsters is linked to ubiquitous telomerase expression
Abstract Mammals have high growth rates in embryonic and juvenile phases and no growth in adult and senescent phases. We analyzed telomerase activity in a fundamentally different animal which grows indeterminately. Lobsters (Homarus americanus) grow throughout their life and the occurrence of senescence is slow. A modified TRAP assay was developed and the lobster telomeric repeat sequence TTAGG was determined.
ATM activity in T cells is critical for immune surveillance of lymphoma in vivo
Abstract The proximal DNA damage response kinase ATM is frequently inactivated in human malignancies. Germline mutations in the ATM gene cause Ataxia-telangiectasia (A-T), characterized by cerebellar ataxia and cancer predisposition. Whether ATM deficiency impacts on tumor initiation or also on the maintenance of the malignant state is unclear. Here, we show that Atm reactivation in initially Atm-deficient B- and T cell lymphomas induces tumor regression.
A novel lymphoma-associated macrophage interaction signature (LAMIS) provides robust risk prognostication in diffuse large B-cell lymphoma clinical trial cohorts of the DSHNHL
Abstract Diffuse large B-cell lymphoma (DLBCL) is a disease with heterogeneous outcome. Stromal signatures have been correlated to survival in DLBCL. Their use, however, is hampered by the lack of assays for formalin-fixed paraffin-embedded material (FFPE). We constructed a lymphoma-associated macrophage interaction signature (LAMIS) interrogating features of the microenvironment using a NanoString assay applicable to FFPE.
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