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Article
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Combination of acalabrutinib with lenalidomide and rituximab in relapsed/refractory aggressive B-cell non-Hodgkin lymphoma: a single-arm phase II trial
Potential synergism between BTK inhibitor and lenalidomide in treating aggressive B-cell lymphoma has been suggested. Here, the authors report a single-arm phase II clinical trial of combination of acalabrutinib, lenalidomide and rituximab in patients with aggressive Relapsed/Refractory aggressive B-cell non-Hodgkin lymphoma.
- Changhee Park
- , Ho Sup Lee
- & Youngil Koh
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Article
| Open Access
Spatially-resolved transcriptomics reveal macrophage heterogeneity and prognostic significance in diffuse large B-cell lymphoma
Macrophages are abundant in the microenvironment of diffuse large B-cell lymphoma (DLBCL). Here, the authors use spatial transcriptomics to characterize macrophages in DLBCL and reactive lymphoid tissues, and propose six spatially-derived macrophage signatures that are associated with features like cell of origin and clinical outcomes.
- Min Liu
- , Giorgio Bertolazzi
- & Anand D. Jeyasekharan
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Article
| Open Access
Mosaic chromosomal alterations in peripheral blood leukocytes of children in sub-Saharan Africa
Mosaic chromosomal alterations (mCAs) in peripheral blood leukocytes are associated with an increased risk of malignancy. Here, the authors use genome-wide genotyping array data to investigate the prevalence of mCAs in sub-Saharan African children with versus those without Burkitt lymphoma.
- Weiyin Zhou
- , Anja Fischer
- & Sam M. Mbulaiteye
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Transcriptomic profiles and 5-year results from the randomized CLL14 study of venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab in chronic lymphocytic leukemia
The CLL14 study (NCT02242942) explored the activity of obinutuzumab (anti-CD20) plus venetoclax (Bcl2 inhibitor) versus obinutuzumab plus chlorambucil in patients with previously untreated chronic lymphocytic leukemia (CLL). Here the authors report the 5-year long-term results of the clinical trial and transcriptional profiles associated with response to therapies.
- Othman Al-Sawaf
- , Can Zhang
- & Kirsten Fischer
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Article
| Open Access
Synthetic lethality of drug-induced polyploidy and BCL-2 inhibition in lymphoma
Genomic instability occurs infrequently in in diffuse large B cell lymphoma (DLBCL), suggesting a therapeutic vulnerability. Here, the authors identify a synergistic combination between the induction of polyploidy by a PLK4 inhibitor and a BCL-2 inhibitor in DLBCL.
- Ana Portelinha
- , Mariana da Silva Ferreira
- & Hans-Guido Wendel
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| Open Access
BET inhibitor trotabresib in heavily pretreated patients with solid tumors and diffuse large B-cell lymphomas
Bromodomain and extraterminal proteins (BET) are reported as targets for anticancer therapy. Here, the authors report the final results of a phase I clinical trial of the BET inhibitor trotabresib in patients with solid tumours and diffuse large B-cell lymphoma.
- Victor Moreno
- , Maria Vieito
- & Irene Braña
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| Open Access
Molecular characterization of Richter syndrome identifies de novo diffuse large B-cell lymphomas with poor prognosis
Richter syndrome (RS) is the transformation of chronic lymphocytic leukaemia (CLL) into aggressive lymphoma, in most cases diffuse large B-cell lymphoma (DLBCL). Here, the authors characterize the DNA methylation and transcriptomic profiles of RS samples, find a clonally-related CLL epigenetic imprint, and develop classifiers for “RS-type” de novo DLBCLs.
- Julien Broséus
- , Sébastien Hergalant
- & Stephan Stilgenbauer
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Article
| Open Access
Dysregulation of PRMT5 in chronic lymphocytic leukemia promotes progression with high risk of Richter’s transformation
Richter’s Transformation is a treatment-resistant and fatal progression from Chronic Lymphocytic Leukemia (CLL) to an aggressive lymphoma. Here, the authors show that PRMT5 is upregulated months prior to and after transformation, PRMT5 overexpression in a CLL mouse model leads to increased risk of transformation, and that targeted PRMT5 inhibition prolongs survival and delays disease development.
- Zachary A. Hing
- , Janek S. Walker
- & Rosa Lapalombella
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Article
| Open Access
Single-cell profiling reveals a memory B cell-like subtype of follicular lymphoma with increased transformation risk
Follicular lymphoma can transform to a more aggressive histology. Here, the authors use bulk and single cell analysis to create a 26 marker panel which could be used to profile FL samples and predict the risk of transformation using flow cytometry.
- Xuehai Wang
- , Michael Nissen
- & Andrew P. Weng
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Article
| Open Access
TP53 mutations and RNA-binding protein MUSASHI-2 drive resistance to PRMT5-targeted therapy in B-cell lymphoma
Inhibition of the protein arginine methyltransferase PRMT5 has been suggested as a promising therapy for lymphoma. Here, the authors show that TP53 loss of function and MUSASHI-2 (MSI2) expression are biomarkers of resistance to PRMT5-targeted therapy in B-cell lymphoma. Moreover, combining PRMT5 inhibition with MSI2 or BCL-2 inhibitors blocks the translation of key drivers of lymphoma, c-MYC and BCL-2, inhibiting cell growth.
- Tatiana Erazo
- , Chiara M. Evans
- & Michael G. Kharas
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Article
| Open Access
Clinical relevance of molecular characteristics in Burkitt lymphoma differs according to age
Survival outcomes in Burkitt lymphoma differ between adult and paediatric patients. Here, the authors show differences in mutational frequencies between age groups, and a transition between mutational profiles which occurs between 25 and 40 years.
- Birgit Burkhardt
- , Ulf Michgehl
- & Georg Lenz
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Article
| Open Access
The genomic and transcriptional landscape of primary central nervous system lymphoma
Primary lymphomas of the central nervous system (PCNSL) are defined as diffuse large B-cell lymphomas (DLBCL) confined to the CNS. Here, the authors complete whole genome sequencing and RNA-seq to characterize 51 PCNSLs, and find common mutations in immune pathways and upregulated TERT expression and find distinct pathway differences between DLBCL and other primary CNS lymphomas.
- Josefine Radke
- , Naveed Ishaque
- & Frank L. Heppner
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| Open Access
A loss-of-adhesion CRISPR-Cas9 screening platform to identify cell adhesion-regulatory proteins and signaling pathways
Targeting integrin-mediated retention of malignant B cells in their protective microenvironment is an efficacious treatment for lymphoma and leukemia. Here, the authors present an unbiased loss-of-adhesion CRISPR screening method, identifying therapeutic targets for these B-cell malignancies.
- Martin F. M. de Rooij
- , Yvonne J. Thus
- & Marcel Spaargaren
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| Open Access
Genetic alterations of the SUMO isopeptidase SENP6 drive lymphomagenesis and genetic instability in diffuse large B-cell lymphoma
SUMOylation is a post-translational modification that has been shown to be altered in cancer. Here, the authors show that loss of the SUMO isopeptidase SENP6 leads to unrestricted SUMOylation and genomic instability promoting lymphomagenesis and generating vulnerability to PARP inhibition.
- Markus Schick
- , Le Zhang
- & Ulrich Keller
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Article
| Open Access
Molecular and functional profiling identifies therapeutically targetable vulnerabilities in plasmablastic lymphoma
Plasmablastic lymphoma (PBL) is an aggressive lymphoma subtype characterized by poor prognosis but the molecular knowledge of the disease is limited. Here, the authors perform whole exome sequencing and copy number determination of primary samples highlighting IRF4 and JAK-STAT pathways as therapeutic targets for PBL.
- Fabian Frontzek
- , Annette M. Staiger
- & Georg Lenz
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Article
| Open Access
Longitudinal single-cell profiling reveals molecular heterogeneity and tumor-immune evolution in refractory mantle cell lymphoma
Mantle cell lymphoma can be refractory to treatment. Here, the authors used single cell sequencing to study the tumours of patients that were responsive and resistant to treatment and find gains of 17q in resistant tumours, which they attribute to increased expression of Birc5 and validate these findings in mouse models of the disease.
- Shaojun Zhang
- , Vivian Changying Jiang
- & Michael Wang
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Article
| Open Access
Targeting N-myristoylation for therapy of B-cell lymphomas
N-myristoyltransferases (NMTs) target many signaling proteins to membranes. Here the authors show an NMT inhibitor named PCLX-001 selectively kills lymphoma cells by shutting down their main survival signaling pathway and offers an additional treatment strategy for lymphoma patients.
- Erwan Beauchamp
- , Megan C. Yap
- & Luc G. Berthiaume
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| Open Access
H3K9me3-mediated epigenetic regulation of senescence in mice predicts outcome of lymphoma patients
Therapy-induced senescence reflects a biological effector principle that is underrecognized in lesion-focused cancer precision medicine. Here the authors utilize mouse lymphoma genetics to functionally dissect senescence and cross-species apply a novel senescence-based prognosticator to lymphoma patients.
- Kolja Schleich
- , Julia Kase
- & Clemens A. Schmitt
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Article
| Open Access
PRDM15 is a key regulator of metabolism critical to sustain B-cell lymphomagenesis
The transcriptional regulator PRDM15 is expressed at low levels in normal tissues but overexpressed in B-cell lymphomas. Here, the authors show that PRDM15 depletion does not affect adult somatic cell homeostasis but leads to a metabolic crisis which impairs B-cell lymphomagenesis.
- Slim Mzoughi
- , Jia Yi Fong
- & Ernesto Guccione
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Article
| Open Access
Two high-risk susceptibility loci at 6p25.3 and 14q32.13 for Waldenström macroglobulinemia
Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) is a non-Hodgkin-type B cell lymphoma. Here, the authors identify two risk loci for WM/LPL in a two-stage GWAS involving a family-oversampling approach and provide evidence for a functional role of the non-coding SNP rs116446171.
- Mary L. McMaster
- , Sonja I. Berndt
- & Neil E. Caporaso
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Article
| Open Access
A licensing step links AID to transcription elongation for mutagenesis in B cells
Activation-induced deaminase (AID) is important for inducing desirable mutations at the B cell receptor genes for effective antibody responses. Here the authors show that three key arginine residues of AID link AID-chromatin association with transcription elongation to license AID for specific mutagenesis in B cells.
- Stephen P. Methot
- , Ludivine C. Litzler
- & Javier M. Di Noia
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Article
| Open Access
AICDA drives epigenetic heterogeneity and accelerates germinal center-derived lymphomagenesis
In diffuse large B-cell lymphoma (DLBCL) increased epigenetic heterogeneity in the form of cytosine methylation is known to link to a poor clinical outcome. Here, the authors show that AICDA, an enzyme required for DLBCL pathogenesis, increases cytosine methylation heterogeneity.
- Matt Teater
- , Pilar M. Dominguez
- & Rita Shaknovich
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Article
| Open Access
HSP70-Hrd1 axis precludes the oncorepressor potential of N-terminal misfolded Blimp-1s in lymphoma cells
The transcriptional repressor Blimp-1 has an important role in B-cell differentiation. Here the authors show that lymphoma-associated Blimp-1 mutants are selectively recognized by HSP70-Hrd1, which leads to their accelerated degradation and propose HSP70 inhibition as a therapeutic approach for certain lymphomas.
- Wen-Fang Wang
- , Li Yan
- & Jiang Zhu
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Article
| Open Access
Unification of de novo and acquired ibrutinib resistance in mantle cell lymphoma
Ibrutinib has demonstrated high response rates in B-cell lymphomas but a lot of ibrutinib-treated patients relapse with resistance. This study unified TME-mediatedde novoand acquired drug resistance through B-cell receptor signalling and PI3K-AKT-mTOR axis and provides a combination therapeutic strategy against B-cell malignancies.
- Xiaohong Zhao
- , Tint Lwin
- & Jianguo Tao
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Article
| Open Access
Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia
Chronic lymphocytic leukaemia has a hereditary component, much of which remains to be identified. Here, the authors perform a genome-wide association study and find new risk loci for the disease, which are associated with genes involved in immune function.
- Philip J. Law
- , Sonja I. Berndt
- & Susan Slager
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| Open Access
miR-17-92 fine-tunes MYC expression and function to ensure optimal B cell lymphoma growth
The synergism between c-MYC and miR-17-19b plays an important role in lymphoma initiation. In this study, the authors identify a panel of targets co-regulated by miR-17-19b and in MYC-driven lymphoma and unravel the molecular mechanism through which miR-17-19b inhibits MYCtranslation.
- Marija Mihailovich
- , Michael Bremang
- & Tiziana Bonaldi
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| Open Access
D2HGDH regulates alpha-ketoglutarate levels and dioxygenase function by modulating IDH2
IDH1- and IDH2-mutant cancer cells aberrantly accumulate D2-hydroxyglutarate (D2-HG). Here, Lin et al. find loss-of-function mutations in D2-hydroxyglutarate dehydrogenase (D2HGDH), which converts D2-HG to alpha-ketoglutarate (α-KG), in diffuse large B-cell lymphomas and show that D2HGDH via α-KG regulates the expression and activity of IDH2.
- An-Ping Lin
- , Saman Abbas
- & Ricardo C. T. Aguiar
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| Open Access
Epigenomic evolution in diffuse large B-cell lymphomas
The contribution of epigenomic alterations to tumour progression and relapse is not well characterized. Here the authors characterize epigenetic evolution in aggressive B-cell lymphoma and find that epigenomic heterogeneity may not only support and drive the relapse phenotype but also be used to predict lymphoma relapse.
- Heng Pan
- , Yanwen Jiang
- & Olivier Elemento
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Article
| Open Access
Neuropilin 1 is an entry factor that promotes EBV infection of nasopharyngeal epithelial cells
Epstein–Barr virus (EBV) is involved in the development of some cancers including nasopharyngeal carcinoma. Here, the authors show that a direct interaction between the viral protein gB and a host protein, neuropilin 1, is required for EBV infection of nasopharyngeal epithelial cells.
- Hong-Bo Wang
- , Hua Zhang
- & Mu-Sheng Zeng
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Clustering of CARMA1 through SH3–GUK domain interactions is required for its activation of NF-κB signalling
Activating mutations in the NF-κB regulator CARMA1 are associated with a form of B-cell lymphoma. Hara et al. show that both physiological and oncogenic CARMA1 signalling can be inhibited by preventing its activation-induced clustering, which is mediated by its SH3 and GUK domains.
- Hiromitsu Hara
- , Tadashi Yokosuka
- & Takashi Saito
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Conversion of the LIMA1 tumour suppressor into an oncogenic LMO-like protein by API2–MALT1 in MALT lymphoma
Protein fusions between the paracaspase MALT1 and API2 (inhibitor of apoptosis 2) are found in B-cell lymphoma. Here the authors identify the tumour suppressor LIMA1 as a new target of API2–MALT1 chimeric protein and show that API2–MALT1-mediated proteolysis generates a LIM domain-only (LMO)-containing fragment with oncogenic properties in vitro and in vivo.
- Zilin Nie
- , Ming-Qing Du
- & Kojo S. J. Elenitoba-Johnson
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| Open Access
MNKs act as a regulatory switch for eIF4E1 and eIF4E3 driven mRNA translation in DLBCL
Diffuse large B-cell lymphoma (DLBCL) is a highly aggressive and heterogeneous type of non-Hodgkin’s lymphoma. Here the authors demonstrate that the differential regulation of eIF4E1 and eIF4E3 by the MAPK-interacting kinases is involved in DLBCL aetiology through modification of the cellular translatome.
- Ari L. Landon
- , Parameswary A. Muniandy
- & Ronald B. Gartenhaus
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Dendritic cell-mediated survival signals in Eμ-Myc B-cell lymphoma depend on the transcription factor C/EBPβ
Dendritic cells (DC) are known to promote cancer progression by suppressing antitumor immunity. Here, Rehm et al. describe a mechanism whereby lymphoma cells induce C/EBPβ activation in DCs, which in turn secrete cytokines that support the proliferation and survival of lymphoma cells.
- Armin Rehm
- , Marcel Gätjen
- & Uta E. Höpken
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Transient expression of Bcl6 is sufficient for oncogenic function and induction of mature B-cell lymphoma
Diffuse large B-cell lymphoma is an aggressive heterogeneous tumour type with poorly understood aetiology. Here, Green et al. show that transient expression of Bcl6in haematopoietic stem cells is sufficient to induce mature B-cell lymphoma, indicating that it acts as a ‘hit-and-run’ oncogene.
- Michael R. Green
- , Carolina Vicente-Dueñas
- & Isidro Sánchez-García
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Smurf2 suppresses B-cell proliferation and lymphomagenesis by mediating ubiquitination and degradation of YY1
Mice deficient in the E3 ubiquitin ligase Smurf2 spontaneously develop B-cell lymphomas. Here Ramkumar et al.show that Smurf2 regulates B-cell proliferation by ubiquitinating the transcription factor YY1, and that Smurf2 expression correlates negatively with survival of patients with diffuse large B-cell lymphoma.
- Charusheila Ramkumar
- , Hang Cui
- & Hong Zhang
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Germinal centre protein HGAL promotes lymphoid hyperplasia and amyloidosis via BCR-mediated Syk activation
The human germinal centre-associated lymphoma gene is expressed in germinal centre B-lymphocytes; however, its function is unknown. Here the authors show that human germinal centre-associated lymphoma activates Syk kinase, leading to lymphoid hyperplasia and systemic reactive amyloid A amyloidosis in transgenic mice.
- Isabel Romero-Camarero
- , Xiaoyu Jiang
- & Izidore S Lossos
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Article
| Open Access
Functional and molecular interactions between ERK and CHK2 in diffuse large B-cell lymphoma
Chk2 is a kinase that is a potential chemotherapeutic target. Here, Chk2 and the kinase ERK are shown to functionally interact, and are elevated in expression in human diffuse B-cell lymphomas. Combinatorial inhibition of the kinases was also shown to block tumour growth in anin vivomouse model.
- Bojie Dai
- , X. Frank Zhao
- & Ronald B. Gartenhaus
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Article
| Open Access
Inflammation driven by tumour-specific Th1 cells protects against B-cell cancer
Inflammation can result in the formation of tumours, but the immune system is also involved in the elimination of cancer cells. Here, the authors show that inflammation driven by tumour-specific CD4+T cells results in tumour regression and identify a list of cytokines associated with cancer prevention.
- Ole Audun Werner Haabeth
- , Kristina Berg Lorvik
- & Alexandre Corthay
Loss of CREBBP and KMT2D cooperate to accelerate lymphomagenesis and shape the lymphoma immune microenvironment