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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
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Structure-guided engineering of immunotherapies targeting TRBC1 and TRBC2 in T cell malignancies
The T cell receptor β-chain is expressed in two isoforms, TRBC1 and TRBC2, with clonally expanded mature T cell lymphomas expressing one of them exclusively, while healthy T cells randomly express either TRBC1 or TRBC2. Here authors show structure-based design of a TRBC2-specific antibody, and depletion of malignant T cells carrying TRBC1 or TRBC2 with CAR-T cells against the cognate receptor chain in murine models.
- Mathieu Ferrari
- , Matteo Righi
- & Martin Pule
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Article
| Open Access
Epstein-Barr virus-driven B cell lymphoma mediated by a direct LMP1-TRAF6 complex
Epstein-Barr virus causes lymphoma. Here the authors describe a direct complex of the viral oncoprotein LMP1 with the cellular TRAF6 protein as a critical virus-host interface for lymphoma survival and validate this complex as a potential therapeutic target.
- Fabian Giehler
- , Michael S. Ostertag
- & Arnd Kieser
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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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Article
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Transcriptional reprogramming by mutated IRF4 in lymphoma
Cancer is often associated with mutant transcription factors (TFs) but their functional characterization is challenging. Here, the authors describe a recurrent mutation within TF IRF4 in human lymphomas and they show how it causes a complex switch in TF specificity and functionality.
- Nikolai Schleussner
- , Pierre Cauchy
- & Stephan Mathas
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| Open Access
Context-defined cancer co-dependency mapping identifies a functional interplay between PRC2 and MLL-MEN1 complex in lymphoma
Co-dependency mapping assays have revealed genetic dependencies in cancer and could shed light on chromatin crosstalk mechanisms. Here, the authors establish a pipeline to integrate co-dependency mapping screens with molecular information in pan-cancer cell lines in order to reveal chromatin complexes and potential drug targets.
- Xiao Chen
- , Yinglu Li
- & Chao Lu
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Article
| Open Access
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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Article
| 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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Article
| 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
Generation of a CRISPR activation mouse that enables modelling of aggressive lymphoma and interrogation of venetoclax resistance
Modelling of aggressive lymphomas, such as double hit lymphoma, has been challenging. Here the authors engineer a CRISPR activation mouse to enable the generation of these aggressive lymphomas and identify the pro-survival BCL-2 protein A1 as a venetoclax resistance factor.
- Yexuan Deng
- , Sarah T. Diepstraten
- & Marco J. Herold
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Article
| Open Access
T cell receptor β-chain-targeting chimeric antigen receptor T cells against T cell malignancies
Healthy T cells are polyclonal, while malignant T cells are developing via clonal expansion. Here authors show that T cell tumours could be eradicated by chimeric antigen receptor T cells targeting the T cell receptor (TCR) β-chain that is specific to malignant T cells, while healthy T cells using diverse TCR β-chains are spared.
- Fanlin Li
- , Huihui Zhang
- & Xuanming Yang
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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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| 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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Article
| Open Access
IRF4 drives clonal evolution and lineage choice in a zebrafish model of T-cell lymphoma
IRF4 is a regulator of immune function, and is overexpressed in lymphoid neoplasms. Here, the authors utilise single cell RNA-seq to show the abundance of double-negative T cells in IRF4 driven zebrafish tumour models, and identify sensitivity of these tumours to BRD inhibition.
- Stella Amanda
- , Tze King Tan
- & Takaomi Sanda
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Article
| 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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Article
| Open Access
Single-cell transcriptomics links malignant T cells to the tumor immune landscape in cutaneous T cell lymphoma
Cutaneous T cell lymphomas (CTCL) are still poorly characterised at the molecular and single-cell level. Here, the authors analyse CTCL patient samples using single-cell RNA-seq, TCR and whole-exome sequencing, revealing the molecular profiles of malignant T cells and their association with the microenvironment and clinical outcomes.
- Xiangjun Liu
- , Shanzhao Jin
- & Yang Wang
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Article
| 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
Immune cell topography predicts response to PD-1 blockade in cutaneous T cell lymphoma
PD-1 blockade is effective for only a subset of patients with cutaneous T cell lymphomas. Here, the authors report a spatial biomarker that uses immune and cancer cell topography to predict response to PD-1 blockade in this disease.
- Darci Phillips
- , Magdalena Matusiak
- & Garry P. Nolan
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Article
| Open Access
Super-enhancer-based identification of a BATF3/IL-2R−module reveals vulnerabilities in anaplastic large cell lymphoma
Anaplastic large cell lymphoma (ALCL) is an aggressive T-cell lymphoma often with poor prognosis. To identify genes defining ALCL cell state and dependencies, the authors here characterize ALCL-specific super-enhancers and describe the BATF3/IL-2R−module as a therapeutic opportunity for ALCL.
- Huan-Chang Liang
- , Mariantonia Costanza
- & Olaf Merkel
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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
Chronological genome and single-cell transcriptome integration characterizes the evolutionary process of adult T cell leukemia-lymphoma
Characterising the clonal architecture of Adult T-cell leukemia-lymphoma (ATL) remains crucial. Here, the authors develop a capture-based sequencing panel and use deep DNA and single cell RNA sequencing and report distinct genomic and transcriptomic features associated with subclonal evolution.
- Makoto Yamagishi
- , Miyuki Kubokawa
- & Kaoru Uchimaru
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Article
| Open Access
Fusion transcripts FYN-TRAF3IP2 and KHDRBS1-LCK hijack T cell receptor signaling in peripheral T-cell lymphoma, not otherwise specified
Peripheral T cell lymphoma (PTCL) not otherwise specified (NOS) is a subgroup of PTCL, which has no distinctive features and is poorly characterized at the genetic level. Here, the authors identify two fusion transcripts that activate T cell receptor complex signalling and confer therapeutic vulnerability in PTCL-NOS.
- Koen Debackere
- , Lukas Marcelis
- & Daan Dierickx
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Article
| Open Access
Robust detection of translocations in lymphoma FFPE samples using targeted locus capture-based sequencing
Preservation of cancer biopsies by FFPE introduces DNA fragmentation, hindering analysis of rearrangements. Here the authors introduce FFPE Targeted Locus Capture for identification of translocations in preserved samples.
- Amin Allahyar
- , Mark Pieterse
- & Wouter de Laat
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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
CXCR5 CAR-T cells simultaneously target B cell non-Hodgkin’s lymphoma and tumor-supportive follicular T helper cells
CAR-T cell therapy targeting CD19 is not as efficient to treat lymphoma with nodal dissemination as it is for B cell leukaemia. Here, the authors generate CAR-T cells against CXCR5 and show they inhibit tumour growth by depleting both B and follicular T helper cells in lymphoma models.
- Mario Bunse
- , Janina Pfeilschifter
- & Uta E. Höpken
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Article
| Open Access
TRIB3 promotes MYC-associated lymphoma development through suppression of UBE3B-mediated MYC degradation
c-MYC is often deregulated in human cancers including lymphomas. Here, the authors show that a member of the pseudokinase family, tribbles homologue 3 (TRIB3), interacts with c-MYC to suppress c-MYC ubiquitination and degradation, leading to increased proliferation and self-renewal of lymphoma cells.
- Ke Li
- , Feng Wang
- & Zhuo-wei Hu
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Article
| Open Access
A deep learning diagnostic platform for diffuse large B-cell lymphoma with high accuracy across multiple hospitals
Replacing diagnostic histopathology with AI-based tools requires large training datasets and robustness to sample variability. Here, the authors present a deep learning platform with high accuracy in large diffuse B-cell lymphoma diagnosis across multiple hospitals, trained on small datasets.
- Dongguang Li
- , Jacob R. Bledsoe
- & Shaoguang Li
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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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Article
| 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
Btk SH2-kinase interface is critical for allosteric kinase activation and its targeting inhibits B-cell neoplasms
Constitutive Btk signaling drives several B-cell cancers. Here the authors demonstrate key allosteric intramolecular interactions between the SH2 domain and the kinase domain of Btk, and propose an alternative approach for inhibition of both wild-type and tyrosine kinase inhibitor-resistant Btk.
- Daniel P. Duarte
- , Allan J. Lamontanara
- & Oliver Hantschel
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Article
| Open Access
Endogenous topoisomerase II-mediated DNA breaks drive thymic cancer predisposition linked to ATM deficiency
The ATM kinase is a key regulator of the DNA damage response to double-strand breaks (DSBs) and its homozygous loss in patients predisposes to lymphoid malignancies. Here, the authors develop a Tdp2−/− Atm−/− double-deficient mouse model to uncover topoisomerase II-induced DSBs as significant drivers of the genomic rearrangements that underpin these tumours.
- Alejandro Álvarez-Quilón
- , José Terrón-Bautista
- & Felipe Cortés-Ledesma
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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
STAT3-coordinated migration facilitates the dissemination of diffuse large B-cell lymphomas
The mechanism underlying the dissemination of diffuse large B-cell lymphoma (DLBCL) is unclear. Here, the authors show that STAT3 controls amoeboid migration in DLBCL via the transcriptional activation of RHOH, which then releases RhoA from RhoGDIγ-mediated suppression, or via regulating microtubule dynamics to activate RhoA.
- Yi-Ru Pan
- , Chih-Cheng Chen
- & Muh-Hwa Yang
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Article
| Open Access
UTX is an escape from X-inactivation tumor-suppressor in B cell lymphoma
UTX is a tumor suppressor gene located on the X-chromosome so it could potentially contribute to the cancer gender bias. Here the authors, using a mouse model of B cell lymphoma, show that UTX is a dosage sensitive tumor suppressor and may be responsible for some of the increased incidence and possibly aggressiveness of male cancers that harbour UTX mutations.
- Xiaoxi Li
- , Yanli Zhang
- & Hai Jiang
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Article
| Open Access
Cooperative STAT/NF-κB signaling regulates lymphoma metabolic reprogramming and aberrant GOT2 expression
Metabolic rewiring of cancer cells can be driven by both extrinsic and intrinsic factors. Here the authors show that microenvironmental factors induce metabolic rewiring of B-cell lymphoma through activation of STAT3 and NF-ΚB resulting in upregulation of the aminotransferase GOT2 and glutamine addiction.
- Maren Feist
- , Philipp Schwarzfischer
- & Dieter Kube
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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
Fatty Acid Synthase induced S6Kinase facilitates USP11-eIF4B complex formation for sustained oncogenic translation in DLBCL
Aberrant protein translation and uncontrolled lipid metabolism are hallmarks of cancer growth. Here, in diffuse large B-cell lymphoma, the authors show that fatty acid synthase increases USP11 interaction with and stability of eIF4B via PI3K-S6Kinase signaling, promoting oncogenic protein translation.
- Bandish Kapadia
- , Nahid M. Nanaji
- & Ronald B. Gartenhaus
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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
Genome-wide association study of classical Hodgkin lymphoma identifies key regulators of disease susceptibility
Classical Hodgkin lymphoma is a cancer that originates in lymph nodes. Little is known about its genetic susceptibility. Here, the authors combined existing and new genome-wide association studies to identify risk loci for classical Hodgkin lymphoma at 6q22.33, and nodular sclerosis Hodgkin lymphoma at 3q28, 6q23.3, 10p14, 13q34, 16p13.13.
- Amit Sud
- , Hauke Thomsen
- & Richard S. Houlston
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Article
| Open Access
Checkpoint kinase 1 is essential for normal B cell development and lymphomagenesis
Checkpoint kinase 1 (CHK1) is critical for intrinsic cell cycle control and coordination of cell cycle progression. Here the authors show that CHK1 loss or chemical inhibition impacts on normal B cell development, lymphomagenesis and cancer cell survival.
- Fabian Schuler
- , Johannes G. Weiss
- & Andreas Villunger
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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
Genomic characterisation of Eμ-Myc mouse lymphomas identifies Bcor as a Myc co-operative tumour-suppressor gene
The Eμ-Myc lymphoma mouse model has been invaluable in the study of this disease. Here, the authors use multiple sequencing strategies to analyse the tumours in these mice and find recurrent inactivating mutations in Bcor, suggesting that this gene has a negative role in Mycsignalling.
- Marcus Lefebure
- , Richard W. Tothill
- & Ricky W. Johnstone
Loss of CREBBP and KMT2D cooperate to accelerate lymphomagenesis and shape the lymphoma immune microenvironment