Featured
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Rewiring cancer drivers to activate apoptosis
A new class of molecules can recruit downstream transcription factors or endogenous cancer drivers to cell death promoters and activate the expression of these genes.
- Sai Gourisankar
- , Andrey Krokhotin
- & Gerald R. Crabtree
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Article
| Open AccessNon-viral, specifically targeted CAR-T cells achieve high safety and efficacy in B-NHL
Non-viral CAR-T cells with gene-specific targeted integration are safe and effective in patients with lymphoma.
- Jiqin Zhang
- , Yongxian Hu
- & He Huang
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Article |
IFITM3 functions as a PIP3 scaffold to amplify PI3K signalling in B cells
IFITM3 shifts upon phosphorylation from acting as an antiviral effector to being a scaffold for PIP3 and thereby amplifies PI3K signalling, which can be co-opted for malignant transformation in B cell leukaemia and lymphoma.
- Jaewoong Lee
- , Mark E. Robinson
- & Markus Müschen
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Article |
Signalling input from divergent pathways subverts B cell transformation
Analysis of B-cell leukaemia samples reveals that oncogenic mutations do not cause malignant transformation unless they converge on the same signalling pathway, and that it may be possible clinically to combine inhibition of the principal oncogenic driver with reactivation of divergent pathways.
- Lai N. Chan
- , Mark A. Murakami
- & Markus Müschen
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Letter |
HIV-1 remission following CCR5Δ32/Δ32 haematopoietic stem-cell transplantation
An adult infected with HIV-1 who underwent allogeneic haematopoietic stem-cell transplantation for Hodgkin’s lymphoma using cells from a CCR5Δ32/Δ32 donor achieved full remission of HIV-1 for 18 months after transplantation and 16 months after cessation of antiretroviral therapy.
- Ravindra K. Gupta
- , Sultan Abdul-Jawad
- & Eduardo Olavarria
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Letter |
A multiprotein supercomplex controlling oncogenic signalling in lymphoma
A pro-survival multiprotein signalling supercomplex consisting of the B cell receptor, MYD88, TLR9 and mTOR is discovered that coordinates NF-κB activation in diffuse large B cell lymphoma, and provides mechanistic insight into the efficacy of drug combinations.
- James D. Phelan
- , Ryan M. Young
- & Louis M. Staudt
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Letter |
Senescence-associated reprogramming promotes cancer stemness
Cellular senescence induced by chemotherapy leads to the acquisition of stemness in cancer cells, which results in enhanced tumour-promoting capacity after forced release or spontaneous escape from the senescent cell-cycle arrest.
- Maja Milanovic
- , Dorothy N. Y. Fan
- & Clemens A. Schmitt
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Letter |
The B-cell receptor controls fitness of MYC-driven lymphoma cells via GSK3β inhibition
Combined studies in MYC-driven mouse lymphomas and human Burkitt lymphoma unravel an essential role for the B-cell antigen receptor in the control of tumour B-cell fitness both in vitro and in vivo, with possible biological and clinical implications.
- Gabriele Varano
- , Simon Raffel
- & Stefano Casola
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Letter |
Antigen presentation profiling reveals recognition of lymphoma immunoglobulin neoantigens
Evidence for the abundant presentation of class II neoantigens by a human B-cell lymphoma.
- Michael S. Khodadoust
- , Niclas Olsson
- & Ash A. Alizadeh
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Letter |
MYC regulates the core pre-mRNA splicing machinery as an essential step in lymphomagenesis
The critical effectors of MYC overexpression during lymphomagenesis in transgenic mice are defined.
- Cheryl M. Koh
- , Marco Bezzi
- & Ernesto Guccione
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Letter |
Loss of signalling via Gα13 in germinal centre B-cell-derived lymphoma
Inactivation of the S1PR2–Gα13–ARHGEF1 signalling pathway in mice allows Akt activation and promotes dissemination of germinal centre B cells, consistent with a role of function-disrupting mutations in the systemic dissemination of diffuse large B-cell lymphoma.
- Jagan R. Muppidi
- , Roland Schmitz
- & Jason G. Cyster
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Letter |
Selective transcriptional regulation by Myc in cellular growth control and lymphomagenesis
Global transcriptional and epigenomic analyses in diverse cell types reveal that the primary action of Myc is to up- and downregulate transcription of distinct groups of genes, rather than to amplify transcription of all active genes; general RNA amplification, when observed, is better explained as an indirect consequence of Myc’s action on cellular physiology.
- Arianna Sabò
- , Theresia R. Kress
- & Bruno Amati
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Letter |
Synthetic lethal metabolic targeting of cellular senescence in cancer therapy
In mice with Eµ-myc transgenic lymphomas in which therapy-induced senescence (TIS) depends on the H3K9 histone methyltransferase Suv39h1, TIS-competent lymphomas but not TIS-incompetent Suv39h1– lymphomas show increased glucose utilization and ATP production after senescence-inducing chemotherapy to cope with proteotoxic stress elicited by factors of the senescence-associated secretory phenotype (SASP); senescent cancers are selectively vulnerable to drugs that block glucose utilization or autophagy.
- Jan R. Dörr
- , Yong Yu
- & Clemens A. Schmitt
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Letter |
EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations
EZH2 is a methyltransferase that is mutated in lymphoma; here a potent small molecule inhibitor of EZH2 is described, which inhibits the proliferation of EZH2 mutant cell lines and growth of EZH2 mutant xenografts in mice, thus providing a potential treatment for EZH2 mutant lymphoma.
- Michael T. McCabe
- , Heidi M. Ott
- & Caretha L. Creasy
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Letter |
Burkitt lymphoma pathogenesis and therapeutic targets from structural and functional genomics
RNA sequencing of Burkitt lymphoma tumours allows identification of mutations affecting the transcription factor TCF3, its negative regulator ID3 and the cell cycle regulator CCND3; these pathways reveal new targets for potential therapeutic intervention.
- Roland Schmitz
- , Ryan M. Young
- & Louis M. Staudt
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Letter |
A tumour suppressor network relying on the polyamine–hypusine axis
AMD1 and eIF5A are identified as two genes involved in the polyamine–hypusine pathway, a new tumour suppressor network regulating apoptosis.
- Claudio Scuoppo
- , Cornelius Miething
- & Scott W. Lowe
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Letter |
FBXO11 targets BCL6 for degradation and is inactivated in diffuse large B-cell lymphomas
FBXO11 is identified as the F-box protein that normally targets BCL6 for degradation, and FBXO11 deletions or mutations that prevent this function and thus stabilize BCL6 are found in B-cell lymphomas.
- Shanshan Duan
- , Lukas Cermak
- & Michele Pagano
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Research Highlights |
Sisterhood of lymphoma
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Article
| Open AccessFrequent mutation of histone-modifying genes in non-Hodgkin lymphoma
- Ryan D. Morin
- , Maria Mendez-Lago
- & Marco A. Marra
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Article |
Inactivating mutations of acetyltransferase genes in B-cell lymphoma
In three different subtypes of B-cell lymphomas, two papers now report frequent somatic mutations in CREBBP and EP300, present in primary tumours or acquired at relapse. These genes encode related acetyltransferases that mainly function to regulate gene expression by acetylating histones and other transcriptional regulators. The mutations found inactivate these activities and thus alter chromatin regulation of gene expression, as well as proliferation and potentially the response to therapeutic drugs.
- Laura Pasqualucci
- , David Dominguez-Sola
- & Riccardo Dalla-Favera
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Letter |
MHC class II transactivator CIITA is a recurrent gene fusion partner in lymphoid cancers
Using whole-transcriptome sequencing, this paper identifies recurrent gene translocations in B-cell lymphomas that involve the MHC class II transactivator CIITA. These translocations lead to downregulation of cell surface HLA class II expression and, in the case of some fusion partners, overexpression of CD274/CD273 ligands, which have the potential to reduce the antitumour response against these lymphomas.
- Christian Steidl
- , Sohrab P. Shah
- & Randy D. Gascoyne
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Letter |
The RAG2 C terminus suppresses genomic instability and lymphomagenesis
Misrepair of DNA double strand breaks produced by the V(D)J recombinase (the RAG1/RAG2 proteins) at immunoglobulin and T-cell receptor loci has been implicated in the pathogenesis of lymphoid malignancies. Here, the RAG2 carboxy terminus is shown to be critical for maintaining genomic stability. Rag2c/c p53−/− mice, unlike Rag1c/c p53−/− and p53−/− mice, rapidly develop thymic lymphomas bearing complex chromosomal translocations, amplifications and deletions involving the Tcrα/δ and Igh loci. These results reveal a new 'genome guardian' role for RAG2 and suggest that similar 'end release/end persistence' mechanisms underlie genomic instability and lymphomagenesis in Rag2c/c p53−/− and Atm−/− mice.
- Ludovic Deriano
- , Julie Chaumeil
- & David B. Roth
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Letter |
SCFFBW7 regulates cellular apoptosis by targeting MCL1 for ubiquitylation and destruction
This is one of two papers demonstrating that in several cancer types including ovarian cancer and T-cell leukaemias, the apoptosis regulator MCL1 is targeted for degradation by the FBW7 tumour suppressor. This study finds that this mechanism can determine the response to drugs targeting BCL2 family apoptosis factors. Deletion or mutation of FBW7 found in cancer patients therefore can render tumours resistant to these therapies.
- Hiroyuki Inuzuka
- , Shavali Shaik
- & Wenyi Wei
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Letter |
Oncogenically active MYD88 mutations in human lymphoma
This study finds frequent mutations in MYD88 in the activated B-cell-like subtype of diffuse large B-cell lymphoma and, with lower frequency, in mucosa-associated lymphoid tissue lymphomas. MYD88 mediates signalling by Toll-like receptors, and the mutations, most of which affect the same amino acid, are shown to activate the pathway and promote cancer cell survival.
- Vu N. Ngo
- , Ryan M. Young
- & Louis M. Staudt
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Research Highlights |
Cancer biology: Cell neighbours aid cancer relapse
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Letter |
OncomiR addiction in an in vivo model of microRNA-21-induced pre-B-cell lymphoma
One model for cancer development posits that the proliferating cells in a tumour can become 'addicted' to activating mutations in an oncogene. With the realization that certain microRNAs promote tumorigenesis, it has been proposed that tumours may also become dependent on such 'oncomiRs'. Here, evidence is provided that the gene encoding microRNA-21 is an oncogene, and that in its absence, tumours undergo apoptosis and regress. Thus tumours can indeed become addicted to oncomiRs.
- Pedro P. Medina
- , Mona Nolde
- & Frank J. Slack
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Letter |
Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma
The role of B-cell-receptor (BCR) signalling in human B cell lymphomas has been a long-standing question, with genetic and functional evidence for its oncogenic role in human lymphomas lacking. Here, a form of 'chronic active' BCR signalling that is required for cell survival in the activated B-cell-like subtype of diffuse large B-cell lymphoma is described and analysed, with potential implications for future therapeutic strategies.
- R. Eric Davis
- , Vu N. Ngo
- & Louis M. Staudt