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| Open AccessRise and fall of subclones from diagnosis to relapse in pediatric B-acute lymphoblastic leukaemia
Genetic heterogeneity and clonal evolution contribute to cancer progression. Here Ma et al.use deep whole-exome sequencing to identify recurrently mutated pathways and clonal architecture in pediatric acute lymphoblastic leukaemia, shedding light on the evolutionary trajectory from diagnosis to relapse
- Xiaotu Ma
- , Michael Edmonson
- & Jinghui Zhang
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| Open AccessIdentification of FOXM1 as a therapeutic target in B-cell lineage acute lymphoblastic leukaemia
FOXM1, a transcription factor with roles in cell cycle progression, is highly expressed in the majority of solid tumours. Here the authors show that FOXM1 is an ideal therapeutic target in B-cell acute lymphoblastic leukaemia (ALL) due to its dispensability for normal B-cell development.
- Maike Buchner
- , Eugene Park
- & Markus Müschen
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Article
| Open AccessNeuropilin 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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| Open AccessSite- and allele-specific polycomb dysregulation in T-cell leukaemia
TAL1 is frequently deregulated in T-cell acute lymphoblastic leukaemias, but the mechanism remains largely unclear. Here the authors show that microinsertions upstream of TAL1 cause its epigenetic reactivation, and that the mode of TAL1activation correlates with prognosis.
- Jean-Marc Navarro
- , Aurore Touzart
- & Bertrand Nadel
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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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Aberrant splicing of U12-type introns is the hallmark of ZRSR2 mutant myelodysplastic syndrome
Somatic mutations in components of the core RNA splicing machinery, including ZRSR2, have been implicated in myelodysplastic syndrome (MDS). Here, Madan et al.show that ZRSR2 plays a pivotal role in splicing of the U12-type introns, while the U2-dependent splicing is largely unaffected in ZRSR2 mutant MDS bone marrow.
- Vikas Madan
- , Deepika Kanojia
- & H. Phillip Koeffler
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Activating mutations of STAT5B and STAT3 in lymphomas derived from γδ-T or NK cells
NK-cell and γδ-T cell lymphoma share clinic-pathological features; however the driving mutations are largely unknown. Here the authors, using a combination of RNA-Seq analysis, targeted re-sequencing and functional analysis, identify frequent activating mutations in STAT3 and STAT5Bthat may be driver mutations in these diseases.
- Can Küçük
- , Bei Jiang
- & Wing C. Chan
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Article
| Open AccessCombining gene mutation with gene expression data improves outcome prediction in myelodysplastic syndromes
The myelodysplastic syndromes (MDS) are a heterogeneous group of chronic blood cancers. Here, the authors analyse genomic and gene expression data from MDS patients to investigate how driver mutations alter gene expression, diagnostic clinical variables and survival.
- Moritz Gerstung
- , Andrea Pellagatti
- & Jacqueline Boultwood
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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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Article
| Open AccessA genome-wide association study of marginal zone lymphoma shows association to the HLA region
Marginal zone lymphoma (MZL) is a common subtype of B-cell non-Hodgkin lymphoma. Here the authors carry out a two-stage genome-wide association study in over 8,000 Europeans and identify two new MZL risk loci at chromosome 6p, implicating the major histocompatibility complex in the disease for the first time.
- Joseph Vijai
- , Zhaoming Wang
- & Alexandra Nieters
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Article
| Open AccessZEB2 drives immature T-cell lymphoblastic leukaemia development via enhanced tumour-initiating potential and IL-7 receptor signalling
Driver mutations in early T-cell precursor leukaemia (ETP-ALL) are poorly characterized. Here the authors show that Zeb2overexpression is often found in ETP-ALL, can recapitulate the disease in transgenic mice and confers survival advantage by upregulating IL-7 signalling.
- Steven Goossens
- , Enrico Radaelli
- & Jody J. Haigh
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| Open AccessIdentification of novel DNA-damage tolerance genes reveals regulation of translesion DNA synthesis by nucleophosmin
Cells cope with replication-blocking DNA lesions by translesion DNA synthesis (TLS) polymerases, including polη. Here, the authors show that NPM1, a gene frequently mutated in acute myeloid leukaemia, protects polη from proteasomal degradation, and that NPM1 deficiency causes a TLS defect.
- Omer Ziv
- , Amit Zeisel
- & Zvi Livneh
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| Open AccessMNKs 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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Loss of IP3R-dependent Ca2+ signalling in thymocytes leads to aberrant development and acute lymphoblastic leukemia
Ca2+signalling pathways are known to influence T-cell development and T-cell leukemia progression. Here the authors show that deletion of all three inositol triphosphate receptor homologues in mice severely impairs T-cell development in the thymus and causes spontaneous T-cell acute lymphoblastic leukemia.
- Kunfu Ouyang
- , Rafael Leandro Gomez-Amaro
- & Ju Chen
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Recurrent CDC25C mutations drive malignant transformation in FPD/AML
Familial platelet disorder with predisposition to acute myelogenous leukaemia (FPD/AML) is characterized by abnormal platelet function and a high risk of haematological malignancies. Here, the authors report frequent CDC25Cmutations in FPD/AML patients and suggest that this gene may influence malignant transformation in FPD/AML.
- Akihide Yoshimi
- , Takashi Toya
- & Mineo Kurokawa
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Frequent cases of RAS-mutated Down syndrome acute lymphoblastic leukaemia lack JAK2 mutations
For children with acute lymphoblastic leukaemia (ALL), those with Down syndrome (DS) have decreased survival compared with children without DS. Here, the authors use exome sequencing to characterise the mutational landscape of patients with both ALL and DS and highlight genes related to survival and relapse.
- Sergey I. Nikolaev
- , Marco Garieri
- & Stylianos E. Antonarakis
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Ezh2 loss promotes development of myelodysplastic syndrome but attenuates its predisposition to leukaemic transformation
Mutations in the EZH2 gene are found in myelodysplastic syndrome (MDS) and are often accompanied by mutations in RUNX1. Here, the authors develop a mouse model of MDS and show that EZH2loss enhances the RUNX1-mediated MDS pathology.
- Goro Sashida
- , Hironori Harada
- & Atsushi Iwama
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A meta-analysis of Hodgkin lymphoma reveals 19p13.3 TCF3 as a novel susceptibility locus
While Hodgkin lymphoma (HL) is a common cancer affecting young adults in Western countries, its genetic basis is poorly understood. Here, the authors carry out a genome-wide association analysis in HL patients and healthy controls; identifying a new HL risk locus and implicating TCF3in the disease aetiology.
- W. Cozen
- , M. N. Timofeeva
- & J. D. McKay
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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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Article
| Open AccessPADI4 acts as a coactivator of Tal1 by counteracting repressive histone arginine methylation
Peptidylarginine deiminase 4 (PADI4) is a transcriptional co-regulator that converts arginine residues at histone tails to citrulline. The authors show that PADI4 interacts with the central haematopoietic transcription factor TAL1 to regulate gene expression in an erythroleukemia cell line.
- Stephan Kolodziej
- , Olga N. Kuvardina
- & Jörn Lausen
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Mutations in epigenetic regulators including SETD2 are gained during relapse in paediatric acute lymphoblastic leukaemia
Epigenetic regulators have been proposed to be modulators of chemoresistance in acute lymphoblastic leukaemia. Here, the authors find enrichment of mutations in epigenetic regulators at relapse, including somatic mutations in SETD2.
- Brenton G. Mar
- , Lars B. Bullinger
- & Scott A. Armstrong
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Loss of NDRG2 expression activates PI3K-AKT signalling via PTEN phosphorylation in ATLL and other cancers
The PI3K pathway that encompasses the tumour suppressor PTEN contributes to tumourigenesis in adult T-cell leukaemia-lymphoma (ATLL). In this study, Nakahata et al. show that PTEN is dephosphorylated by NDRG2, and that loss of NDGR2 in ATLL results in the activation of the PI3K pathway.
- Shingo Nakahata
- , Tomonaga Ichikawa
- & Kazuhiro Morishita
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| Open AccessIdentification of renin progenitors in the mouse bone marrow that give rise to B-cell leukaemia
Renin cells have traditionally been associated with the kidney where they regulate blood pressure and fluid electrolyte homeostasis. In this study, Belyea et al.describe a renin progenitor in the bone marrow that gives rise to B-cell leukaemia when RBP-J, the final effector of the Notch pathway, is deleted.
- Brian C. Belyea
- , Fang Xu
- & R. Ariel Gomez
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Article
| Open AccessHeterogeneity of genomic evolution and mutational profiles in multiple myeloma
Multiple myeloma is a malignant plasma cell disorder with a complex molecular pathogenesis. Here, the authors perform whole-exome sequencing, copy-number profiling and cytogenetic analysis in 84 myeloma samples and highlight the diversity and evolution of the mutational profile underlying the disease.
- Niccolo Bolli
- , Hervé Avet-Loiseau
- & Nikhil C. Munshi
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Variation at 3p24.1 and 6q23.3 influences the risk of Hodgkin’s lymphoma
Hodgkin’s lymphoma has a genetic component that is poorly understood. In this study, Frampton et al. perform a genome-wide association study in German patients and combine the results with a previously published UK genome-wide association study to identify susceptibility loci at 3p24.1 and 6q23.3.
- Matthew Frampton
- , Miguel Inacio da Silva Filho
- & Richard S. Houlston
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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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miR-196b directly targets both HOXA9/MEIS1 oncogenes and FAS tumour suppressor in MLL-rearranged leukaemia
HOX9AandMEIS1are key oncogenes in MLL-rearranged leukaemia. miRNA-196b is shown here to directly suppress their expression and delay MLL-fusion-mediated leukaemia, but to also cause an aggressive leukaemia phenotype when expressed ectopically, suggesting that it targets tumour suppressors as well.
- Zejuan Li
- , Hao Huang
- & Jianjun Chen
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Ectopic expression of the histone methyltransferase Ezh2 in haematopoietic stem cells causes myeloproliferative disease
The histone methyltransferase Ezh2 is thought to have a dual function both as a tumour suppressor and an oncogene. Using mouse models with Ezh2 gain-of-function, Herrera-Merchanet al. show that Ezh2 expression in HSCs severely compromises hematopoietic function, leading to myeloproliferative disease.
- A. Herrera-Merchan
- , L. Arranz
- & S. Gonzalez
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Article
| Open AccessFunctional 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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| Open AccessInflammation 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