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| Open AccessThe targetable kinase PIM1 drives ALK inhibitor resistance in high-risk neuroblastoma independent of MYCN status
Anaplastic lymphoma kinase (ALK) inhibitors are currently being considered in neuroblastoma (NB), but its acquired resistance is reported in non-small cell lung cancers. Here, the authors have found PIM1 overexpression decreases sensitivity to ALK inhibitors in NB and combined ALK and PIM1 inhibition enhances anti-tumour efficacy in vitro and in PDX models.
- Ricky M. Trigg
- , Liam C. Lee
- & Suzanne D. Turner
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Article
| Open AccessIdentification of four novel associations for B-cell acute lymphoblastic leukaemia risk
B-cell acute lymphoblastic leukaemia (B-ALL) is a common childhood cancer. Here, the authors conducted a meta-analysis with four genome-wide association studies, totalling 5,321 cases and 16,666 controls of European descent, identifying B-ALL risk loci, whose integration with epigenomic profiling indicates cell-cycle and B-cell development deregulation as central mechanisms in B-ALL susceptibility, often in a subtype-specific fashion.
- Jayaram Vijayakrishnan
- , Maoxiang Qian
- & Jun J. Yang
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| Open AccessThe long noncoding RNA lncNB1 promotes tumorigenesis by interacting with ribosomal protein RPL35
MYCN amplification is common in neuroblastomas. Here, the authors identify a long noncoding RNA, lncNB1 in these cancers and show that it promotes tumorigenesis by binding to ribosomal protein, RPL35 to enhance E2F1 and DEPDC1B protein synthesis, which phosphorylates ERK to stabilise N-Myc.
- Pei Y. Liu
- , Andrew E. Tee
- & Tao Liu
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| Open AccessCooperation of cancer drivers with regulatory germline variants shapes clinical outcomes
Interactions between germline variants and somatic mutations is a relatively unexplored topic in cancer. Here, in Ewing sarcoma, the authors show that binding of the oncogenic EWSR1-FLI1 fusion transcription factor to a polymorphic enhancer-like DNA element controls MYBL2, whose high expression correlates with prognosis.
- Julian Musa
- , Florencia Cidre-Aranaz
- & Thomas G. P. Grünewald
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Article
| Open AccessYAP1 subgroup supratentorial ependymoma requires TEAD and nuclear factor I-mediated transcriptional programmes for tumorigenesis
The molecular mechanisms driving proliferation in the pediatric brain cancer epdendymoma are poorly understood. Here the authors show that a YAP1- MAMLD1 fusion drives tumor formation in mice and show that the fusion protein can collaborate with the TEAD and NFI transcription factors.
- Kristian W. Pajtler
- , Yiju Wei
- & Daisuke Kawauchi
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Article
| Open AccessGREB1 induced by Wnt signaling promotes development of hepatoblastoma by suppressing TGFβ signaling
The mechanisms promoting hepatoblastoma (HB) progression through Wnt/β-catenin signaling are unclear. Here, the authors show that the Wnt/ β-catenin axis induces GREB1 expression and nuclear localization, and suppresses TGFβ pathway, and propose GREB1 as a therapeutic target in HB.
- Shinji Matsumoto
- , Taku Yamamichi
- & Akira Kikuchi
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Article
| Open AccessMitogenic and progenitor gene programmes in single pilocytic astrocytoma cells
Pilocytic astrocytoma is a low-grade pediatric glioma, characterized by a single BRAF rearrangement. Here, Reitman and colleagues use single-cell RNA sequencing to reveal molecular hallmarks of the disease that might be targeted therapeutically.
- Zachary J. Reitman
- , Brenton R. Paolella
- & Rameen Beroukhim
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Article
| Open AccessJMJD6 is a tumorigenic factor and therapeutic target in neuroblastoma
Although the gain in chromosome 17q21-ter is commonly associated with neuroblastoma, it is not clear which gene of this region mediates tumorigenesis. Here, the authors are showing that JMJD6, which locates in that region, is a neuroblastoma tumorigenic factor.
- Matthew Wong
- , Yuting Sun
- & Tao Liu
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Article
| Open AccessNeuronal differentiation and cell-cycle programs mediate response to BET-bromodomain inhibition in MYC-driven medulloblastoma
BET-bromodomain inhibitors could be used to treat medulloblastoma tumors with Myc amplifications. Here, the authors show that both the response and resistance to BET inhibitors in mice is mediated by bHLH/homeobox transcription factors.
- Pratiti Bandopadhayay
- , Federica Piccioni
- & Rameen Beroukhim
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Article
| Open AccessTumour-associated macrophages exhibit anti-tumoural properties in Sonic Hedgehog medulloblastoma
The Sonic Hedgehog subgroup of medulloblastoma are characterised by the high infiltration of tumour-associated macrophages (TAMs). Here, the authors show that TAM numbers in patients are associated with better prognosis and that, consistently, in a murine model of medulloblastoma, these TAMs have anti-tumoural properties.
- Victor Maximov
- , Zhihong Chen
- & Anna M. Kenney
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Article
| Open AccessA high-throughput screen indicates gemcitabine and JAK inhibitors may be useful for treating pediatric AML
Pediatric AML is traditionally treated with chemotherapy and stem cell transplant but some subsets of patients have a poor response to therapy. Here, the authors perform a high throughput screen and identify several FDA approved drugs that might be useful in treating this disease.
- Christina D. Drenberg
- , Anang Shelat
- & Sharyn D. Baker
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| Open AccessACVR1 R206H cooperates with H3.1K27M in promoting diffuse intrinsic pontine glioma pathogenesis
ACVR1 and H3.1K27M mutations co-occur in diffuse intrinsic pontine glioma. Here, the authors generate a mouse model that recapitulates these genetic lesions and show, using genetic and pharmacological approaches, that the bone morphogenetic protein pathway may be a therapeutic target in these tumours.
- Christine M. Hoeman
- , Francisco J. Cordero
- & Oren J. Becher
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Article
| Open AccessLsd1 as a therapeutic target in Gfi1-activated medulloblastoma
Medulloblastoma is one of the most prevalent malignant brain tumors in children and has very poor prognosis. In this study, the authors show, using a mouse model of medulloblastoma, that Gfi1 promotes tumor growth by recruiting Lsd1, that this interaction inhibits genes involved in neuronal differentiation, and that Lsd1 may be a therapeutic target in Gfi1-activated tumors.
- Catherine Lee
- , Vasilisa A. Rudneva
- & Robert J. Wechsler-Reya
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| Open AccessSRPK1 maintains acute myeloid leukemia through effects on isoform usage of epigenetic regulators including BRD4
SRPK1, a kinase involved in splicing regulation, is a potential therapeutic target for AML patients. Here, the authors show that SRPK1 inhibition changes isoform levels of key epigenetic regulators, including BRD4, and it has anti-tumor effects specifically against MLL-rearranged AML cells.
- Konstantinos Tzelepis
- , Etienne De Braekeleer
- & George S. Vassiliou
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| Open AccessTranscriptome 3′end organization by PCF11 links alternative polyadenylation to formation and neuronal differentiation of neuroblastoma
In gene regulation, diversification at the transcriptome 3′end is linked to differentiation and dedifferentiation. Here, the authors discover extensive transcriptome 3′end-alterations in neuroblastoma, regulated by PCF11, and provide an interactive data repository of transcriptome-wide alternative polyadenylation.
- Anton Ogorodnikov
- , Michal Levin
- & Sven Danckwardt
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Article
| Open AccessAge-specific biological and molecular profiling distinguishes paediatric from adult acute myeloid leukaemias
Acute myeloid leukaemia (AML) affects people of all ages. Here, the authors model AML in vivo and demonstrate that the age of the cell of origin impacts leukaemia development and the genetic signature where adult cells of origin give rise exclusively to AML and young cells of origin give rise to myeloid, lymphoid or mixed phenotype acute leukaemia.
- Shahzya Chaudhury
- , Caitríona O’Connor
- & Karen Keeshan
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Article
| Open AccessMiR-584-5p potentiates vincristine and radiation response by inducing spindle defects and DNA damage in medulloblastoma
The radiation and chemotherapy used for treating medulloblastoma patients cause debilitating side effects. Here, the authors show that miR-584 acts as a therapeutic adjuvant as it sensitizes medulloblastoma to radiation and chemotherapy by targeting HDAC1 or eIF4E3 to enhance spindle defects and DNA damage.
- Nourhan Abdelfattah
- , Subapriya Rajamanickam
- & Manjeet K. Rao
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Article
| Open AccessGenome-wide association study identifies multiple new loci associated with Ewing sarcoma susceptibility
Ewing sarcoma (EWS) is a rare pediatric bone cancer typically involving the EWSR1-FLI1 fusion. Here the authors perform a genome-wide association study and report three new EWS risk loci that reside near GGAA repeat sequences, and identify candidate genes (RREB1 and KIZ) from eQTL analysis.
- Mitchell J. Machiela
- , Thomas G. P. Grünewald
- & Olivier Delattre
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| Open AccessRecurrent homozygous deletion of DROSHA and microduplication of PDE4DIP in pineoblastoma
Pineoblastoma is a highly aggressive and rare childhood brain cancer, and the genetic drivers of sporadic pineoblastoma are unknown. Here, the authors genomically interrogated pediatric and adult pineoblastomas and found novel variants including recurrent homozygous deletions of DROSHA.
- Matija Snuderl
- , Kasthuri Kannan
- & Matthias A. Karajannis
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Article
| Open AccessArmadillo repeat containing 12 promotes neuroblastoma progression through interaction with retinoblastoma binding protein 4
Armadillo (ARM) family proteins can act as oncogenes or tumor suppressors. Here, the authors show that a new ARM protein (ARMC12) is upregulated in neuroblastoma, binds the PRC2 component RBBP4, and inhibits transcription of tumor suppressive genes.
- Dan Li
- , Huajie Song
- & Qiangsong Tong
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Article
| Open AccessLive-cell single-molecule dynamics of PcG proteins imposed by the DIPG H3.3K27M mutation
Diffuse intrinsic pontine gliomas exhibit a characteristic mutation of lysine 27 to methionine (K27M) in genes encoding histone H3.3. Here the authors show that the H3.3K27M mutation imposes a specific pattern of H3.3K27 methylation by altering the target search dynamics of PcG proteins.
- Roubina Tatavosian
- , Huy Nguyen Duc
- & Xiaojun Ren
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| Open AccessGenome-wide association study identifies susceptibility loci for B-cell childhood acute lymphoblastic leukemia
While GWAS have uncovered susceptibility loci for B-cell precursor acute lymphoblastic leukemia (BCP-ALL), much of the heritable risk remains undiscovered. Here, the authors perform a meta-analysis of two existing BCP-ALL GWAS together with an unpublished GWAS to identify risk loci at 8q24.21 and 2q22.3.
- Jayaram Vijayakrishnan
- , James Studd
- & Richard S. Houlston
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| Open AccessGenome-wide DNA methylation is predictive of outcome in juvenile myelomonocytic leukemia
Juvenile myelomonocytic leukemia (JMML) is an aggressive disease with limited options for treatment. Here, the authors utilize DNA methylation based subgroups in JMML to predict clinical outcome.
- Elliot Stieglitz
- , Tali Mazor
- & Mignon L. Loh
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| Open AccessStem cell senescence drives age-attenuated induction of pituitary tumours in mouse models of paediatric craniopharyngioma
Senescent cells can promote tumour progression through the activation of a senescenceassociated secretory phenotype (SASP). Here, the authors show that SASP activation is associated with non-cell autonomous cell transformation and tumour initiation in an in vivo model of adamantinomatous craniopharyngioma.
- Jose Mario Gonzalez-Meljem
- , Scott Haston
- & Juan Pedro Martinez-Barbera
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| Open AccessIdentification of ETV6-RUNX1-like and DUX4-rearranged subtypes in paediatric B-cell precursor acute lymphoblastic leukaemia
The fusion of two genes during the pathogenesis of cancer can create oncogenes. In this study, the authors screen pediatric B-cell precursor acute lymphoblastic leukaemia samples for the presence of fusion genes and describe fusion genes that define new molecular subtypes of the disease
- Henrik Lilljebjörn
- , Rasmus Henningsson
- & Thoas Fioretos
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| Open AccessRecurrent internal tandem duplications of BCOR in clear cell sarcoma of the kidney
The genetic basis of clear cell sarcomas of the kidney is not well understood. In this study, Roy et al. perform whole-exome and RNA sequencing of these tumours and identify recurrent internal tandem duplications in BCOR, a key constituent of a variant polycomb repressive complex.
- Angshumoy Roy
- , Vijetha Kumar
- & D. Williams Parsons
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| Open AccessInherited coding variants at the CDKN2A locus influence susceptibility to acute lymphoblastic leukaemia in children
Genome-wide association studies indicate a strong genetic susceptibility to acute lymphoblastic leukaemia in children, though the effect on protein-coding genes is not fully understood. Here Xu and Zhang et al. identify a missense variant in CDKN2Awhich reduces tumour suppression.
- Heng Xu
- , Hui Zhang
- & Jun J. Yang
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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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Genomic landscape of paediatric adrenocortical tumours
Pediatric adrenocortical carcinoma is a rare malignancy with poor prognosis. Here the authors analyse the genomes, exomes and transcriptomes of 37 such tumours and identify genetic alterations whose nature, timing and potential interactions are key events with prognostic significance in pediatric adrenocortical tumorigenesis.
- Emilia M. Pinto
- , Xiang Chen
- & Gerard P. Zambetti
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Intratumoral genome diversity parallels progression and predicts outcome in pediatric cancer
Phenotypic and genetic heterogeneity of cells within a tumour is thought to mediate treatment resistance and contribute to cancer progression. Here the authors show that genetic diversity in pediatric cancers is common after chemotherapy and can be quantified to predict survival.
- Linda Holmquist Mengelbier
- , Jenny Karlsson
- & David Gisselsson
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The landscape of somatic mutations in epigenetic regulators across 1,000 paediatric cancer genomes
Proteins involved in epigenetic regulation are frequently mutated in several paediatric cancers. Here, Huether et al.characterize the somatic mutation frequency across 21 paediatric cancer subtypes by sequencing 633 epigenetic genes in over 1,000 tumours; generating a rich data set for investigating epigenetic dysregulation.
- Robert Huether
- , Li Dong
- & James R. Downing