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| Open AccessGermline mutations in mitochondrial complex I reveal genetic and targetable vulnerability in IDH1-mutant acute myeloid leukaemia
Mitochondrial metabolism has been associated with tumourigenesis in acute myeloid leukaemia (AML) and currently considered as a potential therapeutic target. Here, the authors show, in patients with AML, that germline mutations in mitochondrial complex I are mutually exclusive with somatic mutations in the metabolic enzyme IDH1, and find IDH1 mutant cells have increased sensitivity to complex I inhibitors.
- Mahmoud A. Bassal
- , Saumya E. Samaraweera
- & Richard J. D’Andrea
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Article
| Open AccessIntegrated profiling of human pancreatic cancer organoids reveals chromatin accessibility features associated with drug sensitivity
The chromatin accessibility landscape and gene regulatory network of pancreatic cancer has not been fully characterised. Here, the authors perform multi-omics analysis of 84 pancreatic cancer organoid lines and reveal gene regulatory networks and distinct molecular subtypes.
- Xiaohan Shi
- , Yunguang Li
- & Dong Gao
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Article
| Open AccessAstroblastomas exhibit radial glia stem cell lineages and differential expression of imprinted and X-inactivation escape genes
Astroblastoma (AB) is an uncommon brain tumour and its origin remains unknown. Here, the authors perform integrative molecular analysis of 35 AB-like tumours and provide evidence that these arise in the context of epigenetic and genetic changes in neural progenitors occurring during brain development.
- Norman L. Lehman
- , Nathalie Spassky
- & Akshitkumar M. Mistry
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Article
| Open AccessESR1 mutant breast cancers show elevated basal cytokeratins and immune activation
Mutations of ESR1, the gene encoding the estrogen receptor alpha, are associated with acquired resistance to therapy in luminalbreast cancer. Here the authors show that ESR1 mutant tumors gain basal-like features with increased expression of basal cytokeratines and immune activation.
- Zheqi Li
- , Olivia McGinn
- & Steffi Oesterreich
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Article
| Open AccessA polygenic risk score for nasopharyngeal carcinoma shows potential for risk stratification and personalized screening
Polygenic Risk Scores (PRS) show promise for facilitating cancer risk stratification. Here, the authors performed a large genome-wide association study and develop a PRS for nasopharyngeal carcinoma, which could improve risk stratification and personalized screening.
- Yong-Qiao He
- , Tong-Min Wang
- & Wei-Hua Jia
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Article
| Open AccessModification of BRCA1-associated breast cancer risk by HMMR overexpression
The effect of hyaluronan-mediated motility receptor (HMMR) expression in BRCA1-associated breast cancer risk remains unknown. Here, HMMR overexpression induces the activation of cGAS-STING and non-canonical NF-κB signalling, instigating an immune permissive environment for breast cancer development.
- Francesca Mateo
- , Zhengcheng He
- & Miquel Angel Pujana
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Article
| Open AccessBRCA2-DSS1 interaction is dispensable for RAD51 recruitment at replication-induced and meiotic DNA double strand breaks
Mishra et al. have generated mice with a single amino acid substitution in BRCA2, which disrupts its interaction with DSS1 resulting in a severe HR defect. They show the interaction to be dispensable for HR at replication induced and meiotic DSBs.
- Arun Prakash Mishra
- , Suzanne A. Hartford
- & Shyam K. Sharan
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Article
| Open AccessComparison of clonal architecture between primary and immunodeficient mouse-engrafted acute myeloid leukemia cells
Clonal dynamics and selection have not been fully understood in patient-derived xenografts (PDX) of acute myeloid leukemia (AML). Here, the authors generate 160 AML-PDX models to track the clonal dynamics of primary and relapsed AML, and find selectively enriched subclones that are associated with resistance to therapy.
- Naomi Kawashima
- , Yuichi Ishikawa
- & Hitoshi Kiyoi
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Article
| Open AccessComprehensive characterization of PTEN mutational profile in a series of 34,129 colorectal cancers
Loss of the tumour suppressor gene PTEN leads to the activation of pro-tumourigenic signalling pathways. Here, the authors analyse sequencing data from a large cohort of colorectal cancer patients harbouring PTEN mutations and identify distinct patterns of associations with genomic and clinical features.
- Ilya G. Serebriiskii
- , Valery Pavlov
- & Erica A. Golemis
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Article
| Open AccessGermline mutation landscape of DNA damage repair genes in African Americans with prostate cancer highlights potentially targetable RAD genes
DNA damage repair genes have been linked with increased aggressiveness of prostate cancer, however, the extent of mutation of these genes has not been analyzed within a cohort of African American patients. Here, the authors identify increased mutation rates in specific DNA repair genes, compared with prostate cancer patients with European Ancestry.
- Indu Kohaar
- , Xijun Zhang
- & Gyorgy Petrovics
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Article
| Open AccessBenchmarking of SpCas9 variants enables deeper base editor screens of BRCA1 and BCL2
Numerous rationally-designed and directed-evolution variants of SpCas9 have been reported to expand the utility of CRISPR technology. Here the authors make comparisons of numerous Cas9 variants, nominate options for base editing screens with denser coverage with A>G and C>T base editing screens and identify loss-of-function mutations in BRCA1 and Venetoclax-resistant mutations in BCL2.
- Annabel K. Sangree
- , Audrey L. Griffith
- & John G. Doench
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Article
| Open AccessClinical and genomic features of Chinese lung cancer patients with germline mutations
Germline variants that predispose to lung cancer have been mostly studied in Western populations, but data from Chinese patients is lacking. Here the authors analyze lung cancer germline variants in 1794 Chinese patients, finding exclusive variants or with different frequency compared to TCGA data.
- Wenying Peng
- , Bin Li
- & Lin Wu
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Article
| Open AccessEBV miRNAs BART11 and BART17-3p promote immune escape through the enhancer-mediated transcription of PD-L1
Epstein-Barr virus (EBV)-encoded latent genes are reported to regulate PD-L1 expression to promote immune escape. Here, the authors show that EBV-encoded miRNAs EBV-miR-BART11 and EBV-miR-BART17-3p upregulate PD-L1 expression in nasopharyngeal carcinoma and gastric cancer by targeting FOXP1 and PBRM1.
- Jie Wang
- , Junshang Ge
- & Zhaoyang Zeng
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Article
| Open AccessA platform for oncogenomic reporting and interpretation
The interpretation of somatic variants in cancer is challenging due to the scale and complexity of sequencing data. Here, the authors present PORI, an open-source framework for interpreting somatic variants in cancer using graph knowledge base tools, automated reporting, and manual curation.
- Caralyn Reisle
- , Laura M. Williamson
- & Steven J. M. Jones
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Article
| Open AccessThe DNA methylome of cervical cells can predict the presence of ovarian cancer
Most ovarian cancers originate from cells originally derived from Müllerian Duct cells. Here, the authors show that the methylation profile of Müllerian Duct cells isolated from cervical samples can predict whether a woman has cervical cancer.
- James E. Barrett
- , Allison Jones
- & Martin Widschwendter
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Article
| Open AccessHIF-1 Interacts with TRIM28 and DNA-PK to release paused RNA polymerase II and activate target gene transcription in response to hypoxia
Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that modulates target gene expression in response to changes in oxygen availability. Here the authors show that HIF-1 forms a complex with TRIM28 and DNA-dependent protein kinase (DNA-PK) that phosphorylates TRIM28. This leads to CDK9 recruitment, which stimulates RNA polymerase II (RNAPII) pause release and transcriptional elongation.
- Yongkang Yang
- , Haiquan Lu
- & Gregg L. Semenza
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Article
| Open AccessMechanism for inverted-repeat recombination induced by a replication fork barrier
Replication stress and abundant repetitive sequences have emerged as primary conditions underlying genomic instability in eukaryotes. Here the authors use a prokaryotic Tus/Ter barrier designed to induce transient replication fork stalling near inverted repeats in the budding yeast genome to support a model for recombination of closely linked repeats at stalled replication forks.
- Léa Marie
- & Lorraine S. Symington
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Article
| Open AccessFunctional dissection of inherited non-coding variation influencing multiple myeloma risk
The causality and functional roles of disease-associated variants revealed by genome-wide association studies (GWAS) are mostly unexplored. Here the authors identify putative causal variants in multiple myeloma and find their association with gene expression and chromatin accessibility.
- Ram Ajore
- , Abhishek Niroula
- & Björn Nilsson
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Article
| Open AccessEpigenetic loss of heterogeneity from low to high grade localized prostate tumours
High tumour heterogeneity hinders the identification of molecular subtypes in prostate cancer. Here, the authors integrate single-cell chromatin accessibility data with multiplex imaging and reveal distinct chromatin features and transcriptional factor binding signatures in high- and low-grade prostate tumours.
- Sebnem Ece Eksi
- , Alex Chitsazan
- & Andrew C. Adey
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Article
| Open AccessHigher order genetic interactions switch cancer genes from two-hit to one-hit drivers
In the classic two-hit model, both alleles of a tumour suppressor gene need to be inactivated in order to promote cancer. Here, the authors challenge this model, finding that many cancer genes can be either one-hit or two-hit drivers depending on the context and other mutations in a tumor.
- Solip Park
- , Fran Supek
- & Ben Lehner
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Article
| Open AccessMolecular and phenotypic profiling of colorectal cancer patients in West Africa reveals biological insights
Understanding the molecular and phenotypic profile of colorectal cancer (CRC) in West Africa is important for early detection and treatment. Here, the authors use a multigene next-generation sequencing panel to identify genomic differences in Nigerian CRCs compared to those from TCGA and MSKCC cohorts.
- Olusegun Isaac Alatise
- , Gregory C. Knapp
- & T. Peter Kingham
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Article
| Open AccessSpatial and temporal intratumour heterogeneity has potential consequences for single biopsy-based neuroblastoma treatment decisions
Neuroblastoma is a devastating tumour in children. Here, the authors analyse multi-region patient samples using genomics and transcriptomics, revealing temporal and spatial heterogeneity and questioning the reliability of single-biopsy based diagnostics.
- Karin Schmelz
- , Joern Toedling
- & Angelika Eggert
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Article
| Open AccessGenetic fusions favor tumorigenesis through degron loss in oncogenes
The impact of genetic fusions on degrons, which are motifs for ubiquitin-mediated protein degradation, has not been fully explored. Here, the authors analyse fusion genes affecting degrons in pan-cancer genomics data, validate their functional impact and find enrichment for both internal and C-terminal degron losses.
- Jing Liu
- , Collin Tokheim
- & Wenyi Wei
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Article
| Open AccessWRN helicase safeguards deprotected replication forks in BRCA2-mutated cancer cells
The tumor suppressor BRCA2 protects stalled DNA replication forks from unrestrained degradation; however the mechanism whereby unprotected stalled forks are preserved and restarted has remained elusive. Here the authors show that the WRN helicase promotes stalled fork recovery and limits fork hyper-degradation in the absence of BRCA2 protection.
- Arindam Datta
- , Kajal Biswas
- & Robert M. Brosh Jr
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Article
| Open AccessReversion analysis reveals the in vivo immunogenicity of a poorly MHC I-binding cancer neoepitope
The immunogenicity of peptides is believed to be determined by their high-affinity binding to MHC I. Here authors show that low-affinity MHC I-peptide interactions are also able to trigger robust T cell response and anti-tumour immunity in vivo.
- Hakimeh Ebrahimi-Nik
- , Marmar Moussa
- & Pramod K. Srivastava
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Article
| Open AccessGenome-wide profiling in colorectal cancer identifies PHF19 and TBC1D16 as oncogenic super enhancers
Active enhancers are still understudied in colorectal cancers (CRC). Here the authors analyse active enhancers in CRC patients using genomics, transcriptomics, and epigenomics, identifying and validating variant super-enhancer loci as well as KLF3 as a relevant transcription factor.
- Qing-Lan Li
- , Xiang Lin
- & Min Wu
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Article
| Open AccessRare t(X;14)(q28;q32) translocation reveals link between MTCP1 and chronic lymphocytic leukemia
Some genes that are part of balanced translocations are reported as drivers for tumourigenesis. Here, the authors report a translocation involving MTCP1 in chronic lymphocytic leukemia and show that MTCP1 overexpression leads to the disease in a murine model.
- Janek S. Walker
- , Zachary A. Hing
- & Rosa Lapalombella
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Article
| Open AccessConvergence of oncogenic cooperation at single-cell and single-gene levels drives leukemic transformation
Identifying how genetic alterations cooperate in cancer is challenging. Here the authors analyze leukemia mouse models with both oncogenic NRAS and EZH2 mutations using single-cell RNA-sequencing, evaluate oncogenic cooperation, and identify GEM as a regulator of leukemia-initiating cells.
- Yuxuan Liu
- , Zhimin Gu
- & Jian Xu
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Article
| Open AccessTET2 mutations are associated with hypermethylation at key regulatory enhancers in normal and malignant hematopoiesis
TET2 mutations are frequent in myeloid malignancies and in elderly individuals with or without cytopenia. Here, the authors analyse the association between TET2 mutations and methylation changes in healthy elderly twins and patients with cytopenia and compare them to those from leukemia.
- Morten Tulstrup
- , Mette Soerensen
- & Kirsten Grønbæk
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Article
| Open AccessCancer gene mutation frequencies for the U.S. population
Understanding the frequency of gene mutations in cancer could be important for generating targeted therapeutics. Here, the authors use SEER data and cancer genomics data from TCGA to estimate the gene mutation frequencies in the US cancer population.
- Gaurav Mendiratta
- , Eugene Ke
- & Edward C. Stites
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Article
| Open AccessGermline determinants of humoral immune response to HPV-16 protect against oropharyngeal cancer
Genetic susceptibility loci for oropharyngeal cancer have been reported but these studies have not always examined human papillomavirus (HPV) status. Here, the authors perform genome-wide analysis taking into account HPV16 serology status and report two independent loci in the HLA region, suggesting the protective role of HLA variants against HPV infection.
- Aida Ferreiro-Iglesias
- , James D. McKay
- & Paul Brennan
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Article
| Open AccessA high-risk retinoblastoma subtype with stemness features, dedifferentiated cone states and neuronal/ganglion cell gene expression
Retinoblastoma is the most frequent intraocular paediatric malignancy whose molecular basis remains poorly understood. Here, the authors perform multi-omic analysis and identify two subtypes; one in a cone differentiated state and one more aggressive showing cone dedifferentiation and expressing neuronal markers.
- Jing Liu
- , Daniela Ottaviani
- & François Radvanyi
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Article
| Open AccessParity associates with chromosomal damage in uterine leiomyomas
Many factors have been associated with chromosomal damage, including mechanical forces in a constrained cellular environment. Here the authors reveal an association between parity and chromosomal damage by analysing karyotypes of 1946 uterine leiomyomas.
- Heli Kuisma
- , Simona Bramante
- & Lauri A. Aaltonen
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Article
| Open AccessGenetic variations of DNA bindings of FOXA1 and co-factors in breast cancer susceptibility
The identification of transcription factors (TFs) whose binding sites are affected by risk genetic variants remains crucial. Here, the authors develop a statistical framework to analyse ChIP-seq and GWAS data, identify 22 breast cancer risk-associated TFs and a core TF-transcriptional network for FOXA1 and co-factors.
- Wanqing Wen
- , Zhishan Chen
- & Xingyi Guo
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Article
| Open AccessSMARCA4/2 loss inhibits chemotherapy-induced apoptosis by restricting IP3R3-mediated Ca2+ flux to mitochondria
SMARCA4/2 loss in ovarian and lung cancers is associated with chemotherapy resistance. Here, the authors show that SMARCA4/2 deficiency in cancer cells reduces the expression of the ER-Ca2+ channel IP3R3 and subsequently calcium transfer to the mitochondria, which inhibits apoptotic cell death.
- Yibo Xue
- , Jordan L. Morris
- & Sidong Huang
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Article
| Open AccessSingle-nuclei transcriptomes from human adrenal gland reveal distinct cellular identities of low and high-risk neuroblastoma tumors
Childhood neuroblastoma can be separated into high and low risk groups, with prognosis depending on age at diagnosis. Here, the authors show that low and high risk neuroblastoma tumours are composed of different cell types with different malignancy potential.
- O. C. Bedoya-Reina
- , W. Li
- & S. Schlisio
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Article
| Open AccessStructural engineering of chimeric antigen receptors targeting HLA-restricted neoantigens
Chimeric antigen receptor T cells in the clinic currently target cell-type-specific extracellular antigens on malignant cells. Here, authors engineer tumor-specific chimeric antigen receptor T cells that target human leukocyte antigen-presented neoantigens derived from mutant intracellular proteins.
- Michael S. Hwang
- , Michelle S. Miller
- & Sandra B. Gabelli
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Article
| Open AccessMolecular 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 AccessRNF168-mediated localization of BARD1 recruits the BRCA1-PALB2 complex to DNA damage
The BRCA1-PALB2-BRCA2-RAD51 (BRCA1-P) complex is well known to play a fundamental role in DNA repair, but how the complex recruitment is regulated is still a matter of interest. Here the authors reveal mechanistic insights into RNF168 activity being responsible for PALB2 recruitment, through BARD1-BRCA1 during homologous recombination repair.
- John J. Krais
- , Yifan Wang
- & Neil Johnson
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Article
| Open AccessChronological 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 AccessIdentification of 22 susceptibility loci associated with testicular germ cell tumors
Testicular germ cell tumors are highly heritable, and the authors present the largest genome association study, identifying 22 novel loci, which account for a third of those identified to date. Implicated pathways include male germ cell development and differentiation, and chromosomal segregation.
- John Pluta
- , Louise C. Pyle
- & Christian Kubisch
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Article
| Open AccessOncogenic enhancers drive esophageal squamous cell carcinogenesis and metastasis
The role of regulatory cis-elements in carcinogenesis and metastasis in esophageal squamous cell carcinoma remains crucial. Here the authors investigate H3K27ac-marked active enhancer profiles and transcriptomes in different types of esophageal tissues and identify oncogenic events and potential therapeutic targets.
- Bo Ye
- , Dandan Fan
- & Yunbo Qiao
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Article
| Open AccessInterplay and cooperation between SREBF1 and master transcription factors regulate lipid metabolism and tumor-promoting pathways in squamous cancer
The relevance and underlying molecular mechanisms of epigenetic regulation in squamous cell carcinomas (SCC) await further characterization. Here, the authors show a transcriptional regulatory loop involving SREBF1, TP63 and KLF5 driving tumourigenesis in SCC through fatty acid, ERBB and mTOR pathway regulation.
- Li-Yan Li
- , Qian Yang
- & De-Chen Lin
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Article
| Open AccessTargeting KRAS4A splicing through the RBM39/DCAF15 pathway inhibits cancer stem cells
Kras is frequently mutated in lung cancer and two isoforms are generated via alternative splicing. Here, the authors show that the two isoforms have divergent roles in cancer stem cells and the main tumour cell population, which are regulated by hypoxia and endoplasmic reticulum stress.
- Wei-Ching Chen
- , Minh D. To
- & Allan Balmain
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Article
| Open AccessOncogenic cooperation between TCF7-SPI1 and NRAS(G12D) requires β-catenin activity to drive T-cell acute lymphoblastic leukemia
SPI1 fusion genes in T-cell acute lymphoblastic leukemia (T-ALL) are commonly found with co-occurring NRAS mutations. Here, the authors show that the combination of these oncogenes is necessary to drive T-ALL in a murine model and that the oncogenic activity of the SPI1 fusion is dependent on β-catenin.
- Quentin Van Thillo
- , Jolien De Bie
- & Charles E. de Bock
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Article
| Open AccessHigh-resolution characterization of gene function using single-cell CRISPR tiling screen
Identifying functional domains and genetic regulatory mechanisms is essential for developing new therapies. Here the authors present sc-Tiling, single-cell high-density CRISPR tiling screening for functional domain characterization.
- Lu Yang
- , Anthony K. N. Chan
- & Chun-Wei Chen
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Article
| Open AccessFusion 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 Access3D genome alterations associated with dysregulated HOXA13 expression in high-risk T-lineage acute lymphoblastic leukemia
The non-coding genome of T-ALL has not been extensively studied. Here, the authors conduct RNA-seq, ATAC-seq and Hi-C seq analyses and find that T-ALL associated neo-loops may regulate key transcription factors including HOXA13; the aberrant expression of which is associated with poor prognosis.
- Lu Yang
- , Fengling Chen
- & Hong Wu
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Comment
| Open AccessHoming in on genomic instability as a therapeutic target in cancer
While genomic instability is a hallmark of cancer, its genetic vulnerabilities remain poorly understood. Identifying strategies that exploit genomic instability to selectively target cancer cells is a central challenge in cancer biology with major implications for anti-cancer drug development.
- Craig M. Bielski
- & Barry S. Taylor