ORCID Profile
0000-0001-9977-2104
Current Organisations
The Rockefeller University & Howard Hughes Medical Institute
,
University of Toronto
,
Lunenfeld-Tanenbaum Research Institute
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Publications
Supplementary Figure S6 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/2643-3230.22587356
Abstract: Supplemental Figure S6 shows the GSEA of ELAVL1 depletion in mouse RN2c and human primary AML cells, ELAVL1 subcellular localization in mouse and human AML, the qRT-PCR of ELAVL1 targets in MS-444-treated RN2c cells, and the integrative analysis of the mouse RNA-seq and eCLIP-seq.
Supplementary Data from Loss of Epigenetic Regulation Disrupts Lineage Integrity, Induces Aberrant Alveogenesis, and Promotes Breast Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541628
Abstract: Supplementary Data from Loss of Epigenetic Regulation Disrupts Lineage Integrity, Induces Aberrant Alveogenesis, and Promotes Breast Cancer
Supplementary Table S8 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2643-3230.22725561
Abstract: Table S8 shows transcripts from the ELAVL1 knockout RNA-sequencing data set that are (a) alternatively spliced and (b) alternatively spliced as well as bound by ELAVL1 as identified by eCLIP-sequencing.
Supplementary Table S7 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2643-3230.22725564
Abstract: Table S7 shows (a) reproducible peaks and (b) GO analysis of ELAVL1-bound transcripts identified in the eCLIP-sequencing data set. The negatively enriched (c) and positively-enriched (d) gene sets identified by GSEA of ELAVL1-bound and differentially expressed transcripts from the RN2c RNA-sequencing data set are shown.
Supplementary Table S3 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2643-3230.22725576.V1
Abstract: Table S3 shows clinical information for all AML patient specimens used in this study.
Supplementary Figure S7 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/2643-3230.22587353
Abstract: Supplemental Figure S7 shows the expression profile of TOMM34 in normal human bone marrow and across different AML and CML data sets. The effects of TOMM34 depletion on human primary AML cells in vitro and validation of TOMM34 knockdown and overexpression is shown.
Supplementary Data from Loss of Epigenetic Regulation Disrupts Lineage Integrity, Induces Aberrant Alveogenesis, and Promotes Breast Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541622.V1
Abstract: Supplementary Data from Loss of Epigenetic Regulation Disrupts Lineage Integrity, Induces Aberrant Alveogenesis, and Promotes Breast Cancer
Supplementary Data from Loss of Epigenetic Regulation Disrupts Lineage Integrity, Induces Aberrant Alveogenesis, and Promotes Breast Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541625
Abstract: Supplementary Data from Loss of Epigenetic Regulation Disrupts Lineage Integrity, Induces Aberrant Alveogenesis, and Promotes Breast Cancer
Supplementary Figure S5 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/2643-3230.22587359
Abstract: Supplemental Figure S5 shows the effects of DHTS treatment on THP-1 and human primary AML cells in vitro, the effects of MS-444 treatment on human umbilical cord blood in vivo, and validation of ELAVL1 overexpression by western blot.
Supplementary Data from Loss of Epigenetic Regulation Disrupts Lineage Integrity, Induces Aberrant Alveogenesis, and Promotes Breast Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541622
Abstract: Supplementary Data from Loss of Epigenetic Regulation Disrupts Lineage Integrity, Induces Aberrant Alveogenesis, and Promotes Breast Cancer
Data from Loss of Epigenetic Regulation Disrupts Lineage Integrity, Induces Aberrant Alveogenesis, and Promotes Breast Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.C.6549708.V1
Abstract: Abstract Systematically investigating the scores of genes mutated in cancer and discerning disease drivers from inconsequential bystanders is a prerequisite for precision medicine but remains challenging. Here, we developed a somatic CRISPR/Cas9 mutagenesis screen to study 215 recurrent “long-tail” breast cancer genes, which revealed epigenetic regulation as a major tumor-suppressive mechanism. We report that components of the BAP1 and COMPASS-like complexes, including KMT2C/D, KDM6A, BAP1, and ASXL1/2 (“EpiDrivers”), cooperate with i PIK3CA /i sup H1047R /sup to transform mouse and human breast epithelial cells. Mechanistically, we find that activation of i PIK3CA /i sup H1047R /sup and concomitant EpiDriver loss triggered an alveolar-like lineage conversion of basal mammary epithelial cells and accelerated formation of luminal-like tumors, suggesting a basal origin for luminal tumors. EpiDriver mutations are found in ∼39% of human breast cancers, and ∼50% of ductal carcinoma i in situ /i express casein, suggesting that lineage infidelity and alveogenic mimicry may significantly contribute to early steps of breast cancer etiology. Significance: Infrequently mutated genes comprise most of the mutational burden in breast tumors but are poorly understood. i In vivo /i CRISPR screening identified functional tumor suppressors that converged on epigenetic regulation. Loss of epigenetic regulators accelerated tumorigenesis and revealed lineage infidelity and aberrant expression of alveogenesis genes as potential early events in tumorigenesis. i a href="ancerdiscovery/article/doi/10.1158/2159-8290.CD-12-12-ITI" target="_blank" This article is highlighted in the In This Issue feature, p. 2711 /a /i /
Supplementary Data from Loss of Epigenetic Regulation Disrupts Lineage Integrity, Induces Aberrant Alveogenesis, and Promotes Breast Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541616.V1
Abstract: Supplementary Data from Loss of Epigenetic Regulation Disrupts Lineage Integrity, Induces Aberrant Alveogenesis, and Promotes Breast Cancer
Supplementary Table S6 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2643-3230.22725567.V1
Abstract: Table S6 shows altered gene sets identified by GSEA of the ELAVL1 knockout RN2c RNA-sequencing data set.
Supplementary Figure S5 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2643-3230.22725591.V1
Abstract: Supplemental Figure S5 shows the effects of DHTS treatment on THP-1 and human primary AML cells in vitro, the effects of MS-444 treatment on human umbilical cord blood in vivo, and validation of ELAVL1 overexpression by western blot.
Supplementary Table S1 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2643-3230.22725582.V1
Abstract: Table S1 shows expression of RBPs in an RNA-sequencing data set of human bone marrow hematopoietic stem and progenitor subpopulations.
Supplementary Table S9 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2643-3230.22725558
Abstract: Table S9 shows the (a) differentially expressed transcripts and (b) altered pathways as identified by GSEA from the ELAVL1 knockdown human primary AML RNA-sequencing data set.
Supplementary Figure S2 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/2643-3230.22587368
Abstract: Supplemental Figure S2 shows validation of sgRNA -mediated knockout of hit RBPs, comparison of hit RBP depletion in RN2c in vitro versus in vivo, effects of ELAVL1 loss on human AML cell lines, characteristics of the MLL-AF9 AML mouse model, and ELAVL1 expression in normal hematopoietic cells.
Supplementary Table S5 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2643-3230.22725570
Abstract: Table S5 shows the log2 fold change of differentially expressed transcripts from the ELAVL1 knockout RN2c RNA-sequencing data set.
Supplementary Data from Loss of Epigenetic Regulation Disrupts Lineage Integrity, Induces Aberrant Alveogenesis, and Promotes Breast Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541637
Abstract: Supplementary Data from Loss of Epigenetic Regulation Disrupts Lineage Integrity, Induces Aberrant Alveogenesis, and Promotes Breast Cancer
Supplementary Table S3 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2643-3230.22725576
Abstract: Table S3 shows clinical information for all AML patient specimens used in this study.
Supplementary Figure S4 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/2643-3230.22587362
Abstract: Supplemental Figure S4 shows the validation of ELAVL1 knockdown by western blot and effects of ELAVL1 loss on human primary AML cells in vitro and in vivo.
Supplementary Figure S3 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/2643-3230.22587365
Abstract: Supplemental Figure S3 shows the generation of the bcCML mouse model and the effects of ELAVL1 on normal bone marrow in vivo.
Supplementary Table S4 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2643-3230.22725573
Abstract: Table S4 shows limiting dilution analysis of secondary recipients transplanted with DMSO- or MS-444-treated bone marrow from primary mice
Supplementary Table S4 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2643-3230.22725573.V1
Abstract: Table S4 shows limiting dilution analysis of secondary recipients transplanted with DMSO- or MS-444-treated bone marrow from primary mice
Supplementary Table S9 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/2643-3230.22587326.V1
Abstract: Table S9 shows the (a) differentially expressed transcripts and (b) altered pathways as identified by GSEA from the ELAVL1 knockdown human primary AML RNA-sequencing data set.
Supplementary Figure S4 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2643-3230.22725594.V1
Abstract: Supplemental Figure S4 shows the validation of ELAVL1 knockdown by western blot and effects of ELAVL1 loss on human primary AML cells in vitro and in vivo.
Supplementary Data from Loss of Epigenetic Regulation Disrupts Lineage Integrity, Induces Aberrant Alveogenesis, and Promotes Breast Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541631
Abstract: Supplementary Data from Loss of Epigenetic Regulation Disrupts Lineage Integrity, Induces Aberrant Alveogenesis, and Promotes Breast Cancer
A non-coding single nucleotide polymorphism at 8q24 drives IDH1-mutant glioma formation
Publisher: Cold Spring Harbor Laboratory
Date: 10-03-2022
DOI: 10.1101/2022.03.08.22272044
Abstract: Establishing causal links between inherited polymorphisms and cancer risk is challenging. Here, we focus on the single nucleotide polymorphism rs55705857 (A G), which confers a 6-fold increased risk of IDH-mutant low-grade glioma (LGG) and is amongst the highest genetic associations with cancer. By fine-mapping the locus, we reveal that rs55705857 itself is the causal variant and is associated with molecular pathways that drive LGG. Mechanistically, we show that rs55705857 resides within a brain-specific enhancer, where the risk allele disrupts OCT2/4 binding, allowing increased interaction with the Myc promoter and increased Myc expression. To functionally test rs55705857, we generated an IDH1 R132H -driven LGG mouse model and show that mutating the highly conserved, orthologous mouse rs55705857 locus dramatically accelerated tumor development from 463 to 172 days and increased penetrance from 30% to 75%. Overall, our work generates new LGG models and reveals mechanisms of the heritable predisposition to lethal glioma in ∼40% of LGG-patients.
A CRISPR Path to Finding Vulnerabilities and Solving Drug Resistance: Targeting the Diverse Cancer Landscape and Its Ecosystem.
Publisher: Wiley
Date: 09-11-2022
Abstract: Cancer is the second leading cause of death globally, with therapeutic resistance being a major cause of treatment failure in the clinic. The dynamic signaling that occurs between tumor cells and the erse cells of the surrounding tumor microenvironment actively promotes disease progression and therapeutic resistance. Improving the understanding of how tumors evolve following therapy and the molecular mechanisms underpinning de novo or acquired resistance is thus critical for the identification of new targets and for the subsequent development of more effective combination regimens. Simultaneously targeting multiple hallmark capabilities of cancer to circumvent adaptive or evasive resistance may lead to significantly improved treatment response in the clinic. Here, the latest applications of functional genomics tools, such as clustered regularly interspaced short palindromic repeats (CRISPR) editing, to characterize the dynamic cancer resistance mechanisms, from improving the understanding of resistance to classical chemotherapeutics, to deciphering unique mechanisms that regulate tumor responses to new targeted agents and immunotherapies, are discussed. Potential avenues of future research in combating therapeutic resistance, the contribution of tumor–stroma signaling in this setting, and how advanced functional genomics tools can help streamline the identification of key molecular determinants of drug response are explored.
Supplementary Data from Loss of Epigenetic Regulation Disrupts Lineage Integrity, Induces Aberrant Alveogenesis, and Promotes Breast Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541634
Abstract: Supplementary Data from Loss of Epigenetic Regulation Disrupts Lineage Integrity, Induces Aberrant Alveogenesis, and Promotes Breast Cancer
Prevalence of the Brazilian TP53 Founder c.1010G>A (p.Arg337His) in Lung Adenocarcinoma: Is Genotyping Warranted in All Brazilian Patients?
Publisher: Frontiers Media SA
Date: 02-02-2021
DOI: 10.3389/FGENE.2021.606537
Abstract: In Southern and Southeastern Brazil, there is a germline pathogenic variant with incomplete penetrance located in the oligomerization domain of TP53 , c.1010G& A (p.Arg337His). Due to a founder effect, the variant is present in 0.3% of the general population of the region. Recently, this variant was identified in 4.4 and 8.9% of two apparently unselected, single center case series of Brazilian lung adenocarcinoma (LUAD) patients from the Southeastern and Central regions of the country, respectively. In the present study, our aim was to examine TP53 c.1010G& A allele and genotype frequencies in LUAD s les obtained from patients diagnosed in Southern Brazil. A total of 586 LUAD s les (tumor DNA) recruited from multiple centers in the region were tested, and the mutant allele was identified using TaqMan ® assays in seven cases (7/586, 1.2%) which were submitted to next generation sequencing analyses for confirmation. Somatic EGFR mutations were more frequent in TP53 c.1010G& A carriers than in non-carriers (57.1 vs. 17.6%, respectively). Further studies are needed to confirm if TP53 c.1010G& A is a driver in LUAD carcinogenesis and to verify if there is a combined effect of EGFR and germline TP53 c.1010G& A. Although variant frequency was higher than observed in the general population, it is less than previously reported in LUAD patients from other Brazilian regions. Additional data, producing regional allele frequency information in larger series of patients and including cost-effectiveness analyses, are necessary to determine if TP53 c.1010G& A screening in all Brazilian LUAD patients is justified.
Germline HAVCR2 mutations altering TIM-3 characterize subcutaneous panniculitis-like T cell lymphomas with hemophagocytic lymphohistiocytic syndrome
Publisher: Springer Science and Business Media LLC
Date: 29-10-2018
DOI: 10.1038/S41588-018-0251-4
Abstract: Subcutaneous panniculitis-like T cell lymphoma (SPTCL), a non-Hodgkin lymphoma, can be associated with hemophagocytic lymphohistiocytosis (HLH), a life-threatening immune activation that adversely affects survival
Aberrant regulation of RANKL/OPG in women at high risk of developing breast cancer
Publisher: Impact Journals, LLC
Date: 18-12-2016
Translation from unconventional 5' start sites drives tumour initiation.
Publisher: Springer Science and Business Media LLC
Date: 2017
DOI: 10.1038/NATURE21036
Metabolic Regulation of the Epigenome Drives Lethal Infantile Ependymoma
Publisher: Elsevier BV
Date: 06-2020
DOI: 10.1016/J.CELL.2020.04.047
Abstract: Posterior fossa A (PFA) ependymomas are lethal malignancies of the hindbrain in infants and toddlers. Lacking highly recurrent somatic mutations, PFA ependymomas are proposed to be epigenetically driven tumors for which model systems are lacking. Here we demonstrate that PFA ependymomas are maintained under hypoxia, associated with restricted availability of specific metabolites to diminish histone methylation, and increase histone demethylation and acetylation at histone 3 lysine 27 (H3K27). PFA ependymomas initiate from a cell lineage in the first trimester of human development that resides in restricted oxygen. Unlike other ependymomas, transient exposure of PFA cells to ambient oxygen induces irreversible cellular toxicity. PFA tumors exhibit a low basal level of H3K27me3, and, paradoxically, inhibition of H3K27 methylation specifically disrupts PFA tumor growth. Targeting metabolism and/or the epigenome presents a unique opportunity for rational therapy for infants with PFA ependymoma.
In vivo CRISPR screens reveal potent driver mutations in head and neck cancers
Publisher: Informa UK Limited
Date: 13-05-2020
Binary pan-cancer classes with distinct vulnerabilities defined by pro- or anti-cancer YAP/TEAD activity
Publisher: Elsevier BV
Date: 08-2021
Supplementary Data from Loss of Epigenetic Regulation Disrupts Lineage Integrity, Induces Aberrant Alveogenesis, and Promotes Breast Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541634.V1
Abstract: Supplementary Data from Loss of Epigenetic Regulation Disrupts Lineage Integrity, Induces Aberrant Alveogenesis, and Promotes Breast Cancer
Supplementary Table S7 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/2643-3230.22587332.V1
Abstract: Table S7 shows (a) reproducible peaks and (b) GO analysis of ELAVL1-bound transcripts identified in the eCLIP-sequencing data set. The negatively enriched (c) and positively-enriched (d) gene sets identified by GSEA of ELAVL1-bound and differentially expressed transcripts from the RN2c RNA-sequencing data set are shown.
Supplementary Table S8 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/2643-3230.22587329.V1
Abstract: Table S8 shows transcripts from the ELAVL1 knockout RNA-sequencing data set that are (a) alternatively spliced and (b) alternatively spliced as well as bound by ELAVL1 as identified by eCLIP-sequencing.
Supplementary Table S6 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2643-3230.22725567
Abstract: Table S6 shows altered gene sets identified by GSEA of the ELAVL1 knockout RN2c RNA-sequencing data set.
Supplementary Figure S1 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/2643-3230.22587371
Abstract: Supplemental Figure S1 shows expression of RBPs in healthy HSPCs and RN2c cells, sgRNA drop out dynamics in primary and secondary transplants, the molecular functions and biological processes associated with the hit RBPs and their gene essentialities.
Supplementary Figure S2 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2643-3230.22725600
Abstract: Supplemental Figure S2 shows validation of sgRNA -mediated knockout of hit RBPs, comparison of hit RBP depletion in RN2c in vitro versus in vivo, effects of ELAVL1 loss on human AML cell lines, characteristics of the MLL-AF9 AML mouse model, and ELAVL1 expression in normal hematopoietic cells.
Supplementary Figure S1 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2643-3230.22725603
Abstract: Supplemental Figure S1 shows expression of RBPs in healthy HSPCs and RN2c cells, sgRNA drop out dynamics in primary and secondary transplants, the molecular functions and biological processes associated with the hit RBPs and their gene essentialities.
Supplementary Table S1 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2643-3230.22725582
Abstract: Table S1 shows expression of RBPs in an RNA-sequencing data set of human bone marrow hematopoietic stem and progenitor subpopulations.
ETS family transcriptional regulators drive chromatin dynamics and malignancy in squamous cell carcinomas.
Publisher: eLife Sciences Publications, Ltd
Date: 21-11-2015
DOI: 10.7554/ELIFE.10870
Abstract: Tumor-initiating stem cells (SCs) exhibit distinct patterns of transcription factors and gene expression compared to healthy counterparts. Here, we show that dramatic shifts in large open-chromatin domain (super-enhancer) landscapes underlie these differences and reflect tumor microenvironment. By in vivo super-enhancer and transcriptional profiling, we uncover a dynamic cancer-specific epigenetic network selectively enriched for binding motifs of a transcription factor cohort expressed in squamous cell carcinoma SCs (SCC-SCs). Many of their genes, including Ets2 and Elk3, are themselves regulated by SCC-SC super-enhancers suggesting a cooperative feed-forward loop. Malignant progression requires these genes, whose knockdown severely impairs tumor growth and prohibits progression from benign papillomas to SCCs. ETS2-deficiency disrupts the SCC-SC super-enhancer landscape and downstream cancer genes while ETS2-overactivation in epidermal-SCs induces hyperproliferation and SCC super-enhancer-associated genes Fos, Junb and Klf5. Together, our findings unearth an essential regulatory network required for the SCC-SC chromatin landscape and unveil its importance in malignant progression.
RANKL/RANK control Brca1 mutation-driven mammary tumors
Publisher: Springer Science and Business Media LLC
Date: 31-05-2016
DOI: 10.1038/CR.2016.69
Supplementary Table S1 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/2643-3230.22587350.V1
Abstract: Table S1 shows expression of RBPs in an RNA-sequencing data set of human bone marrow hematopoietic stem and progenitor subpopulations.
CDK/cyclin dependencies define extreme cancer cell-cycle heterogeneity and collateral vulnerabilities.
Publisher: Elsevier BV
Date: 03-2022
Supplementary Figure S7 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2643-3230.22725585
Abstract: Supplemental Figure S7 shows the expression profile of TOMM34 in normal human bone marrow and across different AML and CML data sets. The effects of TOMM34 depletion on human primary AML cells in vitro and validation of TOMM34 knockdown and overexpression is shown.
Supplementary Table S3 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/2643-3230.22587344.V1
Abstract: Table S3 shows clinical information for all AML patient specimens used in this study.
Mutant ACVR1 Arrests Glial Cell Differentiation to Drive Tumorigenesis in Pediatric Gliomas.
Publisher: Elsevier BV
Date: 03-2020
AIF-regulated oxidative phosphorylation supports lung cancer development
Publisher: Springer Science and Business Media LLC
Date: 27-05-2019
Supplementary Figure S6 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2643-3230.22725588.V1
Abstract: Supplemental Figure S6 shows the GSEA of ELAVL1 depletion in mouse RN2c and human primary AML cells, ELAVL1 subcellular localization in mouse and human AML, the qRT-PCR of ELAVL1 targets in MS-444-treated RN2c cells, and the integrative analysis of the mouse RNA-seq and eCLIP-seq.
Rare driver mutations in head and neck squamous cell carcinomas converge on NOTCH signaling.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 13-03-2020
Abstract: Cancer genome–sequencing projects have emphasized the handful of genes mutated at high frequency in patients. Less attention has been directed to the hundreds of genes mutated in only a few patients—the so-called “long tail” mutations. Although rare, these mutations may nonetheless inform patient care. Loganathan et al. developed a reverse genetic CRISPR screen that allowed them to functionally assess in mice nearly 500 long tail gene mutations that occur in human head and neck squamous cell carcinoma (HNSCC). They identified 15 tumor-suppressor genes with activities that converged on the NOTCH signaling pathway. Given that NOTCH itself is mutated at high frequency in HNSCC, these results suggest that the growth of these tumors is largely driven by NOTCH inactivation. Science , this issue p. 1264
Data from Loss of Epigenetic Regulation Disrupts Lineage Integrity, Induces Aberrant Alveogenesis, and Promotes Breast Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.C.6549708
Abstract: Abstract Systematically investigating the scores of genes mutated in cancer and discerning disease drivers from inconsequential bystanders is a prerequisite for precision medicine but remains challenging. Here, we developed a somatic CRISPR/Cas9 mutagenesis screen to study 215 recurrent “long-tail” breast cancer genes, which revealed epigenetic regulation as a major tumor-suppressive mechanism. We report that components of the BAP1 and COMPASS-like complexes, including KMT2C/D, KDM6A, BAP1, and ASXL1/2 (“EpiDrivers”), cooperate with i PIK3CA /i sup H1047R /sup to transform mouse and human breast epithelial cells. Mechanistically, we find that activation of i PIK3CA /i sup H1047R /sup and concomitant EpiDriver loss triggered an alveolar-like lineage conversion of basal mammary epithelial cells and accelerated formation of luminal-like tumors, suggesting a basal origin for luminal tumors. EpiDriver mutations are found in ∼39% of human breast cancers, and ∼50% of ductal carcinoma i in situ /i express casein, suggesting that lineage infidelity and alveogenic mimicry may significantly contribute to early steps of breast cancer etiology. Significance: Infrequently mutated genes comprise most of the mutational burden in breast tumors but are poorly understood. i In vivo /i CRISPR screening identified functional tumor suppressors that converged on epigenetic regulation. Loss of epigenetic regulators accelerated tumorigenesis and revealed lineage infidelity and aberrant expression of alveogenesis genes as potential early events in tumorigenesis. i a href="ancerdiscovery/article/doi/10.1158/2159-8290.CD-12-12-ITI" target="_blank" This article is highlighted in the In This Issue feature, p. 2711 /a /i /
Supplementary Table S6 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/2643-3230.22587335.V1
Abstract: Table S6 shows altered gene sets identified by GSEA of the ELAVL1 knockout RN2c RNA-sequencing data set.
Supplementary Figure S1 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2643-3230.22725603.V1
Abstract: Supplemental Figure S1 shows expression of RBPs in healthy HSPCs and RN2c cells, sgRNA drop out dynamics in primary and secondary transplants, the molecular functions and biological processes associated with the hit RBPs and their gene essentialities.
Supplementary Table S2 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2643-3230.22725579
Abstract: Table S2 shows sequences of (a) sgRNAs from the RBP screen, (b) sequencing primers, (c) shRNAs and human-targeting sgRNAs, (d) eCLIP oligos.
In Vivo CRISPR/Cas9 Screening to Simultaneously Evaluate Gene Function in Mouse Skin and Oral Cavity.
Publisher: MyJove Corporation
Date: 02-11-2020
DOI: 10.3791/61693
Supplementary Data from Loss of Epigenetic Regulation Disrupts Lineage Integrity, Induces Aberrant Alveogenesis, and Promotes Breast Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541628.V1
Abstract: Supplementary Data from Loss of Epigenetic Regulation Disrupts Lineage Integrity, Induces Aberrant Alveogenesis, and Promotes Breast Cancer
Supplementary Data from Loss of Epigenetic Regulation Disrupts Lineage Integrity, Induces Aberrant Alveogenesis, and Promotes Breast Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541625.V1
Abstract: Supplementary Data from Loss of Epigenetic Regulation Disrupts Lineage Integrity, Induces Aberrant Alveogenesis, and Promotes Breast Cancer
Supplementary Figure S4 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 05-2033
DOI: 10.1158/2643-3230.22725594
Abstract: Supplemental Figure S4 shows the validation of ELAVL1 knockdown by western blot and effects of ELAVL1 loss on human primary AML cells in vitro and in vivo.
Supplementary Figure S5 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2643-3230.22725591
Abstract: Supplemental Figure S5 shows the effects of DHTS treatment on THP-1 and human primary AML cells in vitro, the effects of MS-444 treatment on human umbilical cord blood in vivo, and validation of ELAVL1 overexpression by western blot.
Supplementary Figure S3 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2643-3230.22725597
Abstract: Supplemental Figure S3 shows the generation of the bcCML mouse model and the effects of ELAVL1 on normal bone marrow in vivo.
Data from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2643-3230.C.6572000
Abstract: Abstract Acute myeloid leukemia (AML) is fueled by leukemic stem cells (LSC) whose determinants are challenging to discern from hematopoietic stem cells (HSC) or uncover by approaches focused on general cell properties. We have identified a set of RNA-binding proteins (RBP) selectively enriched in human AML LSCs. Using an i in vivo /i two-step CRISPR-Cas9 screen to assay stem cell functionality, we found 32 RBPs essential for LSCs in MLL-AF9 Nras sup G12D /sup AML. Loss-of-function approaches targeting key hit RBP ELAVL1 compromised LSC-driven i in vivo /i leukemic reconstitution, and selectively depleted primitive malignant versus healthy cells. Integrative multiomics revealed differentiation, splicing, and mitochondrial metabolism as key features defining the leukemic ELAVL1–mRNA interactome with mitochondrial import protein, TOMM34, being a direct ELAVL1-stabilized target whose repression impairs AML propagation. Altogether, using a stem cell–adapted i in vivo /i CRISPR screen, this work demonstrates pervasive reliance on RBPs as regulators of LSCs and highlights their potential as therapeutic targets in AML. Significance: LSC-targeted therapies remain a significant unmet need in AML. We developed a stem-cell–adapted i in vivo /i CRISPR screen to identify key LSC drivers. We uncover widespread RNA-binding protein dependencies in LSCs, including ELAVL1, which we identify as a novel therapeutic vulnerability through its regulation of mitochondrial metabolism. i a href="loodcancerdiscov/article/doi/10.1158/2643-3230.BCD-4-3-ITI" target="_blank" This article is highlighted in the In This Issue feature, p. 171 /a /i /
Supplementary Table S4 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/2643-3230.22587341.V1
Abstract: Table S4 shows limiting dilution analysis of secondary recipients transplanted with DMSO- or MS-444-treated bone marrow from primary mice
Supplementary Data from Loss of Epigenetic Regulation Disrupts Lineage Integrity, Induces Aberrant Alveogenesis, and Promotes Breast Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541631.V1
Abstract: Supplementary Data from Loss of Epigenetic Regulation Disrupts Lineage Integrity, Induces Aberrant Alveogenesis, and Promotes Breast Cancer
Supplementary Table S2 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2643-3230.22725579.V1
Abstract: Table S2 shows sequences of (a) sgRNAs from the RBP screen, (b) sequencing primers, (c) shRNAs and human-targeting sgRNAs, (d) eCLIP oligos.
Toronto Workshop on Late Recurrence in Estrogen Receptor–Positive Breast Cancer: Part 1: Late Recurrence: Current Understanding, Clinical Considerations
Publisher: Oxford University Press (OUP)
Date: 10-08-2019
Abstract: Disease recurrence (locoregional, distant) exerts a significant clinical impact on the survival of estrogen receptor–positive breast cancer patients. Many of these recurrences occur late, more than 5 years after original diagnosis, and represent a major obstacle to the effective treatment of this disease. Indeed, methods to identify patients at risk of late recurrence and therapeutic strategies designed to avert or treat these recurrences are lacking. Therefore, an international workshop was convened in Toronto, Canada, in February 2018 to review the current understanding of late recurrence and to identify critical issues that require future study. In this article, the major issues surrounding late recurrence are defined and current approaches that may be applicable to this challenge are discussed. Specifically, diagnostic tests with potential utility in late-recurrence prediction are described as well as a variety of patient-related factors that may influence recurrence risk. Clinical and therapeutic approaches are also reviewed, with a focus on patient surveillance and the implementation of extended endocrine therapy in the context of late-recurrence prevention. Understanding and treating late recurrence in estrogen receptor–positive breast cancer is a major unmet clinical need. A concerted effort of basic and clinical research is required to confront late recurrence and improve disease management and patient survival.
Toronto Workshop on Late Recurrence in Estrogen Receptor-Positive Breast Cancer: Part 2: Approaches to Predict and Identify Late Recurrence, Research Directions
Publisher: Oxford University Press (OUP)
Date: 10-08-2019
Abstract: Late disease recurrence (more than 5 years after initial diagnosis) represents a clinical challenge in the treatment and management of estrogen receptor-positive breast cancer (BC). An international workshop was convened in Toronto, Canada, in February 2018 to review the current understanding of late recurrence and to identify critical issues that require future study. The underlying biological causes of late recurrence are complex, with the processes governing cancer cell dormancy, including immunosurveillance, cell proliferation, angiogenesis, and cellular stemness, being integral to disease progression. These critical processes are described herein as well as their role in influencing risk of recurrence. Moreover, observational and interventional clinical trials are proposed, with a focus on methods to identify patients at risk of recurrence and possible strategies to combat this in patients with estrogen receptor-positive BC. Because the problem of late BC recurrence of great importance, recent advances in disease detection and patient monitoring should be incorporated into novel clinical trials to evaluate approaches to enhance patient management. Indeed, future research on these issues is planned and will offer new options for effective late recurrence treatment and prevention strategies.
Supplementary Figure S2 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2643-3230.22725600.V1
Abstract: Supplemental Figure S2 shows validation of sgRNA -mediated knockout of hit RBPs, comparison of hit RBP depletion in RN2c in vitro versus in vivo, effects of ELAVL1 loss on human AML cell lines, characteristics of the MLL-AF9 AML mouse model, and ELAVL1 expression in normal hematopoietic cells.
Supplementary Table S5 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/2643-3230.22587338.V1
Abstract: Table S5 shows the log2 fold change of differentially expressed transcripts from the ELAVL1 knockout RN2c RNA-sequencing data set.
Supplementary Figure S7 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2643-3230.22725585.V1
Abstract: Supplemental Figure S7 shows the expression profile of TOMM34 in normal human bone marrow and across different AML and CML data sets. The effects of TOMM34 depletion on human primary AML cells in vitro and validation of TOMM34 knockdown and overexpression is shown.
Supplementary Figure S6 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2643-3230.22725588
Abstract: Supplemental Figure S6 shows the GSEA of ELAVL1 depletion in mouse RN2c and human primary AML cells, ELAVL1 subcellular localization in mouse and human AML, the qRT-PCR of ELAVL1 targets in MS-444-treated RN2c cells, and the integrative analysis of the mouse RNA-seq and eCLIP-seq.
Afatinib restrains K-RAS–driven lung tumorigenesis
Publisher: American Association for the Advancement of Science (AAAS)
Date: 20-06-2018
DOI: 10.1126/SCITRANSLMED.AAO2301
Abstract: K-RAS –mutated lung adenocarcinomas depend on ERBB signaling, and pan-ERBB inhibitors impair K-RAS–driven lung tumorigenesis.
Apelin inhibition prevents resistance and metastasis associated with anti‐angiogenic therapy
Publisher: EMBO
Date: 24-06-2019
The GATOR–Rag GTPase pathway inhibits mTORC1 activation by lysosome-derived amino acids
Publisher: American Association for the Advancement of Science (AAAS)
Date: 15-10-2020
Abstract: The mechanistic target of rapamycin complex 1 (mTORC1) couples nutrient sufficiency to cell growth. mTORC1 is activated by exogenously acquired amino acids sensed through the GATOR–Rag guanosine triphosphatase (GTPase) pathway, or by amino acids derived through lysosomal degradation of protein by a poorly defined mechanism. Here, we revealed that amino acids derived from the degradation of protein (acquired through oncogenic Ras-driven macropinocytosis) activate mTORC1 by a Rag GTPase–independent mechanism. mTORC1 stimulation through this pathway required the HOPS complex and was negatively regulated by activation of the GATOR-Rag GTPase pathway. Therefore, distinct but functionally coordinated pathways control mTORC1 activity on late endocytic organelles in response to distinct sources of amino acids.
Supplementary Figure S1 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/2643-3230.22587371.V1
Abstract: Supplemental Figure S1 shows expression of RBPs in healthy HSPCs and RN2c cells, sgRNA drop out dynamics in primary and secondary transplants, the molecular functions and biological processes associated with the hit RBPs and their gene essentialities.
CRISPR-UMI: single-cell lineage tracing of pooled CRISPR–Cas9 screens
Publisher: Springer Science and Business Media LLC
Date: 16-10-2017
DOI: 10.1038/NMETH.4466
Abstract: Pooled CRISPR screens are a powerful tool for assessments of gene function. However, conventional analysis is based exclusively on the relative abundance of integrated single guide RNAs (sgRNAs) between populations, which does not discern distinct phenotypes and editing outcomes generated by identical sgRNAs. Here we present CRISPR-UMI, a single-cell lineage-tracing methodology for pooled screening to account for cell heterogeneity. We generated complex sgRNA libraries with unique molecular identifiers (UMIs) that allowed for screening of clonally expanded, in idually tagged cells. A proof-of-principle CRISPR-UMI negative-selection screen provided increased sensitivity and robustness compared with conventional analysis by accounting for underlying cellular and editing-outcome heterogeneity and detection of outlier clones. Furthermore, a CRISPR-UMI positive-selection screen uncovered new roadblocks in reprogramming mouse embryonic fibroblasts as pluripotent stem cells, distinguishing reprogramming frequency and speed (i.e., effect size and probability). CRISPR-UMI boosts the predictive power, sensitivity, and information content of pooled CRISPR screens.
Recognition of Semaphorin Proteins by P. sordellii Lethal Toxin Reveals Principles of Receptor Specificity in Clostridial Toxins
Publisher: Elsevier BV
Date: 07-2020
CRISPR-Switch regulates sgRNA activity by Cre recombination for sequential editing of two loci
Publisher: Springer Science and Business Media LLC
Date: 29-11-2019
DOI: 10.1038/S41467-019-13403-Y
Abstract: CRISPR-Cas9 is an efficient and versatile tool for genome engineering in many species. However, inducible CRISPR-Cas9 editing systems that regulate Cas9 activity or sgRNA expression often suffer from significant limitations, including reduced editing capacity, off-target effects, or leaky expression. Here, we develop a precisely controlled sgRNA expression cassette that can be combined with widely-used Cre systems, termed CRISPR-Switch (SgRNA With Induction/Termination by Cre Homologous recombination). Switch-ON facilitates controlled, rapid induction of sgRNA activity. In turn, Switch-OFF-mediated termination of editing improves generation of heterozygous genotypes and can limit off-target effects. Furthermore, we design sequential CRISPR-Switch-based editing of two loci in a strictly programmable manner and determined the order of mutagenic events that leads to development of glioblastoma in mice. Thus, CRISPR-Switch substantially increases the versatility of gene editing through precise and rapid switching ON or OFF sgRNA activity, as well as switching OVER to secondary sgRNAs.
Genome-wide CRISPR screens identify novel regulators of wild-type and mutant p53 stability
Publisher: Cold Spring Harbor Laboratory
Date: 14-03-2022
DOI: 10.1101/2022.03.13.483372
Abstract: Tumour suppressor p53 ( TP53 ) is the most frequently mutated gene in cancer. Several hotspot p53 mutants not only lose tumour suppressive capabilities, but also function in a dominant-negative manner, suppressing canonical wild-type p53 function. Furthermore, some hotspot p53 mutants promote oncogenesis by gain-of-function mechanisms. Levels of p53 are regulated predominantly through regulation of protein stability and while wild-type p53 is normally kept at very low levels at steady-state, p53 mutants are often stabilized in tumours, which may be vital for their oncogenic properties. Here, we systematically profiled the factors that regulate protein stability of wild-type and mutant p53 using marker-based genome-wide CRISPR screens. We found that most proteins that regulate wild-type p53 also regulate a subset of p53 mutants with the exception of p53 R337H regulators, which are largely private to this mutant. Mechanistically, we identified FBXO42 as a novel positive regulator of a subset of p53 mutants comprising R273H, R248Q and R248W. We show that FBXO42 acts together with CCDC6 to regulate USP28-mediated p53 stabilization. Our work also identifies C16orf72 as a negative regulator of the stability of wild-type p53 and of all p53 mutants tested. C16orf72 is lified in breast cancer, and we show that C16orf72 regulates p53 levels in mammary epithelium of mice and its overexpression results in accelerated breast cancer with reduced p53 levels. Together, this work provides a network view of the processes that regulate p53 stability, which might provide clues for reinforcing wild-type p53 or targeting mutant p53 in cancer.
The NOTCH-RIPK4-IRF6-ELOVL4 Axis Suppresses Squamous Cell Carcinoma
Publisher: MDPI AG
Date: 25-01-2023
Abstract: Receptor-interacting serine/threonine protein kinase 4 (RIPK4) and its kinase substrate the transcription factor interferon regulatory factor 6 (IRF6) play critical roles in the development and maintenance of the epidermis. In addition, ourselves and others have previously shown that RIPK4 is a NOTCH target gene that suppresses the development of cutaneous and head and neck squamous cell carcinomas (HNSCCs). In this study, we used autochthonous mouse models, where the expression of Pik3caH1047R oncogene predisposes the skin and oral cavity to tumor development, and show that not only loss of Ripk4, but also loss of its kinase substrate Irf6, triggers rapid SCC development. In vivo rescue experiments using Ripk4 or a kinase-dead Ripk4 mutant showed that the tumor suppressive function of Ripk4 is dependent on its kinase activity. To elucidate critical mediators of this tumor suppressive pathway, we performed transcriptional profiling of Ripk4-deficient epidermal cells followed by multiplexed in vivo CRISPR screening to identify genes with tumor suppressive capabilities. We show that Elovl4 is a critical Notch-Ripk4-Irf6 downstream target gene, and that Elovl4 loss itself triggers SCC development. Importantly, overexpression of Elovl4 suppressed tumor growth of Ripk4-deficient keratinocytes. Altogether, our work identifies a potent Notch1-Ripk4-Irf6-Elovl4 tumor suppressor axis.
Supplementary Figure S4 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/2643-3230.22587362.V1
Abstract: Supplemental Figure S4 shows the validation of ELAVL1 knockdown by western blot and effects of ELAVL1 loss on human primary AML cells in vitro and in vivo.
Supplementary Figure S6 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/2643-3230.22587356.V1
Abstract: Supplemental Figure S6 shows the GSEA of ELAVL1 depletion in mouse RN2c and human primary AML cells, ELAVL1 subcellular localization in mouse and human AML, the qRT-PCR of ELAVL1 targets in MS-444-treated RN2c cells, and the integrative analysis of the mouse RNA-seq and eCLIP-seq.
Observation of a L12 superlattice in Fe3Ni
Publisher: Elsevier BV
Date: 1995
Pan-cancer analysis of non-coding transcripts reveals the prognostic onco-lncRNA HOXA10-AS in gliomas
Publisher: Elsevier BV
Date: 10-2021
DOI: 10.1016/J.CELREP.2021.109873
Abstract: Long non-coding RNAs (lncRNAs) are increasingly recognized as functional units in cancer and powerful biomarkers however, most remain uncharacterized. Here, we analyze 5,592 prognostic lncRNAs in 9,446 cancers of 30 types using machine learning. We identify 166 lncRNAs whose expression correlates with survival and improves the accuracy of common clinical variables, molecular features, and cancer subtypes. Prognostic lncRNAs are often characterized by switch-like expression patterns. In low-grade gliomas, HOXA10-AS activation is a robust marker of poor prognosis that complements IDH1/2 mutations, as validated in another retrospective cohort, and correlates with developmental pathways in tumor transcriptomes. Loss- and gain-of-function studies in patient-derived glioma cells, organoids, and xenograft models identify HOXA10-AS as a potent onco-lncRNA that regulates cell proliferation, contact inhibition, invasion, Hippo signaling, and mitotic and neuro-developmental pathways. Our study underscores the pan-cancer potential of the non-coding transcriptome for identifying biomarkers and regulators of cancer progression.
Supplementary Table S2 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/2643-3230.22587347.V1
Abstract: Table S2 shows sequences of (a) sgRNAs from the RBP screen, (b) sequencing primers, (c) shRNAs and human-targeting sgRNAs, (d) eCLIP oligos.
Supplementary Figure S2 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/2643-3230.22587368.V1
Abstract: Supplemental Figure S2 shows validation of sgRNA -mediated knockout of hit RBPs, comparison of hit RBP depletion in RN2c in vitro versus in vivo, effects of ELAVL1 loss on human AML cell lines, characteristics of the MLL-AF9 AML mouse model, and ELAVL1 expression in normal hematopoietic cells.
Supplementary Figure S7 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/2643-3230.22587353.V1
Abstract: Supplemental Figure S7 shows the expression profile of TOMM34 in normal human bone marrow and across different AML and CML data sets. The effects of TOMM34 depletion on human primary AML cells in vitro and validation of TOMM34 knockdown and overexpression is shown.
Supplementary Table S9 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/2643-3230.22587326
Abstract: Table S9 shows the (a) differentially expressed transcripts and (b) altered pathways as identified by GSEA from the ELAVL1 knockdown human primary AML RNA-sequencing data set.
Supplementary Table S8 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/2643-3230.22587329
Abstract: Table S8 shows transcripts from the ELAVL1 knockout RNA-sequencing data set that are (a) alternatively spliced and (b) alternatively spliced as well as bound by ELAVL1 as identified by eCLIP-sequencing.
AJUBA: A regulator of epidermal homeostasis and cancer
Publisher: Wiley
Date: 26-01-2021
DOI: 10.1111/EXD.14272
In vivo CRISPR screens reveal SCAF1 and USP15 as novel drivers of pancreatic cancer
Publisher: Research Square Platform LLC
Date: 22-12-2022
DOI: 10.21203/RS.3.RS-2352174/V1
Abstract: Functionally characterizing the genetic alterations that drive pancreatic cancer is a prerequisite for precision medicine. Here, we performed somatic CRISPR/Cas9 mutagenesis screens to assess the transforming potential of 125 recurrently mutated pancreatic cancer genes, which revealed USP15 and SCAF1 as novel pancreatic tumor suppressors. Mechanistically, we found that USP15 functions in a haplo-insufficient manner and that loss of USP15 or SCAF1 leads to reduced inflammatory TNFα, TGF-β and IL6 responses and increased sensitivity to PARP inhibition and Gemcitabine. Furthermore, we found that loss of SCAF1 led to the formation of a truncated, inactive USP15 isoform at the expense of full-length USP15, functionally coupling SCAF1 and USP15. Notably, USP15 and SCAF1 alterations are observed in 31% of pancreatic cancer patients. Our results highlight the utility of in vivo CRISPR screens to integrate human cancer genomics and mouse modeling for the discovery of novel cancer driver genes with potential prognostic and therapeutic implications.
Disruption of STAT3 signalling promotes KRAS-induced lung tumorigenesis
Publisher: Springer Science and Business Media LLC
Date: 03-03-2015
DOI: 10.1038/NCOMMS7285
Abstract: STAT3 is considered to play an oncogenic role in several malignancies including lung cancer consequently, targeting STAT3 is currently proposed as therapeutic intervention. Here we demonstrate that STAT3 plays an unexpected tumour-suppressive role in KRAS mutant lung adenocarcinoma (AC). Indeed, lung tissue-specific inactivation of Stat3 in mice results in increased Kras G12D -driven AC initiation and malignant progression leading to markedly reduced survival. Knockdown of STAT3 in xenografted human AC cells increases tumour growth. Clinically, low STAT3 expression levels correlate with poor survival and advanced malignancy in human lung AC patients with smoking history, which are prone to KRAS mutations. Consistently, KRAS mutant lung tumours exhibit reduced STAT3 levels. Mechanistically, we demonstrate that STAT3 controls NF-κB-induced IL-8 expression by sequestering NF-κB within the cytoplasm, thereby inhibiting IL-8-mediated myeloid tumour infiltration and tumour vascularization and hence tumour progression. These results elucidate a novel STAT3–NF-κB–IL-8 axis in KRAS mutant AC with therapeutic and prognostic relevance.
Data from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2643-3230.C.6572000.V2
Abstract: Abstract Acute myeloid leukemia (AML) is fueled by leukemic stem cells (LSC) whose determinants are challenging to discern from hematopoietic stem cells (HSC) or uncover by approaches focused on general cell properties. We have identified a set of RNA-binding proteins (RBP) selectively enriched in human AML LSCs. Using an i in vivo /i two-step CRISPR-Cas9 screen to assay stem cell functionality, we found 32 RBPs essential for LSCs in MLL-AF9 Nras sup G12D /sup AML. Loss-of-function approaches targeting key hit RBP ELAVL1 compromised LSC-driven i in vivo /i leukemic reconstitution, and selectively depleted primitive malignant versus healthy cells. Integrative multiomics revealed differentiation, splicing, and mitochondrial metabolism as key features defining the leukemic ELAVL1–mRNA interactome with mitochondrial import protein, TOMM34, being a direct ELAVL1-stabilized target whose repression impairs AML propagation. Altogether, using a stem cell–adapted i in vivo /i CRISPR screen, this work demonstrates pervasive reliance on RBPs as regulators of LSCs and highlights their potential as therapeutic targets in AML. Significance: LSC-targeted therapies remain a significant unmet need in AML. We developed a stem-cell–adapted i in vivo /i CRISPR screen to identify key LSC drivers. We uncover widespread RNA-binding protein dependencies in LSCs, including ELAVL1, which we identify as a novel therapeutic vulnerability through its regulation of mitochondrial metabolism. i a href="loodcancerdiscov/article/doi/10.1158/2643-3230.BCD-4-3-ITI" target="_blank" This article is highlighted in the In This Issue feature, p. 171 /a /i /
Supplementary Figure S3 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2643-3230.22725597.V1
Abstract: Supplemental Figure S3 shows the generation of the bcCML mouse model and the effects of ELAVL1 on normal bone marrow in vivo.
Supplementary Table S6 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/2643-3230.22587335
Abstract: Table S6 shows altered gene sets identified by GSEA of the ELAVL1 knockout RN2c RNA-sequencing data set.
Data from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/2643-3230.C.6572000.V1
Abstract: Abstract Acute myeloid leukemia (AML) is fueled by leukemic stem cells (LSC) whose determinants are challenging to discern from hematopoietic stem cells (HSC) or uncover by approaches focused on general cell properties. We have identified a set of RNA-binding proteins (RBP) selectively enriched in human AML LSCs. Using an i in vivo /i two-step CRISPR-Cas9 screen to assay stem cell functionality, we found 32 RBPs essential for LSCs in MLL-AF9 Nras sup G12D /sup AML. Loss-of-function approaches targeting key hit RBP ELAVL1 compromised LSC-driven i in vivo /i leukemic reconstitution, and selectively depleted primitive malignant versus healthy cells. Integrative multiomics revealed differentiation, splicing, and mitochondrial metabolism as key features defining the leukemic ELAVL1–mRNA interactome with mitochondrial import protein, TOMM34, being a direct ELAVL1-stabilized target whose repression impairs AML propagation. Altogether, using a stem cell–adapted i in vivo /i CRISPR screen, this work demonstrates pervasive reliance on RBPs as regulators of LSCs and highlights their potential as therapeutic targets in AML. Significance: LSC-targeted therapies remain a significant unmet need in AML. We developed a stem-cell–adapted i in vivo /i CRISPR screen to identify key LSC drivers. We uncover widespread RNA-binding protein dependencies in LSCs, including ELAVL1, which we identify as a novel therapeutic vulnerability through its regulation of mitochondrial metabolism. /
Supplementary Table S7 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 12-07-2021
DOI: 10.1158/2643-3230.22587332
Abstract: Table S7 shows (a) reproducible peaks and (b) GO analysis of ELAVL1-bound transcripts identified in the eCLIP-sequencing data set. The negatively enriched (c) and positively-enriched (d) gene sets identified by GSEA of ELAVL1-bound and differentially expressed transcripts from the RN2c RNA-sequencing data set are shown.
A designer peptide against the EAG2–Kvβ2 potassium channel targets the interaction of cancer cells and neurons to treat glioblastoma
Publisher: Springer Science and Business Media LLC
Date: 11-09-2023
Supplementary Table S5 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/2643-3230.22587338
Abstract: Table S5 shows the log2 fold change of differentially expressed transcripts from the ELAVL1 knockout RN2c RNA-sequencing data set.
Cross-talk between mutant p53 and p62/SQSTM1 augments cancer cell migration by promoting the degradation of cell adhesion proteins
Publisher: Proceedings of the National Academy of Sciences
Date: 19-04-2022
Abstract: Missense mutations in the TP53 gene, encoding the p53 tumor suppressor, are very frequent in human cancer. Some of those mutations, particularly the more common (“hotspot”) ones, not only abrogate p53’s tumor suppressor activities but also endow the mutant protein with oncogenic gain of function (GOF). We report that p53 R273H , the most common p53 mutant in pancreatic cancer, interacts with the SQSTM1 62 protein to accelerate the degradation of cell adhesion proteins. This enables pancreatic cancer cells to detach from the epithelial sheet and engage in in idualized cell migration, probably augmenting metastatic spread. By providing insights into mechanisms that underpin mutant p53 GOF, this study may suggest ways to interfere with the progression of cancers bearing particular p53 mutants.
Supplementary Data from Loss of Epigenetic Regulation Disrupts Lineage Integrity, Induces Aberrant Alveogenesis, and Promotes Breast Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541637.V1
Abstract: Supplementary Data from Loss of Epigenetic Regulation Disrupts Lineage Integrity, Induces Aberrant Alveogenesis, and Promotes Breast Cancer
In vivo CRISPR screens reveal Serpinb9 and Adam2 as regulators of immune therapy response in lung cancer
Publisher: Springer Science and Business Media LLC
Date: 31-05-2023
DOI: 10.1038/S41467-023-38841-7
Abstract: How the genetic landscape governs a tumor’s response to immunotherapy remains poorly understood. To assess the immune-modulatory capabilities of 573 genes associated with altered cytotoxicity in human cancers, here we perform CRISPR/Cas9 screens directly in mouse lung cancer models. We recover the known immune evasion factors Stat1 and Serpinb9 and identify the cancer testis antigen Adam2 as an immune modulator, whose expression is induced by Kras G12D and further elevated by immunotherapy. Using loss- and gain-of-function experiments, we show that ADAM2 functions as an oncogene by restraining interferon and TNF cytokine signaling causing reduced presentation of tumor-associated antigens. ADAM2 also restricts expression of the immune checkpoint inhibitors PDL1, LAG3, TIGIT and TIM3 in the tumor microenvironment, which might explain why ex vivo expanded and adoptively transferred cytotoxic T-cells show enhanced cytotoxic efficacy in ADAM2 overexpressing tumors. Together, direct in vivo CRISPR/Cas9 screens can uncover genetic alterations that control responses to immunotherapies.
Supplementary Table S8 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2643-3230.22725561.V1
Abstract: Table S8 shows transcripts from the ELAVL1 knockout RNA-sequencing data set that are (a) alternatively spliced and (b) alternatively spliced as well as bound by ELAVL1 as identified by eCLIP-sequencing.
Developmental priming of cancer susceptibility
Publisher: Cold Spring Harbor Laboratory
Date: 15-09-2023
Supplementary Table S5 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2643-3230.22725570.V1
Abstract: Table S5 shows the log2 fold change of differentially expressed transcripts from the ELAVL1 knockout RN2c RNA-sequencing data set.
Copper bioavailability is a KRAS-specific vulnerability in colorectal cancer
Publisher: Springer Science and Business Media LLC
Date: 24-07-2020
DOI: 10.1038/S41467-020-17549-Y
Abstract: Despite its importance in human cancers, including colorectal cancers (CRC), oncogenic KRAS has been extremely challenging to target therapeutically. To identify potential vulnerabilities in KRAS-mutated CRC, we characterize the impact of oncogenic KRAS on the cell surface of intestinal epithelial cells. Here we show that oncogenic KRAS alters the expression of a myriad of cell-surface proteins implicated in erse biological functions, and identify many potential surface-accessible therapeutic targets. Cell surface-based loss-of-function screens reveal that ATP7A, a copper-exporter upregulated by mutant KRAS, is essential for neoplastic growth. ATP7A is upregulated at the surface of KRAS-mutated CRC, and protects cells from excess copper-ion toxicity. We find that KRAS-mutated cells acquire copper via a non-canonical mechanism involving macropinocytosis, which appears to be required to support their growth. Together, these results indicate that copper bioavailability is a KRAS-selective vulnerability that could be exploited for the treatment of KRAS-mutated neoplasms.
Supplementary Table S3 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/2643-3230.22587344
Abstract: Table S3 shows clinical information for all AML patient specimens used in this study.
Supplementary Table S2 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/2643-3230.22587347
Abstract: Table S2 shows sequences of (a) sgRNAs from the RBP screen, (b) sequencing primers, (c) shRNAs and human-targeting sgRNAs, (d) eCLIP oligos.
Supplementary Data from Loss of Epigenetic Regulation Disrupts Lineage Integrity, Induces Aberrant Alveogenesis, and Promotes Breast Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541616
Abstract: Supplementary Data from Loss of Epigenetic Regulation Disrupts Lineage Integrity, Induces Aberrant Alveogenesis, and Promotes Breast Cancer
Supplementary Table S4 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/2643-3230.22587341
Abstract: Table S4 shows limiting dilution analysis of secondary recipients transplanted with DMSO- or MS-444-treated bone marrow from primary mice
Loss of Epigenetic Regulation Disrupts Lineage Integrity, Induces Aberrant Alveogenesis, and Promotes Breast Cancer.
Publisher: American Association for Cancer Research (AACR)
Date: 15-09-2022
DOI: 10.1158/2159-8290.CD-21-0865
Abstract: Infrequently mutated genes comprise most of the mutational burden in breast tumors but are poorly understood. In vivo CRISPR screening identified functional tumor suppressors that converged on epigenetic regulation. Loss of epigenetic regulators accelerated tumorigenesis and revealed lineage infidelity and aberrant expression of alveogenesis genes as potential early events in tumorigenesis. This article is highlighted in the In This Issue feature, p. 2711
Author Reply to Peer Reviews of Genome-wide CRISPR screens identify novel regulators of wild-type and mutant p53 stability
Publisher: EMBO
Date: 07-09-2022
Supplementary Figure S5 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/2643-3230.22587359.V1
Abstract: Supplemental Figure S5 shows the effects of DHTS treatment on THP-1 and human primary AML cells in vitro, the effects of MS-444 treatment on human umbilical cord blood in vivo, and validation of ELAVL1 overexpression by western blot.
In Vivo Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 09-02-2023
DOI: 10.1158/2643-3230.BCD-22-0086
Abstract: LSC-targeted therapies remain a significant unmet need in AML. We developed a stem-cell–adapted in vivo CRISPR screen to identify key LSC drivers. We uncover widespread RNA-binding protein dependencies in LSCs, including ELAVL1, which we identify as a novel therapeutic vulnerability through its regulation of mitochondrial metabolism. This article is highlighted in the In This Issue feature, p. 171
Supplementary Table S7 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2643-3230.22725564.V1
Abstract: Table S7 shows (a) reproducible peaks and (b) GO analysis of ELAVL1-bound transcripts identified in the eCLIP-sequencing data set. The negatively enriched (c) and positively-enriched (d) gene sets identified by GSEA of ELAVL1-bound and differentially expressed transcripts from the RN2c RNA-sequencing data set are shown.
Supplementary Table S9 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 05-2023
DOI: 10.1158/2643-3230.22725558.V1
Abstract: Table S9 shows the (a) differentially expressed transcripts and (b) altered pathways as identified by GSEA from the ELAVL1 knockdown human primary AML RNA-sequencing data set.
Author Correction: In vivo CRISPR screens reveal Serpinb9 and Adam2 as regulators of immune therapy response in lung cancer
Publisher: Springer Science and Business Media LLC
Date: 05-09-2023
Supplementary Figure S3 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/2643-3230.22587365.V1
Abstract: Supplemental Figure S3 shows the generation of the bcCML mouse model and the effects of ELAVL1 on normal bone marrow in vivo.
A noncoding single-nucleotide polymorphism at 8q24 drives
Publisher: American Association for the Advancement of Science (AAAS)
Date: 07-10-2022
Abstract: Establishing causal links between inherited polymorphisms and cancer risk is challenging. Here, we focus on the single-nucleotide polymorphism rs55705857, which confers a sixfold greater risk of isocitrate dehydrogenase (
Supplementary Table S1 from <i>In Vivo</i> Screening Unveils Pervasive RNA-Binding Protein Dependencies in Leukemic Stem Cells and Identifies ELAVL1 as a Therapeutic Target
Publisher: American Association for Cancer Research (AACR)
Date: 11-04-2023
DOI: 10.1158/2643-3230.22587350
Abstract: Table S1 shows expression of RBPs in an RNA-sequencing data set of human bone marrow hematopoietic stem and progenitor subpopulations.
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