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         headline:Integrative genomic analyses reveal mechanisms of glucocorticoid resistance in acute lymphoblastic leukemia
         description:Identification of genomic and epigenomic determinants of drug resistance provides important insights for improving cancer treatment. Using agnostic genome-wide interrogation of messenger RNA and microRNA (miRNA) expression, DNA methylation, single-nucleotide polymorphisms, copy number alterations and single-nucleotide variants/indels in primary human acute lymphoblastic leukemia cells, we identified 463 genomic features associated with glucocorticoid resistance. Gene-level aggregation identified 118 overlapping genes, 15 of which were confirmed by genome-wide CRISPR screen. Collectively, this identified 30 of 38 (79%) known glucocorticoid-resistance genes/miRNAs and all 38 known resistance pathways, while revealing 14 genes not previously associated with glucocorticoid resistance. Single-cell RNA-sequencing and network-based transcriptomic modeling corroborated the top previously undiscovered gene, CELSR2. Manipulation of CELSR2 recapitulated glucocorticoid resistance in human leukemia cell lines and revealed a synergistic drug combination (prednisolone and venetoclax) that mitigated resistance in mouse xenograft models. These findings illustrate the power of an integrative genomic strategy for elucidating genes and pathways conferring drug resistance in cancer cells. Autry et al. combine genome-wide genomic, epigenetic and transcriptomic analyses in an integrated polygenomic approach to identify mechanisms of glucocorticoid resistance in acute lymphoblastic leukemia.
         datePublished:2020-03-09T00:00:00Z
         dateModified:2020-03-09T00:00:00Z
         pageStart:329
         pageEnd:344
         sameAs:https://doi.org/10.1038/s43018-020-0037-3
         keywords:
            Acute lymphocytic leukaemia
            Cancer genomics
            Pharmacogenomics
            Life Sciences
            general
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               2662-1347
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         author:
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      headline:Integrative genomic analyses reveal mechanisms of glucocorticoid resistance in acute lymphoblastic leukemia
      description:Identification of genomic and epigenomic determinants of drug resistance provides important insights for improving cancer treatment. Using agnostic genome-wide interrogation of messenger RNA and microRNA (miRNA) expression, DNA methylation, single-nucleotide polymorphisms, copy number alterations and single-nucleotide variants/indels in primary human acute lymphoblastic leukemia cells, we identified 463 genomic features associated with glucocorticoid resistance. Gene-level aggregation identified 118 overlapping genes, 15 of which were confirmed by genome-wide CRISPR screen. Collectively, this identified 30 of 38 (79%) known glucocorticoid-resistance genes/miRNAs and all 38 known resistance pathways, while revealing 14 genes not previously associated with glucocorticoid resistance. Single-cell RNA-sequencing and network-based transcriptomic modeling corroborated the top previously undiscovered gene, CELSR2. Manipulation of CELSR2 recapitulated glucocorticoid resistance in human leukemia cell lines and revealed a synergistic drug combination (prednisolone and venetoclax) that mitigated resistance in mouse xenograft models. These findings illustrate the power of an integrative genomic strategy for elucidating genes and pathways conferring drug resistance in cancer cells. Autry et al. combine genome-wide genomic, epigenetic and transcriptomic analyses in an integrated polygenomic approach to identify mechanisms of glucocorticoid resistance in acute lymphoblastic leukemia.
      datePublished:2020-03-09T00:00:00Z
      dateModified:2020-03-09T00:00:00Z
      pageStart:329
      pageEnd:344
      sameAs:https://doi.org/10.1038/s43018-020-0037-3
      keywords:
         Acute lymphocytic leukaemia
         Cancer genomics
         Pharmacogenomics
         Life Sciences
         general
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         name:Nature Cancer
         issn:
            2662-1347
         volumeNumber:1
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            Periodical
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         name:Nature Publishing Group US
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      author:
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                  address:
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            name:St. Jude Children’s Research Hospital
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            name:St. Jude Children’s Research Hospital
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            name:St. Jude Children’s Research Hospital
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            name:St. Jude Children’s Research Hospital
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               name:Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, USA
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            name:St. Jude Children’s Research Hospital
            address:
               name:Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children’s Research Hospital, Memphis, USA
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               name:Department of Leukemia, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, USA
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               name:Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children’s Research Hospital, Memphis, USA
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               name:Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children’s Research Hospital, Memphis, USA
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            address:
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            name:St. Jude Children’s Research Hospital
            address:
               name:Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, USA
               type:PostalAddress
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      name:Jiyang Yu
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            address:
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               type:PostalAddress
            type:Organization
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            name:St. Jude Children’s Research Hospital
            address:
               name:Department of Oncology, St. Jude Children’s Research Hospital, Memphis, USA
               type:PostalAddress
            type:Organization
            name:St. Jude Children’s Research Hospital
            address:
               name:Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, USA
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            address:
               name:Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children’s Research Hospital, Memphis, USA
               type:PostalAddress
            type:Organization
            name:St. Jude Children’s Research Hospital
            address:
               name:Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, USA
               type:PostalAddress
            type:Organization
            name:University of Tennessee Health Science Center
            address:
               name:Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, USA
               type:PostalAddress
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            address:
               name:Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children’s Research Hospital, Memphis, USA
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            name:St. Jude Children’s Research Hospital
            address:
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               type:PostalAddress
            type:Organization
            name:St. Jude Children’s Research Hospital
            address:
               name:Department of Oncology, St. Jude Children’s Research Hospital, Memphis, USA
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               name:Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children’s Research Hospital, Memphis, USA
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               name:Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, USA
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      name:Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, USA
      name:Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, USA
      name:Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children’s Research Hospital, Memphis, USA
      name:Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, USA
      name:Department of Oncology, St. Jude Children’s Research Hospital, Memphis, USA
      name:Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, USA
      name:Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, USA
      name:Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, USA
      name:Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children’s Research Hospital, Memphis, USA
      name:Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, USA
      name:Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children’s Research Hospital, Memphis, USA
      name:Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, USA
      name:Pediatric Oncology Education Program, St. Jude Children’s Research Hospital, Memphis, USA
      name:Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children’s Research Hospital, Memphis, USA
      name:Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, USA
      name:Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children’s Research Hospital, Memphis, USA
      name:Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, USA
      name:Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children’s Research Hospital, Memphis, USA
      name:Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, USA
      name:Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children’s Research Hospital, Memphis, USA
      name:Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, USA
      name:Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, USA
      name:Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children’s Research Hospital, Memphis, USA
      name:Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, USA
      name:Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children’s Research Hospital, Memphis, USA
      name:Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, USA
      name:Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, USA
      name:Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children’s Research Hospital, Memphis, USA
      name:Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, USA
      name:Department of Oncology, St. Jude Children’s Research Hospital, Memphis, USA
      name:Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, USA
      name:Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, USA
      name:Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children’s Research Hospital, Memphis, USA
      name:Department of Oncology, St. Jude Children’s Research Hospital, Memphis, USA
      name:Comprehensive Cancer Center, St. Jude Children’s Research Hospital, Memphis, USA
      name:Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children’s Research Hospital, Memphis, USA
      name:Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, USA
      name:Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children’s Research Hospital, Memphis, USA
      name:Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, USA
      name:Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children’s Research Hospital, Memphis, USA
      name:Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, USA
      name:Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children’s Research Hospital, Memphis, USA
      name:Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, USA
      name:Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, USA
      name:Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children’s Research Hospital, Memphis, USA
      name:Department of Pathology, St. Jude Children’s Research Hospital, Memphis, USA
      name:Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, USA
      name:Department of Leukemia, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, USA
      name:Hematopoiesis and Hematological Malignancies Program, University of Chicago, Chicago, USA
      name:Department of Medicine, Albert Einstein College of Medicine, Montefiore Medical Center, North Division, Bronx, USA
      name:Division of Hematology and Department of Internal Medicine, Mayo Clinic, Rochester, USA
      name:Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children’s Research Hospital, Memphis, USA
      name:Department of Oncology, St. Jude Children’s Research Hospital, Memphis, USA
      name:Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children’s Research Hospital, Memphis, USA
      name:Department of Oncology, St. Jude Children’s Research Hospital, Memphis, USA
      name:Department of Pathology, St. Jude Children’s Research Hospital, Memphis, USA
      name:Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children’s Research Hospital, Memphis, USA
      name:Department of Oncology, St. Jude Children’s Research Hospital, Memphis, USA
      name:Department of Pathology, St. Jude Children’s Research Hospital, Memphis, USA
      name:Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children’s Research Hospital, Memphis, USA
      name:Department of Oncology, St. Jude Children’s Research Hospital, Memphis, USA
      name:Department of Pathology, St. Jude Children’s Research Hospital, Memphis, USA
      name:Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, USA
      name:Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children’s Research Hospital, Memphis, USA
      name:Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, USA
      name:Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, USA
      name:Department of Oncology, St. Jude Children’s Research Hospital, Memphis, USA
      name:Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, USA
      name:Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children’s Research Hospital, Memphis, USA
      name:Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, USA
      name:Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, USA
      name:Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children’s Research Hospital, Memphis, USA
      name:Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, USA
      name:Department of Oncology, St. Jude Children’s Research Hospital, Memphis, USA
      name:Hematological Malignancies Program and Center for Precision Medicine in Leukemia, St. Jude Children’s Research Hospital, Memphis, USA
      name:Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, USA
      name:Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, USA
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