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  1. Article ; Online: Therapeutic targeting of DNA methylation alterations in cancer.

    Lee, Abigail V / Nestler, Kevin A / Chiappinelli, Katherine B

    Pharmacology & therapeutics

    2024  Volume 258, Page(s) 108640

    Abstract: DNA methylation is a critical component of gene regulation and plays an important role in the development of cancer. Hypermethylation of tumor suppressor genes and silencing of DNA repair pathways facilitate uncontrolled cell growth and synergize with ... ...

    Abstract DNA methylation is a critical component of gene regulation and plays an important role in the development of cancer. Hypermethylation of tumor suppressor genes and silencing of DNA repair pathways facilitate uncontrolled cell growth and synergize with oncogenic mutations to perpetuate cancer phenotypes. Additionally, aberrant DNA methylation hinders immune responses crucial for antitumor immunity. Thus, inhibiting dysregulated DNA methylation is a promising cancer therapy. Pharmacologic inhibition of DNA methylation reactivates silenced tumor suppressors and bolster immune responses through induction of viral mimicry. Now, with the advent of immunotherapies and discovery of the immune-modulatory effects of DNA methylation inhibitors, there is great interest in understanding how targeting DNA methylation in combination with other therapies can enhance antitumor immunity. Here, we describe the role of aberrant DNA methylation in cancer and mechanisms by which it promotes tumorigenesis and modulates immune responses. Finally, we review the initial discoveries and ongoing efforts to target DNA methylation as a cancer therapeutic.
    MeSH term(s) Humans ; DNA Methylation/drug effects ; Neoplasms/genetics ; Neoplasms/drug therapy ; Animals ; Antineoplastic Agents/therapeutic use ; Antineoplastic Agents/pharmacology ; Molecular Targeted Therapy ; Immunotherapy/methods
    Chemical Substances Antineoplastic Agents
    Language English
    Publishing date 2024-04-01
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 194735-7
    ISSN 1879-016X ; 0163-7258
    ISSN (online) 1879-016X
    ISSN 0163-7258
    DOI 10.1016/j.pharmthera.2024.108640
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    In stock of ZB MED Cologne/Königswinter

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  2. Article: Longitudinal Large-Scale Semiquantitative Proteomic Data Stability Across Multiple Instrument Platforms

    Lu, Congcong / Glisovic-Aplenc, Tina / Bernt, Kathrin M. / Nestler, Kevin / Cesare, Joseph / Cao, Lusha / Lee, Hyoungjoo / Fazelinia, Hossein / Chinwalla, Asif / Xu, Yang / Shestova, Olga / Xing, Yi / Gill, Saar / Li, Mingyao / Garcia, Benjamin / Aplenc, Richard

    Journal of proteome research. 2021 Oct. 20, v. 20, no. 11

    2021  

    Abstract: With the rapid developments in mass spectrometry (MS)-based proteomics methods, label-free semiquantitative proteomics has become an increasingly popular tool for profiling global protein abundances in an unbiased manner. However, the reproducibility of ... ...

    Abstract With the rapid developments in mass spectrometry (MS)-based proteomics methods, label-free semiquantitative proteomics has become an increasingly popular tool for profiling global protein abundances in an unbiased manner. However, the reproducibility of these data across time and LC–MS platforms is not well characterized. Here, we evaluate the performance of three LC–MS platforms (Orbitrap Elite, Q Exactive HF, and Orbitrap Fusion) in label-free semiquantitative analysis of cell surface proteins over a six-year period. Sucrose gradient ultracentrifugation was used for surfaceome enrichment, following gel separation for in-depth protein identification. With our established workflow, we consistently detected and reproducibly quantified >2300 putative cell surface proteins in a human acute myeloid leukemia (AML) cell line on all three platforms. To our knowledge this is the first study reporting highly reproducible semiquantitative proteomic data collection of biological replicates across multiple years and LC–MS platforms. These data provide experimental justification for semiquantitative proteomic study designs that are executed over multiyear time intervals and on different platforms. Multiyear and multiplatform experimental designs will likely enable larger scale proteomic studies and facilitate longitudinal proteomic studies by investigators lacking access to high throughput MS facilities. Data are available via ProteomeXchange with identifier PXD022721.
    Keywords cell lines ; data collection ; gels ; humans ; mass spectrometry ; myeloid leukemia ; proteome ; proteomics ; research ; sucrose ; ultracentrifugation
    Language English
    Dates of publication 2021-1020
    Size p. 5203-5211.
    Publishing place American Chemical Society
    Document type Article
    ZDB-ID 2078618-9
    ISSN 1535-3907 ; 1535-3893
    ISSN (online) 1535-3907
    ISSN 1535-3893
    DOI 10.1021/acs.jproteome.1c00624
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  3. Article: Intrinsically disordered Meningioma-1 stabilizes the BAF complex to cause AML

    Riedel, Simone S / Lu, Congcong / Xie, Hongbo M / Nestler, Kevin / Vermunt, Marit W / Lenard, Alexandra / Bennett, Laura / Speck, Nancy A / Hanamura, Ichiro / Lessard, Julie A / Blobel, Gerd A / Garcia, Benjamin A / Bernt, Kathrin M

    Molecular cell. 2021 June 03, v. 81, no. 11

    2021  

    Abstract: Meningioma-1 (MN1) overexpression in AML is associated with poor prognosis, and forced expression of MN1 induces leukemia in mice. We sought to determine how MN1 causes AML. We found that overexpression of MN1 can be induced by translocations that result ...

    Abstract Meningioma-1 (MN1) overexpression in AML is associated with poor prognosis, and forced expression of MN1 induces leukemia in mice. We sought to determine how MN1 causes AML. We found that overexpression of MN1 can be induced by translocations that result in hijacking of a downstream enhancer. Structure predictions revealed that the entire MN1 coding frame is disordered. We identified the myeloid progenitor-specific BAF complex as the key interaction partner of MN1. MN1 over-stabilizes BAF on enhancer chromatin, a function directly linked to the presence of a long polyQ-stretch within MN1. BAF over-stabilization at binding sites of transcription factors regulating a hematopoietic stem/progenitor program prevents the developmentally appropriate decommissioning of these enhancers and results in impaired myeloid differentiation and leukemia. Beyond AML, our data detail how the overexpression of a polyQ protein, in the absence of any coding sequence mutation, can be sufficient to cause malignant transformation.
    Keywords chromatin ; leukemia ; mutation ; prognosis
    Language English
    Dates of publication 2021-0603
    Size p. 2332-2348.e9.
    Publishing place Elsevier Inc.
    Document type Article
    Note NAL-AP-2-clean
    ZDB-ID 1415236-8
    ISSN 1097-4164 ; 1097-2765
    ISSN (online) 1097-4164
    ISSN 1097-2765
    DOI 10.1016/j.molcel.2021.04.014
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  4. Article ; Online: Intrinsically disordered Meningioma-1 stabilizes the BAF complex to cause AML.

    Riedel, Simone S / Lu, Congcong / Xie, Hongbo M / Nestler, Kevin / Vermunt, Marit W / Lenard, Alexandra / Bennett, Laura / Speck, Nancy A / Hanamura, Ichiro / Lessard, Julie A / Blobel, Gerd A / Garcia, Benjamin A / Bernt, Kathrin M

    Molecular cell

    2021  Volume 81, Issue 11, Page(s) 2332–2348.e9

    Abstract: Meningioma-1 (MN1) overexpression in AML is associated with poor prognosis, and forced expression of MN1 induces leukemia in mice. We sought to determine how MN1 causes AML. We found that overexpression of MN1 can be induced by translocations that result ...

    Abstract Meningioma-1 (MN1) overexpression in AML is associated with poor prognosis, and forced expression of MN1 induces leukemia in mice. We sought to determine how MN1 causes AML. We found that overexpression of MN1 can be induced by translocations that result in hijacking of a downstream enhancer. Structure predictions revealed that the entire MN1 coding frame is disordered. We identified the myeloid progenitor-specific BAF complex as the key interaction partner of MN1. MN1 over-stabilizes BAF on enhancer chromatin, a function directly linked to the presence of a long polyQ-stretch within MN1. BAF over-stabilization at binding sites of transcription factors regulating a hematopoietic stem/progenitor program prevents the developmentally appropriate decommissioning of these enhancers and results in impaired myeloid differentiation and leukemia. Beyond AML, our data detail how the overexpression of a polyQ protein, in the absence of any coding sequence mutation, can be sufficient to cause malignant transformation.
    MeSH term(s) Animals ; Base Sequence ; Carcinogenesis/genetics ; Carcinogenesis/metabolism ; Carcinogenesis/pathology ; Cell Line, Tumor ; Chromatin/genetics ; Chromatin/metabolism ; Chromatin/pathology ; DNA Helicases/genetics ; DNA Helicases/metabolism ; Enhancer Elements, Genetic ; Female ; Gene Expression Regulation, Leukemic ; Gene Regulatory Networks ; Humans ; Intrinsically Disordered Proteins/genetics ; Intrinsically Disordered Proteins/metabolism ; Leukemia, Myeloid, Acute/genetics ; Leukemia, Myeloid, Acute/metabolism ; Leukemia, Myeloid, Acute/mortality ; Leukemia, Myeloid, Acute/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Peptides/genetics ; Peptides/metabolism ; Protein Interaction Mapping ; Protein Stability ; Protein Transport ; Signal Transduction ; Survival Analysis ; Trans-Activators/genetics ; Trans-Activators/metabolism ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Tumor Suppressor Proteins/genetics ; Tumor Suppressor Proteins/metabolism
    Chemical Substances Chromatin ; Intrinsically Disordered Proteins ; MN1 protein, human ; Mn1 protein, mouse ; Nuclear Proteins ; Peptides ; Trans-Activators ; Transcription Factors ; Tumor Suppressor Proteins ; polyglutamine (26700-71-0) ; SMARCA4 protein, human (EC 3.6.1.-) ; Smarca4 protein, mouse (EC 3.6.1.-) ; DNA Helicases (EC 3.6.4.-)
    Language English
    Publishing date 2021-05-10
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1415236-8
    ISSN 1097-4164 ; 1097-2765
    ISSN (online) 1097-4164
    ISSN 1097-2765
    DOI 10.1016/j.molcel.2021.04.014
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5055: Show issues Location:
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  5. Article ; Online: Longitudinal Large-Scale Semiquantitative Proteomic Data Stability Across Multiple Instrument Platforms.

    Lu, Congcong / Glisovic-Aplenc, Tina / Bernt, Kathrin M / Nestler, Kevin / Cesare, Joseph / Cao, Lusha / Lee, Hyoungjoo / Fazelinia, Hossein / Chinwalla, Asif / Xu, Yang / Shestova, Olga / Xing, Yi / Gill, Saar / Li, Mingyao / Garcia, Benjamin / Aplenc, Richard

    Journal of proteome research

    2021  Volume 20, Issue 11, Page(s) 5203–5211

    Abstract: With the rapid developments in mass spectrometry (MS)-based proteomics methods, label-free semiquantitative proteomics has become an increasingly popular tool for profiling global protein abundances in an unbiased manner. However, the reproducibility of ... ...

    Abstract With the rapid developments in mass spectrometry (MS)-based proteomics methods, label-free semiquantitative proteomics has become an increasingly popular tool for profiling global protein abundances in an unbiased manner. However, the reproducibility of these data across time and LC-MS platforms is not well characterized. Here, we evaluate the performance of three LC-MS platforms (Orbitrap Elite, Q Exactive HF, and Orbitrap Fusion) in label-free semiquantitative analysis of cell surface proteins over a six-year period. Sucrose gradient ultracentrifugation was used for surfaceome enrichment, following gel separation for in-depth protein identification. With our established workflow, we consistently detected and reproducibly quantified >2300 putative cell surface proteins in a human acute myeloid leukemia (AML) cell line on all three platforms. To our knowledge this is the first study reporting highly reproducible semiquantitative proteomic data collection of biological replicates across multiple years and LC-MS platforms. These data provide experimental justification for semiquantitative proteomic study designs that are executed over multiyear time intervals and on different platforms. Multiyear and multiplatform experimental designs will likely enable larger scale proteomic studies and facilitate longitudinal proteomic studies by investigators lacking access to high throughput MS facilities. Data are available via ProteomeXchange with identifier PXD022721.
    MeSH term(s) Humans ; Mass Spectrometry/methods ; Proteome/analysis ; Proteomics/methods ; Reproducibility of Results ; Workflow
    Chemical Substances Proteome
    Language English
    Publishing date 2021-10-20
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2078618-9
    ISSN 1535-3907 ; 1535-3893
    ISSN (online) 1535-3907
    ISSN 1535-3893
    DOI 10.1021/acs.jproteome.1c00624
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 6189: Show issues Location:
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