دورية أكاديمية
أعرض في EDS

Genetic deletion or small-molecule inhibition of the arginine methyltransferase PRMT5 exhibit anti-tumoral activity in mouse models of MLL-rearranged AML.

التفاصيل البيبلوغرافية
العنوان: Genetic deletion or small-molecule inhibition of the arginine methyltransferase PRMT5 exhibit anti-tumoral activity in mouse models of MLL-rearranged AML.
المؤلفون: Kaushik S; Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Liu F; Department of Biochemistry and Molecular Biology, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA., Veazey KJ; Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Gao G; Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Das P; Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Neves LF; Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX, USA., Lin K; Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Center for Cancer Epigenetics, Houston, TX, USA., Zhong Y; Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Center for Cancer Epigenetics, Houston, TX, USA., Lu Y; Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Center for Cancer Epigenetics, Houston, TX, USA., Giuliani V; Institute for Applied Cancer Science/Center for Co-clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Bedford MT; Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Center for Cancer Epigenetics, Houston, TX, USA., Nimer SD; Department of Biochemistry and Molecular Biology, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA.; Department of Medicine, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA., Santos MA; Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Center for Cancer Epigenetics, Houston, TX, USA.
المصدر: Leukemia [Leukemia] 2018 Feb; Vol. 32 (2), pp. 499-509. Date of Electronic Publication: 2017 Jun 30.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Nature Publishing Group, Specialist Journals Country of Publication: England NLM ID: 8704895 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5551 (Electronic) Linking ISSN: 08876924 NLM ISO Abbreviation: Leukemia Subsets: MEDLINE
أسماء مطبوعة: Publication: 2000- : London : Nature Publishing Group, Specialist Journals
Original Publication: [Baltimore, Md.] : Williams & Wilkins, [c1987-
مواضيع طبية MeSH: Antineoplastic Agents/*pharmacology , Histone-Lysine N-Methyltransferase/*genetics , Leukemia, Myeloid, Acute/*drug therapy , Leukemia, Myeloid, Acute/*genetics , Myeloid-Lymphoid Leukemia Protein/*genetics , Protein-Arginine N-Methyltransferases/*antagonists & inhibitors , Small Molecule Libraries/*pharmacology, Animals ; Cell Line, Tumor ; Disease Models, Animal ; Gene Deletion ; Gene Expression Regulation, Leukemic/drug effects ; Gene Expression Regulation, Leukemic/genetics ; Gene Rearrangement/drug effects ; Gene Rearrangement/genetics ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Oncogene Proteins, Fusion/genetics
مستخلص: The hematological malignancies classified as mixed lineage leukemias (MLL) harbor fusions of the MLL1 gene to partners that are members of transcriptional elongation complexes. MLL-rearranged leukemias are associated with extremely poor prognosis, and response to conventional therapies and efforts to identify molecular targets are urgently needed. Using mouse models of MLL-rearranged acute myeloid leukemia, here we show that genetic inactivation or small-molecule inhibition of the protein arginine methyltransferase PRMT5 exhibit anti-tumoral activity in MLL-fusion protein-driven transformation. Genome-wide transcriptional analysis revealed that inhibition of PRMT5 methyltransferase activity overrides the differentiation block in leukemia cells without affecting the expression of MLL-fusion direct oncogenic targets. Furthermore, we find that this differentiation block is mediated by transcriptional silencing of the cyclin-dependent kinase inhibitor p21 (CDKN1a) gene in leukemia cells. Our study provides pre-clinical rationale for targeting PRMT5 using small-molecule inhibitors in the treatment of leukemias harboring MLL rearrangements.
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معلومات مُعتمدة: P30 CA016672 United States CA NCI NIH HHS
المشرفين على المادة: 0 (Antineoplastic Agents)
0 (Oncogene Proteins, Fusion)
0 (Small Molecule Libraries)
149025-06-9 (Myeloid-Lymphoid Leukemia Protein)
EC 2.1.1.319 (Prmt5 protein, mouse)
EC 2.1.1.319 (Protein-Arginine N-Methyltransferases)
EC 2.1.1.43 (Histone-Lysine N-Methyltransferase)
EC 2.1.1.43 (Kmt2a protein, mouse)
تواريخ الأحداث: Date Created: 20170701 Date Completed: 20190102 Latest Revision: 20200306
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC5865447
DOI: 10.1038/leu.2017.206
PMID: 28663579
قاعدة البيانات: MEDLINE
الوصف
تدمد:1476-5551
DOI:10.1038/leu.2017.206