دورية أكاديمية
أعرض في EDS

Proteasome inhibition targets the KMT2A transcriptional complex in acute lymphoblastic leukemia.

التفاصيل البيبلوغرافية
العنوان: Proteasome inhibition targets the KMT2A transcriptional complex in acute lymphoblastic leukemia.
المؤلفون: Kamens JL; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA., Nance S; Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA., Koss C; Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA., Xu B; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA., Cotton A; Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA., Lam JW; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA., Garfinkle EAR; The University of Tennessee Health Science Center, Memphis, TN, USA., Nallagatla P; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA., Smith AMR; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA., Mitchell S; Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA., Ma J; Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA., Currier D; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA., Wright WC; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA., Kavdia K; Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, Memphis, TN, USA., Pagala VR; Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, Memphis, TN, USA., Kim W; Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA., Wallace LM; Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA., Cho JH; Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, Memphis, TN, USA., Fan Y; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA., Seth A; Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA., Twarog N; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA., Choi JK; Department of Pathology, University of Alabama School of Medicine, Birmingham, AL, USA., Obeng EA; Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA., Hatley ME; Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA., Metzger ML; Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA., Inaba H; Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA., Jeha S; Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA., Rubnitz JE; Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA., Peng J; Center for Proteomics and Metabolomics, St. Jude Children's Research Hospital, Memphis, TN, USA.; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.; Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, USA., Chen T; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA., Shelat AA; Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA., Guy RK; Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY, USA., Gruber TA; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. tagruber@stanford.edu.; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. tagruber@stanford.edu.
المصدر: Nature communications [Nat Commun] 2023 Feb 13; Vol. 14 (1), pp. 809. Date of Electronic Publication: 2023 Feb 13.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [London] : Nature Pub. Group
مواضيع طبية MeSH: Proteasome Endopeptidase Complex*/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma*/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma*/genetics, Infant ; Adult ; Humans ; Child ; Lysine/genetics ; Myeloid-Lymphoid Leukemia Protein/genetics ; Transcriptome
مستخلص: Rearrangments in Histone-lysine-N-methyltransferase 2A (KMT2Ar) are associated with pediatric, adult and therapy-induced acute leukemias. Infants with KMT2Ar acute lymphoblastic leukemia (ALL) have a poor prognosis with an event-free-survival of 38%. Herein we evaluate 1116 FDA approved compounds in primary KMT2Ar infant ALL specimens and identify a sensitivity to proteasome inhibition. Upon exposure to this class of agents, cells demonstrate a depletion of histone H2B monoubiquitination (H2Bub1) and histone H3 lysine 79 dimethylation (H3K79me2) at KMT2A target genes in addition to a downregulation of the KMT2A gene expression signature, providing evidence that it targets the KMT2A transcriptional complex and alters the epigenome. A cohort of relapsed/refractory KMT2Ar patients treated with this approach on a compassionate basis had an overall response rate of 90%. In conclusion, we report on a high throughput drug screen in primary pediatric leukemia specimens whose results translate into clinically meaningful responses. This innovative treatment approach is now being evaluated in a multi-institutional upfront trial for infants with newly diagnosed ALL.
(© 2023. The Author(s).)
التعليقات: Erratum in: Nat Commun. 2023 Mar 9;14(1):1297. doi: 10.1038/s41467-023-37141-4. (PMID: 36894563)
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معلومات مُعتمدة: T32 CA236748 United States CA NCI NIH HHS
المشرفين على المادة: EC 3.4.25.1 (Proteasome Endopeptidase Complex)
K3Z4F929H6 (Lysine)
149025-06-9 (Myeloid-Lymphoid Leukemia Protein)
تواريخ الأحداث: Date Created: 20230213 Date Completed: 20230215 Latest Revision: 20240718
رمز التحديث: 20240718
مُعرف محوري في PubMed: PMC9925443
DOI: 10.1038/s41467-023-36370-x
PMID: 36781850
قاعدة البيانات: MEDLINE
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