تقرير
Mutant NPM1 Directly Regulates Oncogenic Transcription in Acute Myeloid Leukemia.
| العنوان: | Mutant NPM1 Directly Regulates Oncogenic Transcription in Acute Myeloid Leukemia. |
|---|---|
| المؤلفون: | Uckelmann HJ; Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, and Harvard Medical School, Boston, Massachusetts., Haarer EL; Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, and Harvard Medical School, Boston, Massachusetts., Takeda R; Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, and Harvard Medical School, Boston, Massachusetts., Wong EM; Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, and Harvard Medical School, Boston, Massachusetts., Hatton C; Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, and Harvard Medical School, Boston, Massachusetts., Marinaccio C; Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, and Harvard Medical School, Boston, Massachusetts., Perner F; Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, and Harvard Medical School, Boston, Massachusetts., Rajput M; Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, and Harvard Medical School, Boston, Massachusetts.; German Cancer Research Center, DKFZ, Heidelberg, Germany., Antonissen NJC; Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, and Harvard Medical School, Boston, Massachusetts., Wen Y; Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, and Harvard Medical School, Boston, Massachusetts., Yang L; Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, California., Brunetti L; Department of Medicine and Surgery, University of Perugia, Perugia, Italy.; Department of Clinical and Molecular Sciences, Marche Polytechnic University, Ancona, Italy., Chen CW; Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, California., Armstrong SA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, and Harvard Medical School, Boston, Massachusetts. |
| المصدر: | Cancer discovery [Cancer Discov] 2023 Mar 01; Vol. 13 (3), pp. 746-765. |
| نوع المنشور: | Editorial; Research Support, N.I.H., Extramural; Comment |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 101561693 Publication Model: Print Cited Medium: Internet ISSN: 2159-8290 (Electronic) Linking ISSN: 21598274 NLM ISO Abbreviation: Cancer Discov Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Philadelphia, PA : American Association for Cancer Research |
| مواضيع طبية MeSH: | Nuclear Proteins*/genetics , Nuclear Proteins*/metabolism , Leukemia, Myeloid, Acute*/pathology, Humans ; Nucleophosmin ; Mutation ; Chromatin/genetics |
| مستخلص: | The dysregulation of developmental and stem cell-associated genes is a common phenomenon during cancer development. Around half of patients with acute myeloid leukemia (AML) express high levels of HOXA cluster genes and MEIS1. Most of these AML cases harbor an NPM1 mutation (NPM1c), which encodes for an oncoprotein mislocalized from the nucleolus to the cytoplasm. How NPM1c expression in hematopoietic cells leads to its characteristic gene-expression pattern remains unclear. Here, we show that NPM1c directly binds to specific chromatin targets, which are co-occupied by the histone methyltransferase KMT2A (MLL1). Targeted degradation of NPM1c leads to a rapid decrease in gene expression and loss of RNA polymerase II, as well as activating histone modifications at its targets. We demonstrate that NPM1c directly regulates oncogenic gene expression in collaboration with the MLL1 complex and define the mechanism by which MLL1-Menin small-molecule inhibitors produce clinical responses in patients with NPM1-mutated AML. Significance: We uncovered an important functional role of mutant NPM1 as a crucial direct driver of oncogenic gene expression in AML. NPM1c can bind to chromatin and cooperate with the MLL complex, providing the first functional insight into the mechanism of Menin-MLL inhibition in NPM1c leukemias. See related article by Wang et al., p. 724. This article is highlighted in the In This Issue feature, p. 517. (©2022 American Association for Cancer Research.) |
| التعليقات: | Comment in: Cancer Discov. 2023 Mar 1;13(3):724-745. (PMID: 36455589) Comment on: Cancer Discov. 2023 Mar 1;13(3):724-745. (PMID: 36455589) |
| References: | Mol Cell Biol. 2005 Sep;25(17):7534-45. (PMID: 16107701) Cancer Cell. 2016 Apr 11;29(4):574-586. (PMID: 27070704) Nature. 2018 Oct;562(7728):526-531. (PMID: 30333627) Int J Hematol. 2019 Aug;110(2):150-160. (PMID: 30632059) Mol Cell. 2022 Mar 17;82(6):1140-1155.e11. (PMID: 35245435) Cancer Cell. 2018 Sep 10;34(3):499-512.e9. (PMID: 30205049) Cancer Cell. 2008 Jul 8;14(1):36-46. (PMID: 18598942) Sci Adv. 2022 Apr 29;8(17):eabm3945. (PMID: 35476441) Nat Protoc. 2016 Aug;11(8):1455-76. (PMID: 27442863) Mol Cell. 2021 Mar 4;81(5):998-1012.e7. (PMID: 33440169) Nat Rev Cancer. 2006 Jul;6(7):493-505. (PMID: 16794633) J Clin Invest. 2020 Feb 3;130(2):981-997. (PMID: 31855575) Mol Cell Biol. 2009 Sep;29(18):5115-27. (PMID: 19581289) Cancer Discov. 2022 Mar 1;12(3):792-811. (PMID: 34853079) Cell Rep. 2016 Aug 16;16(7):2003-16. (PMID: 27498870) BMC Bioinformatics. 2019 May 20;20(1):258. (PMID: 31109287) Blood. 2010 Apr 8;115(14):2910-8. (PMID: 20130239) Blood. 2009 Mar 26;113(13):3088-91. (PMID: 19171880) N Engl J Med. 2013 May 30;368(22):2059-74. (PMID: 23634996) Science. 2020 Jan 31;367(6477):586-590. (PMID: 32001657) Mol Cell Biol. 2006 May;26(10):3902-16. (PMID: 16648484) Cold Spring Harb Perspect Med. 2017 Nov 1;7(11):. (PMID: 28242784) N Engl J Med. 2016 Jun 9;374(23):2209-2221. (PMID: 27276561) Nat Chem Biol. 2018 May;14(5):431-441. (PMID: 29581585) Cancer Discov. 2016 Oct;6(10):1166-1181. (PMID: 27535106) Cancer Res. 2006 Mar 15;66(6):3044-50. (PMID: 16540653) N Engl J Med. 2015 Sep 17;373(12):1136-52. (PMID: 26376137) Cancer Cell. 2019 Dec 9;36(6):660-673.e11. (PMID: 31821784) Nat Protoc. 2016 Feb;11(2):316-26. (PMID: 26797456) Cancer Res. 2008 Mar 1;68(5):1398-406. (PMID: 18316603) Science. 2013 Feb 22;339(6122):950-3. (PMID: 23430654) Elife. 2019 Nov 22;8:. (PMID: 31755865) Nature. 2020 Jan;577(7789):266-270. (PMID: 31827282) Biochem J. 2005 May 15;388(Pt 1):7-15. (PMID: 15737070) Cold Spring Harb Symp Quant Biol. 1998;63:365-70. (PMID: 10384301) J Clin Invest. 2018 Oct 1;128(10):4260-4279. (PMID: 30015632) Blood. 2020 Oct 8;136(15):1707-1721. (PMID: 32609823) Nat Cell Biol. 2002 Jul;4(7):529-33. (PMID: 12080348) Leukemia. 2020 May;34(5):1278-1290. (PMID: 31831844) N Engl J Med. 2005 Jan 20;352(3):254-66. (PMID: 15659725) J Biol Chem. 2000 Aug 11;275(32):24451-7. (PMID: 10829026) Nat Biotechnol. 2015 Jun;33(6):661-7. (PMID: 25961408) Mol Cell Biol. 2008 May;28(10):3114-26. (PMID: 18332108) Blood Adv. 2022 Nov 22;6(22):5938-5949. (PMID: 36037515) Haematologica. 2007 Apr;92(4):519-32. (PMID: 17488663) Science. 2018 May 18;360(6390):800-805. (PMID: 29622725) |
| معلومات مُعتمدة: | P01 CA066996 United States CA NCI NIH HHS; P50 CA206963 United States CA NCI NIH HHS; R01 CA259273 United States CA NCI NIH HHS; R37 CA233691 United States CA NCI NIH HHS |
| المشرفين على المادة: | 0 (Nuclear Proteins) 117896-08-9 (Nucleophosmin) 0 (Chromatin) |
| تواريخ الأحداث: | Date Created: 20221201 Date Completed: 20230302 Latest Revision: 20230902 |
| رمز التحديث: | 20231215 |
| مُعرف محوري في PubMed: | PMC10084473 |
| DOI: | 10.1158/2159-8290.CD-22-0366 |
| PMID: | 36455613 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 2159-8290 |
|---|---|
| DOI: | 10.1158/2159-8290.CD-22-0366 |