دورية أكاديمية
The menin-MLL1 interaction is a molecular dependency in NUP98-rearranged AML.
| العنوان: | The menin-MLL1 interaction is a molecular dependency in NUP98-rearranged AML. |
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| المؤلفون: | Heikamp EB; Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, and Harvard Medical School, Boston, MA., Henrich JA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, and Harvard Medical School, Boston, MA., Perner F; Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, and Harvard Medical School, Boston, MA.; Internal Medicine C, Greifswald University Medical Center, Greifswald, Germany., Wong EM; Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, and Harvard Medical School, Boston, MA., Hatton C; Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, and Harvard Medical School, Boston, MA., Wen Y; Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, and Harvard Medical School, Boston, MA., Barwe SP; Nemours Center for Cancer and Blood Disorders/Alfred I. DuPont Hospital for Children, Wilmington, DE., Gopalakrishnapillai A; Nemours Center for Cancer and Blood Disorders/Alfred I. DuPont Hospital for Children, Wilmington, DE., Xu H; Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, and Harvard Medical School, Boston, MA., Uckelmann HJ; Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, and Harvard Medical School, Boston, MA., Takao S; Tow Center for Developmental Oncology, Sloan Kettering Institute, and Department of Pediatrics, Weill Medical College of Cornell University, and Memorial Sloan-Kettering Cancer Center, New York, NY; and., Kazansky Y; Tow Center for Developmental Oncology, Sloan Kettering Institute, and Department of Pediatrics, Weill Medical College of Cornell University, and Memorial Sloan-Kettering Cancer Center, New York, NY; and., Pikman Y; Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, and Harvard Medical School, Boston, MA., McGeehan GM; Syndax Pharmaceuticals, Inc., Waltham, MA., Kolb EA; Nemours Center for Cancer and Blood Disorders/Alfred I. DuPont Hospital for Children, Wilmington, DE., Kentsis A; Tow Center for Developmental Oncology, Sloan Kettering Institute, and Department of Pediatrics, Weill Medical College of Cornell University, and Memorial Sloan-Kettering Cancer Center, New York, NY; and., Armstrong SA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, and Harvard Medical School, Boston, MA. |
| المصدر: | Blood [Blood] 2022 Feb 10; Vol. 139 (6), pp. 894-906. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Country of Publication: United States NLM ID: 7603509 Publication Model: Print Cited Medium: Internet ISSN: 1528-0020 (Electronic) Linking ISSN: 00064971 NLM ISO Abbreviation: Blood Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2021- : [New York] : Elsevier Original Publication: New York, Grune & Stratton [etc.] |
| مواضيع طبية MeSH: | Histone-Lysine N-Methyltransferase/*metabolism , Leukemia, Myeloid, Acute/*genetics , Myeloid-Lymphoid Leukemia Protein/*metabolism , Nuclear Pore Complex Proteins/*genetics , Proto-Oncogene Proteins/*metabolism, Animals ; Cell Line, Tumor ; Gene Expression Regulation, Leukemic ; Gene Rearrangement ; Histone-Lysine N-Methyltransferase/genetics ; Leukemia, Myeloid, Acute/metabolism ; Mice ; Mice, Inbred C57BL ; Myeloid-Lymphoid Leukemia Protein/genetics ; Nuclear Pore Complex Proteins/metabolism ; Oncogene Proteins, Fusion/genetics ; Oncogene Proteins, Fusion/metabolism ; Protein Interaction Maps ; Proto-Oncogene Proteins/genetics |
| مستخلص: | Translocations involving the NUP98 gene produce NUP98-fusion proteins and are associated with a poor prognosis in acute myeloid leukemia (AML). MLL1 is a molecular dependency in NUP98-fusion leukemia, and therefore we investigated the efficacy of therapeutic blockade of the menin-MLL1 interaction in NUP98-fusion leukemia models. Using mouse leukemia cell lines driven by NUP98-HOXA9 and NUP98-JARID1A fusion oncoproteins, we demonstrate that NUP98-fusion-driven leukemia is sensitive to the menin-MLL1 inhibitor VTP50469, with an IC50 similar to what we have previously reported for MLL-rearranged and NPM1c leukemia cells. Menin-MLL1 inhibition upregulates markers of differentiation such as CD11b and downregulates expression of proleukemogenic transcription factors such as Meis1 in NUP98-fusion-transformed leukemia cells. We demonstrate that MLL1 and the NUP98 fusion protein itself are evicted from chromatin at a critical set of genes that are essential for the maintenance of the malignant phenotype. In addition to these in vitro studies, we established patient-derived xenograft (PDX) models of NUP98-fusion-driven AML to test the in vivo efficacy of menin-MLL1 inhibition. Treatment with VTP50469 significantly prolongs survival of mice engrafted with NUP98-NSD1 and NUP98-JARID1A leukemias. Gene expression analysis revealed that menin-MLL1 inhibition simultaneously suppresses a proleukemogenic gene expression program, including downregulation of the HOXa cluster, and upregulates tissue-specific markers of differentiation. These preclinical results suggest that menin-MLL1 inhibition may represent a rational, targeted therapy for patients with NUP98-rearranged leukemias. (© 2022 by The American Society of Hematology.) |
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| معلومات مُعتمدة: | T32 HL007574 United States HL NHLBI NIH HHS; R01 CA204396 United States CA NCI NIH HHS; U54 CA243124 United States CA NCI NIH HHS; P01 CA066996 United States CA NCI NIH HHS; P30 CA008748 United States CA NCI NIH HHS; R21 CA235285 United States CA NCI NIH HHS; R01 CA176745 United States CA NCI NIH HHS; P30 CA006516 United States CA NCI NIH HHS; K08 CA222684 United States CA NCI NIH HHS |
| المشرفين على المادة: | 0 (Men1 protein, mouse) 0 (Nuclear Pore Complex Proteins) 0 (Oncogene Proteins, Fusion) 0 (Proto-Oncogene Proteins) 0 (nuclear pore complex protein 98) 149025-06-9 (Myeloid-Lymphoid Leukemia Protein) EC 2.1.1.43 (Histone-Lysine N-Methyltransferase) EC 2.1.1.43 (Kmt2a protein, mouse) |
| تواريخ الأحداث: | Date Created: 20210928 Date Completed: 20220223 Latest Revision: 20230407 |
| رمز التحديث: | 20240628 |
| مُعرف محوري في PubMed: | PMC8832476 |
| DOI: | 10.1182/blood.2021012806 |
| PMID: | 34582559 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1528-0020 |
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| DOI: | 10.1182/blood.2021012806 |