The menin-MLL1 interaction is a molecular dependency in NUP98-rearranged AML.

Autor:	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.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2022 Feb 10; Vol. 139 (6), pp. 894-906.
DOI:	10.1182/blood.2021012806
Abstrakt:	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.)
Databáze:	MEDLINE
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