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

• Main Authors: Armstrong, S.A (Author), Barwe, S.P (Author), Gopalakrishnapillai, A. (Author), Hatton, C. (Author), Heikamp, E.B (Author), Henrich, J.A (Author), Kazansky, Y. (Author), Kentsis, A. (Author), Kolb, E.A (Author), McGeehan, G.M (Author), Perner, F. (Author), Pikman, Y. (Author), Takao, S. (Author), Uckelmann, H.J (Author), Wen, Y. (Author), Wong, E.M (Author), Xu, H. (Author)
• Format: Article
• Language: English
• Published: Elsevier B.V. 2022
• Subjects: acute myeloid leukemia; animal; animal cell; animal experiment; animal model; animal tissue; Animals; antineoplastic agent; Article; C57BL mouse; cancer survival; CD11b antigen; Cell Line, Tumor; chromatin; controlled study; down regulation; fusion protein; gene cluster; gene expression; gene expression profiling; gene expression regulation; Gene Expression Regulation, Leukemic; gene rearrangement; Gene Rearrangement; genetics; histone lysine methyltransferase; Histone-Lysine N-Methyltransferase; IC50; in vitro study; in vivo study; Kmt2a protein, mouse; leukemia cell line; Leukemia, Myeloid, Acute; Men1 protein, mouse; metabolism; methionine; Mice; Mice, Inbred C57BL; mixed lineage leukemia protein; mouse; murine leukemia; Myeloid-Lymphoid Leukemia Protein; nonhuman; nuclear pore complex protein 98; Nuclear Pore Complex Proteins; nucleoporin; nucleoporin 98; nup98 gene; oncogene; Oncogene Proteins, Fusion; oncoprotein; phenotype; protein analysis; Protein Interaction Maps; protein protein interaction; Proto-Oncogene Proteins; retinoblastoma binding protein 2; transcription factor HoxA9; tumor cell line; tumor xenograft; unclassified drug; upregulation; vtp 50469
• Online Access: View Fulltext in Publisher

 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 American Society of Hematology