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

作者：Emily Heikamp, Jill A. Henrich, Florian Perner, Eric M. C. Wong, Charlie Hatton, Yanhe Wen, Sonali P. Barwe, Anilkumar Gopalakrishnapillai, Haiming Xu, Hannah J. Uckelmann, Sumiko Takao, Yaniv Kazansky, Yana Pikman, Gerard M. McGeehan, Edward Anders Kolb, Alex Kentsis, Scott A. Armstrong · 发表于：Blood · 年份：2021 · DOI：10.1182/blood.2021012806 · 被引用次数：153 · 研究领域：Acute Myeloid Leukemia Research、Protein Degradation and Inhibitors、Multiple Myeloma Research and Treatments

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 tis...