The menin-MLL1 interaction is a molecular dependency in NUP98-rearranged AML.
Emily B Heikamp, Jill A Henrich, Florian Perner, Eric M Wong, Charles Hatton, Yanhe Wen, Sonali P Barwe, Anilkumar Gopalakrishnapillai, Haiming Xu, Hannah J Uckelmann, Sumiko Takao, Yaniv Kazansky, Yana Pikman, Gerard M McGeehan, Edward A Kolb, Alex Kentsis, Scott A Armstrong
Blood 2022 Feb 10Translocations 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.
Citation
Emily B Heikamp, Jill A Henrich, Florian Perner, Eric M Wong, Charles Hatton, Yanhe Wen, Sonali P Barwe, Anilkumar Gopalakrishnapillai, Haiming Xu, Hannah J Uckelmann, Sumiko Takao, Yaniv Kazansky, Yana Pikman, Gerard M McGeehan, Edward A Kolb, Alex Kentsis, Scott A Armstrong. The menin-MLL1 interaction is a molecular dependency in NUP98-rearranged AML. Blood. 2022 Feb 10;139(6):894-906
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PMID: 34582559
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