The menin-MLL1 interaction is a molecular dependency in NUP98-rearranged AML Journal Article
| Authors: | Heikamp, E. B.; Henrich, J. A.; Perner, F.; Wong, E. M.; Hatton, C.; Wen, Y.; Barwe, S. P.; Gopalakrishnapillai, A.; Xu, H.; Uckelmann, H. J.; Takao, S.; Kazansky, Y.; Pikman, Y.; McGeehan, G. M.; Kolb, E. A.; Kentsis, A.; Armstrong, S. A. |
| Article Title: | The menin-MLL1 interaction is a molecular dependency in NUP98-rearranged AML |
| Abstract: | 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 meninMLL1 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. |
| Keywords: | leukemia; proteins; expression; stem-cells; activation; models |
| Journal Title: | Blood |
| Volume: | 139 |
| Issue: | 6 |
| ISSN: | 0006-4971 |
| Publisher: | American Society of Hematology |
| Date Published: | 2022-02-10 |
| Start Page: | 894 |
| End Page: | 906 |
| Language: | English |
| ACCESSION: | WOS:000773438000011 |
| DOI: | 10.1182/blood.2021012806 |
| PROVIDER: | wos |
| PMCID: | PMC8832476 |
| PUBMED: | 34582559 |
| Notes: | Article -- Source: Wos |
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