期刊
BLOOD
卷 139, 期 6, 页码 894-906出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2021012806
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类别
资金
- National Institutes of Health (NIH) [CA176745, CA066996, R01 CA204396, P30 CA008748]
- NIH [5T32HL007574-36]
- Leukemia and Lymphoma Society
- Leukemia Research Foundation of Delaware
- Lisa Dean Moseley Foundation Award
- NCI Cancer Center Support Grant [NIH 5 P30 CA06516]
- [U54 CA243124]
Translocations involving the NUP98 gene are associated with poor prognosis in acute myeloid leukemia (AML). In this study, the efficacy of therapeutic blockade of the menin-MLL1 interaction in NUP98-fusion leukemia models was investigated. The results showed that menin-MLL1 inhibition can effectively suppress the growth of NUP98-fusion-driven leukemia cells and promote their differentiation. Furthermore, in vivo experiments using patient-derived xenograft (PDX) models demonstrated that menin-MLL1 inhibition significantly prolongs the survival of mice with NUP98-fusion-driven AML. These findings suggest that menin-MLL1 inhibition could be a promising targeted therapy for patients with NUP98-rearranged leukemias.
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.
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