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Targeted combination therapies for leukemia with NUP98 translocations

Jolanta Grembecka

Jolanta Grembecka


Regents of the University of Michigan

Project Term: July 1, 2022 - June 30, 2025

Leukemia patients with chromosomal translocations of the Nucleoporin (NUP98) gene suffer from very poor prognosis. In this project we will identify new treatment for these patients by combining menin inhibitor with FDA approved drugs. We will evaluate effectiveness, mechanism of action and biomarkers of treatment response to these combinations in advanced pre-clinical models of NUP98 leukemia. We expect these studies will lead to future clinical trials in AML patients with NUP98 translocations.

Lay Abstract

Chromosomal translocations of the Nucleoporin 98 (NUP98) gene, which replace the C-terminal portion of NUP98 with one out of 30 fusion partners, are found in patients with various hematologic malignancies, including acute myeloid (AML) and lymphoid (ALL) leukemia. NUP98 translocations are most frequently found in pediatric AML patients, constituting ~6-10% of all childhood leukemia cases. It has been demonstrated that the presence of NUP98 translocations leads to a very poor clinical outcome, with only ~10% event-free survival 3 years after diagnosis, leading to less than 30% survival rate. Thus, there is a critical need for new effective therapies for leukemia patients with NUP98 translocations. The protein-protein interaction between MLL1 and menin was found to play a crucial role in leukemogenesis mediated by NUP98 fusion proteins by regulating the expression of HOXA and MEIS1 genes. Disruption of the menin-MLL1 interaction using small molecules in leukemia cells with NUP98 translocations leads to inhibition of cell proliferation, differentiation and downregulation of target genes critical to leukemogenesis. Furthermore, menin inhibitors reduce leukemia progression in vivo in mouse models of leukemia with NUP98 rearrangements. However, leukemia cells with NUP98 translocations frequently harbor other mutations, suggesting that multiple pathways contribute to leukemogenesis and supporting the need for drug combinations. In this project we will perform combinatorial studies of our advanced menin inhibitor with the FDA approved targeted drugs in the pre-clinical models of the NUP98-rearranged leukemia to identify the best combinations for future clinical studies. This represents a highly novel approach as the menin inhibitor-based combinations were not assessed in leukemia with NUP98 translocations. We will evaluate the effect and mechanism of action of these combinations and will identify the biomarkers of treatment response to these combinations using patient-derived xenograft (PDX) models of the NUP98-rearranged leukemia, which represent highly clinically relevant pre-clinical models. We anticipate that these studies will lead to future clinical trials of the most optimal combinations of menin inhibitors with other agents in NUP98 leukemia patients.

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