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Eradicating acute myeloid leukemia in a Mll(PTD/wt):Flt3(ITD/wt) murine model: a path to novel therapeutic approaches
Kelsie M Bernot1, John S Nemer, Ramasamy Santhanam
1The Ohio State University Comprehensive Cancer Center and The James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH;
Abstract:
The coexpression of the MLL partial tandem duplication (PTD) and the FLT3 internal tandem duplication (ITD) mutations associate with a poor outcome in cytogenetically normal acute myeloid leukemia (AML). In mice, a double knock-in (dKI) of Mll(PTD/wt) and Flt3(ITD/wt) mutations induces spontaneous AML with an increase in DNA methyltransferases (Dnmt1, 3a, and 3b) and global DNA methylation index, thereby recapitulating its human AML counterpart. We determined that a regulator of Dnmts, miR-29b, is downregulated in bone marrow of dKI AML mice. Bortezomib exerted a dose-dependent increase in miR-29b expression in AML blasts ex vivo, followed by decreased Dnmts, reduced proliferation, and increased apoptosis. In vivo, bortezomib was not active against dKI AML, yet liposomal-encapsulated bortezomib, as a single agent, reversed downregulation of miR-29b in vivo and induced a long-term (90-day) disease-free remission in 80% of dKI AML mice that exhibited high leukemic burden at the start of therapy, yet showed no signs of relapse at autopsy. Taken together, these data support that liposomal bortezomib, as a single agent, eradicates Mll(PTD/wt):Flt3(ITD/wt) AML in mouse and may represent a powerful and potentially curative approach to high-risk human disease.
Insights
Liposomal bortezomib eradicates MLL-PTD and FLT3-ITD mutated acute myeloid leukemia (AML) in mice. This therapy, targeting miR-29b and DNA methyltransferases, offers a potential cure for high-risk AML.
Area of Science:
- Hematology
- Molecular Biology
- Oncology
Background:
- Coexpression of MLL-PTD and FLT3-ITD mutations predicts poor outcomes in acute myeloid leukemia (AML).
- A mouse model (dKI) with Mll(PTD/wt) and Flt3(ITD/wt) mutations spontaneously develops AML, mirroring human disease with increased DNA methyltransferases (DNMTs) and global DNA methylation.
- MicroRNA-29b (miR-29b), a DNMT regulator, is downregulated in this dKI AML model.
Purpose of the Study:
- To investigate the therapeutic potential of bortezomib, alone and encapsulated in liposomes, against MLL-PTD and FLT3-ITD mutated AML.
- To explore the mechanism involving miR-29b and DNMTs in response to bortezomib treatment.
Main Methods:
- Ex vivo and in vivo studies using a genetically engineered mouse model (dKI) of AML.
- Treatment with free bortezomib and liposomal-encapsulated bortezomib.
- Assessment of miR-29b expression, DNMT levels, cell proliferation, and apoptosis.
- Evaluation of long-term disease-free remission and relapse in treated mice.
Main Results:
- Ex vivo, bortezomib increased miR-29b, decreased DNMTs, reduced proliferation, and induced apoptosis in AML blasts.
- In vivo, free bortezomib was ineffective against dKI AML.
- Liposomal bortezomib as a single agent reversed miR-29b downregulation, induced long-term (90-day) disease-free remission in 80% of mice with high leukemic burden, and prevented relapse.
Conclusions:
- Liposomal bortezomib demonstrates potent single-agent activity against MLL-PTD:FLT3-ITD AML in mice.
- This formulation effectively targets the miR-29b/DNMT axis, offering a potentially curative strategy for high-risk AML.
