1. Mice harboring tumors with translocations of the mixed lineage leukemia (MLL) gene showed decreased tumor size and increased survival times when treated with a pharmacologic inhibitor of a menin-MLL interaction.
2. Menin-MLL inhibitors selectively killed colony forming cells from human leukemia patients with MLL translocations.Â
Evidence Rating Level: 1 (Excellent)
Study Rundown: Leukemia originating from MLL translocations accounts for the majority of acute leukemia cases in infants and is particularly resistant to treatment. MLL translocation leads to production of MLL fusion proteins, which in turn causes the acute leukemia. The leukemogenic activity of these MLL fusion proteins has been shown to depend on MLL binding of the protein, menin. Previous work showed genetic ablation of this binding event blocks development of acute leukemia. This current study generated pharmacological inhibitors of the MLL-menin interaction and established their efficacy inhibiting leukemia progression both in vitro and in vivo.
The authors used structure-based design to build upon previously characterized MLL-menin binding inhibitors to create two similar molecules, MI-463 and MI-503. Treatment with either of these nontoxic, orally-bioavailable compounds decreased growth of cells transformed with MLL oncogenes, while not affecting cells transformed with other (non-MLL) oncogenes. In multiple mouse models of MLL leukemia, treatment with either inhibitor resulted in decreased tumor volume and increased survival times. No drug resistance or toxicity-related symptoms were developed in long-term (20+ day) treatment studies. In a first step towards human translation, the researchers demonstrated that in vitro treatment with either of the two compounds selectively killed cells taken from human MLL leukemia patients. No growth effect was seen for treated cells from non-MLL acute myeloid leukemia (AML) patients.
This work represents a promising first step towards treating MLL leukemia using pharmacological methods. Although the report includes some evaluations of the compounds’ safety in mice, future work will require more comprehensive safety assessments in larger animals and for longer treatment times.
Click to read the study in Cancer Cell
Relevant Reading: Interaction of MLL amino terminal sequences with menin is required for transformation
In-Depth [in vitro and animal studies]: Multiple in vitro tests and mouse leukemia models were used in this study to examine the efficacy and safety of MI-463 and MI-503, novel MLL-menin binding inhibitors. These pharmacologic inhibitors were identified based on their binding affinity for menin, and selected for their strong pharmacokinetic profile and metabolic stability in mice. Initial in vitro experiments to assess the activity and selectivity of the drugs showed that murine bone marrow cells transformed with an MLL oncogene exhibited decreased cell viability when treated with either compound, with half maximal inhibitions of cell proliferation in the sub-micromolar range. Gene expression studies revealed treatment with the inhibitors caused a shift in gene expression away from the profile associated with MLL-rearranged leukemia cells.
In a first set of in vivo studies, researchers implanted human MLL leukemia cells in mice, allowing tumor formation, and subsequently treated with an inhibitor. Mice treated once daily with 60 mg/kg of MI-503 exhibited an approximately 8-fold decrease in tumor volume at 35 days as compared to control mice, while mice treated with 35 mg/kg of MI-463 showed an approximately 3-fold relative decrease at 28 days (n=6 per group). A separate, more aggressive mouse MLL leukemia model was employed to evaluate survival benefits of the inhibitors. In this model mice were transplanted with bone marrow cells from mice harboring MLL-derived leukemia. Treating these mice with MI-463 or MI-503 5 days after transplantation increased median survival time by 70% and 45%, respectively as compared to controls (n=9 per group). Bone marrow cellularity, myeloid counts, and blood cell progenitor counts did not change in healthy mice treated with either compound.
In a final set of experiments, the authors treated primary cells from human leukemia patients with MI-503 or MI-463. Low micro-molar concentrations of either drug reduced resulting cell colony numbers by over 50% in 3 MLL patient samples, while having little or no effect on the viability of cells from AML patients.
Image: PD
©2015 2 Minute Medicine, Inc. All rights reserved. No works may be reproduced without expressed written consent from 2 Minute Medicine, Inc. Inquire about licensing here. No article should be construed as medical advice and is not intended as such by the authors or by 2 Minute Medicine, Inc.