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Tumor Engraftment in a Xenograft Mouse Model of Human Mantle Cell Lymphoma
Published on: March 30, 2018
Targeting of MCL-1 kills MYC-driven mouse and human lymphomas even when they bear mutations in p53
Gemma L Kelly1, Stephanie Grabow, Stefan P Glaser
1The Walter and Eliza Hall Institute, Parkville, Victoria 3052, Australia;
Abstract:
The transcriptional regulator c-MYC is abnormally overexpressed in many human cancers. Evasion from apoptosis is critical for cancer development, particularly c-MYC-driven cancers. We explored which anti-apoptotic BCL-2 family member (expressed under endogenous regulation) is essential to sustain c-MYC-driven lymphoma growth to reveal which should be targeted for cancer therapy. Remarkably, inducible Cre-mediated deletion of even a single Mcl-1 allele substantially impaired the growth of c-MYC-driven mouse lymphomas. Mutations in p53 could diminish but not obviate the dependency of c-MYC-driven mouse lymphomas on MCL-1. Importantly, targeting of MCL-1 killed c-MYC-driven human Burkitt lymphoma cells, even those bearing mutations in p53. Given that loss of one allele of Mcl-1 is well tolerated in healthy tissues, our results suggest that therapeutic targeting of MCL-1 would be an attractive therapeutic strategy for MYC-driven cancers.
Insights
Targeting MCL-1, an anti-apoptotic protein, is crucial for treating MYC-driven cancers. Inhibiting MCL-1 effectively halts lymphoma growth and kills cancer cells, even with p53 mutations.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- c-MYC overexpression drives numerous human cancers, necessitating strategies to overcome apoptosis evasion.
- Understanding the role of anti-apoptotic BCL-2 family members is key to targeting c-MYC-driven cancers.
Purpose of the Study:
- To identify the essential anti-apoptotic BCL-2 family member sustaining c-MYC-driven lymphoma growth.
- To evaluate MCL-1 as a therapeutic target for MYC-driven cancers.
Main Methods:
- Utilized inducible Cre-mediated deletion in mouse models to assess Mcl-1 allele dependency.
- Investigated the impact of MCL-1 targeting on c-MYC-driven human Burkitt lymphoma cells, including those with p53 mutations.
Main Results:
- Deletion of a single Mcl-1 allele significantly impaired c-MYC-driven mouse lymphoma growth.
- MCL-1 dependency persisted even in lymphomas with p53 mutations.
- Targeting MCL-1 demonstrated efficacy against c-MYC-driven human Burkitt lymphoma cells, irrespective of p53 status.
Conclusions:
- MCL-1 is essential for the survival of c-MYC-driven lymphomas.
- Therapeutic targeting of MCL-1 presents a promising strategy for treating MYC-driven cancers, with potential for reduced toxicity in healthy tissues.
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