Targeting of MCL-1 kills MYC-driven mouse and human lymphomas even when they bear mutations in p53

GL Kelly, S Grabow, SP Glaser… - Genes & …, 2014 - genesdev.cshlp.org
GL Kelly, S Grabow, SP Glaser, L Fitzsimmons, BJ Aubrey, T Okamoto, LJ Valente, M Robati…
Genes & development, 2014genesdev.cshlp.org
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 …
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.
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