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dc.contributor.authorHurst, Slater Nelsonen_US
dc.date.accessioned2016-03-02T14:34:52Z
dc.date.available2016-03-02T14:34:52Z
dc.date.issued2014
dc.identifier.urihttps://hdl.handle.net/2144/14675
dc.description.abstractLenalidomide is an FDA approved immunomodulatory drug (IMID) that is highly efficacious in myelodysplastic syndrome with del(5q), multiple myeloma, as well as other B cell malignancies.1 Furthermore, lenalidomide promotes a multitude of physiological effects, which include increased IL-2 cytokine production, inhibition of TNF alpha by monocytes and teratogenicity.3 The molecular mechanism of action responsible for these pleiotropic effects has eluded researchers for nearly 50 years.5 Recently, we identified lenalidomide to bind to and activate CRBN E3 ligase to specifically ubiquitinate two lymphoid transcription factors named IKZF1 (Ikaros) and IKZF3 (Aiolos), resulting in their proteasomal degradation. Targeted depletion of IKZF1 and IKZF3 inhibits growth of myeloma cells and IL-2 release in T cells, explaining two properties of the drug.8 Another identified lenalidomide regulated substrate of CRBN is casein kinase 1α (CSNK1A1), potentially connecting lenalidomide's activity in MDS with del(5q).8 While lenalidomide promotes these effects in human cells, the drug does not show activity in murine cells.7 Using this distinction as a vehicle to study the lenalidomide-CRBN interaction, we tested human-mouse chimera CRBN proteins in order to characterize the region of CRBN that is critical for lenalidomide activity. We were able to identify a group of non-conserved amino acids on CRBN necessary for lenalidomide activity. A single amino acid substitution is responsible for the different effects observed in humans and mice. Our findings will not only allow for the use of murine models in the study of lenalidomide and its analogs, but also help provide further insight into the drug's molecular mechanism.en_US
dc.language.isoen_US
dc.subjectMedicineen_US
dc.titleCharacterizing the mechanism of action of lenalidomide in a mouse modelen_US
dc.typeThesis/Dissertationen_US
dc.date.updated2016-01-22T18:57:26Z
etd.degree.nameMaster of Scienceen_US
etd.degree.levelmastersen_US
etd.degree.disciplineMedical Sciencesen_US
etd.degree.grantorBoston Universityen_US


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