A joint project of the Graduate School, Peabody College, and the Jean & Alexander Heard Library

Title page for ETD etd-05132019-125732


Type of Document Dissertation
Author Aho, Erin Renee
URN etd-05132019-125732
Title Pharmacological WDR5 WIN site inhibition as an anti-leukemia target
Degree PhD
Department Cell and Developmental Biology
Advisory Committee
Advisor Name Title
Ethan Lee, M.D, Ph.D. Committee Chair
Jason MacGurn, Ph.D. Committee Member
Maureen Gannon, Ph.D Committee Member
Scott Hiebert, Ph.D. Committee Member
William P. Tansey, Ph.D. Committee Member
Keywords
  • WDR5
  • small molecule inhibitor
  • gene expression
  • chromatin
  • cancer therapy
  • MLL
Date of Defense 2019-04-19
Availability restricted
Abstract
The epigenetic regulator WDR5 is a promising therapeutic target in leukemias expressing oncogenic translocations of the MLL1 histone methyltransferase gene. Despite the validation of the WIN site of WDR5 as a pharmacological anti-cancer target, the molecular mechanism through which inhibition of the WIN site selectively kills certain leukemia cell types remains unclear. The lack of clarity stems from a insufficiency in understanding of the genes regulated by WDR5 and the primary effects of WDR5 WIN site inhibitors. In order to better decipher the biological consequences of inhibiting WDR5 in leukemia cells, the Fesik Laboratory discovered novel and highly potent small molecule inhibitors of the WDR5 WIN site that could be utilized as tool compounds in biological experiments. By utilizing these novel tool compounds, it was found that WDR5 regulates the expression of a select set of ribosome protein genes that is conserved across disparate cell types. WDR5 is displaced from chromatin at these genes upon small molecule inhibitor treatment and ultimately, displacement of WDR5 from chromatin causes reduced expression of WDR5-bound genes, impeded protein translation, induction of nucleolar stress, and p53-dependent apoptosis in leukemia cells.
Files
  Filename       Size       Approximate Download Time (Hours:Minutes:Seconds) 
 
 28.8 Modem   56K Modem   ISDN (64 Kb)   ISDN (128 Kb)   Higher-speed Access 
[campus] Aho.pdf 162.95 Mb 12:34:22 06:27:58 05:39:28 02:49:44 00:14:29
[campus] indicates that a file or directory is accessible from the campus network only.

Browse All Available ETDs by ( Author | Department )

If you have more questions or technical problems, please Contact LITS.