Testing Novel Ash1L Inhibitors in Leukemia

Background:
ASH1L is an epigenetic regulator that is thought to act in gene expression through its activity as a histone H3, lysine 36 methylase.  It has also been shown to act synergistically with the MLL1 proto-oncoprotein to regulate important pro-leukemogenic targets.

Project Goal:

This proposal will capitalize on the work of MD/PhD candidate David Rogawski in Dr. Jolanta Grembecka's lab at University of Michigan. His PhD work has focused on the development of novel Ash1L methyltransferase inhibitors and their biochemical and biophysical characterization. His program requires a period of study in a distinct laboratory, thus this proposal will capitalize on his drug development progress and the mouse model expertise in the host lab (Dr. Ernst). The project will focus on rapid testing of the new compounds using a series of murine leukemia models with defined genetic manipulations, including T-ALL with Notch1 intracellular domain overexpression, MLL-fusion protein initiated AML, and B-ALL with BCR-ABL overexpression. Through these studies we hope to

1) provide a complimentary research environment for the trainee such that he is versed in the establishment and use of animal models for drug testing,

2) identify a subset of leukemia which would benefit from Ash1L inhibition and

3) discover pathways affected by Ash1L that are relevant to leukemogenesis.