A Translational Approach to Identify Drugs with Specific Activity Against EZH2 Mutant High Risk T-ALLs and ETP ALLs that Overexpress the JDP2 bZIP Transcription Factor
Outcomes for children with acute lymphoblastic leukemia (ALL), the most common childhood malignancy, have improved dramatically over the last 20 years. However, a subset of patients with ETP-ALL have an extremely poor prognosis. Very recently, it was discovered that many of these high-risk tumors and other high-risk T-ALLs have acquired disruptions of the EZH2 gene. We have shown that the JDP2 gene is upregulated in both ETP-ALL and other high-risk T-ALLs and is required for the growth and survival of these leukemia cells. Thus, JDP2 is a major mediator of aberrant ALL cell survival, drug resistance and the poor prognosis in high-risk ETP- and T-ALL.
I have established a transgenic zebrafish model that overexpresses JDP2 in thymocytes and develops T-ALL with high penetrance. In this project, I will use these zebrafish to identify small-molecule drugs that will kill the lymphoblasts that express cancer-causing levels of JDP2, but are not toxic to normal cells. I will experimentally prove that these drugs have similar specific effects in high-risk human T-ALL using primary patient derived xenograft models, and then these drugs will represent ideal candidates that will be pursued as potential new anticancer drugs for both high-risk ETP-ALL and T-ALL. I will analyze the anti-leukemic activity of known drugs, including roughly 860 FDA-approved drugs. This strategy will accelerate the entrance of such compounds into clinical trials because the analysis of toxicity, side effects, and other characteristics of the drugs have been already investigated in human patients.