T cell acute lymphoblastic leukemia (T-ALL) is a heterogeneous blood malignancy occurring primarily in children, accounting for approximately 15% of acute leukemia cases. Despite a survival rate of up to 85% (pediatric T-ALL; &lt;50% for adult T-ALL), the prognosis for relapse cases is dismal due to chemoresistance and migration of T-ALL stem cells to the central nervous system. Although activating mutations in the transcriptional regulator NOTCH1 occur in over 50% of T-ALL cases, attempts to directly target NOTCH1 have been unsuccessful due to high levels of toxicity. Therefore, there is a strong need for new targeted therapies, including methods of targeting NOTCH1 pathologic effects with reduced toxicity. Our proteomics screens for binding partners of the T-ALL proto-oncogene JMJD3 have identified a deubiquitinase, the ubiquitin-specific protease 7 (USP7) as a member of the NOTCH1 transcriptional complex important for oncogenic transcriptional control and thus as a promising candidate for T-ALL therapy. Recent genomic studies of T-ALL revealed mutations in USP7. USP7 is upregulated in T-ALL, and our previous studies have shown that JMJD3 is a binding partner of NOTCH1 and drives transcription of NOTCH1 targets in T-ALL. My preliminary data indicate that JMDJ3 interacts with USP7, and that USP7 regulates JMJD3 protein levels. Therefore, experiments in this proposal will test the hypothesis that USP7 is necessary for oncogene-dependent gene regulation in T-ALL and evaluate this deubiquitinase as a therapeutic target in this disease. Aim 1 will characterize the role of USP7 in an in vitro model of human T-ALL, using shRNA-mediated knockdown to investigate the mechanisms by which USP7 regulates oncogenic targets and leukemia growth. In Aim 2, mouse xenograft models of human cell lines and primary patient samples (diagnosis-relapsed disease) will be used to test USP7 inhibitors in vivo. Finally, experiments in Aim 3 will evaluate the role of other members of the USP family as potential therapeutic targets in T-ALL using a CRISPR/Cas9 genetic screen. Information gained from these studies will provide insight into the functions of USP7 in T-ALL to evaluate small molecule inhibitors of USP7 as a novel therapeutic strategy.
|Effective start/end date||7/1/17 → 7/4/17|
- American Society of Hematology (ASH 11/22/2016)
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