MYC, a potent proto-oncogene, is aberrantly and widely expressed in human cancers, including the leukemias and lymphomas. The long-term goal of this proposal is to discover the molecules that are necessary to sustain MYC-driven tumors, T-cell acute lymphoblastic leukemia (T-ALL) in particular, and hence might serve as useful targets for the development of novel molecular therapeutics. Using a transgenic zebrafish model in which murine Myc is expressed in thymocytes and reliably generates T-cell leukemia, I conducted a dominant genetic modifier screen to identify and study """"""""oncorequisite"""""""" genes whose mutation delays the onset of leukemia. My screen pinpointed a specific gene encoding dihydrolipoamide Ssuccinyltransferase (DLST) whose heterozygous inactivation significantly delays the onset of lymphoma/leukemia in zebrafish expressing the Myc oncogene. Zebrafish Dlst was upregulated in tumor cells with Myc overexpression, compared to normal cells without Myc overexpression. In addition, this upreguiation of DLST was associated with an increased fraction of cells in 8 phase and genomic instability. Tumor cells with 50% reduction of Dlst tended to be in G1 phase and morphologically more differentiated with a stable genome. I have clarified the importance of the human ortholog of DLST in T-ALL and found that DLST is aberrantly upregulated in the majority of T-ALL cell lines. Small molecule treatment of both human T-ALL cell lines and zebrafish with lymphoma is effective, leading to less viable cells in vitro and delayed tumor progression in vivo. Hence, I consider the human ortholog of this Kreb's cycle transferase as a promising therapeutic target for treating human T-ALL. During ROO phase of the grant, I will further characterize the importance of DLST in human neuroblastoma pathophysiology (new Aim 1) and identify its synergic genes and pathways (new Aim 2). Meanwhile, I will identify additional """"""""oncorequisite"""""""" genes in MYC-mediated transformation through zebrafish genetic screens (Aim 3). The rationale and feasibility of this approach are well-illustrated by my data acquired during the K99 phase.
Many human cancers rely on the MYC oncogene for their support. By identifying mutant genes that delay the onset of Myc-driven T-cell leukemia in fish, this project seeks to discover useful therapeutic targets in human MYC-related cancers.
|Huiting, L N; Samaha, Y; Zhang, G L et al. (2018) UFD1 contributes to MYC-mediated leukemia aggressiveness through suppression of the proapoptotic unfolded protein response. Leukemia :|
|Lian, Haiwei; Li, Dun; Zhou, Yun et al. (2017) CK2 inhibitor CX-4945 destabilizes NOTCH1 and synergizes with JQ1 against human T-acute lymphoblastic leukemic cells. Haematologica 102:e17-e21|
|Anderson, N M; Li, D; Peng, H L et al. (2016) The TCA cycle transferase DLST is important for MYC-mediated leukemogenesis. Leukemia 30:1365-74|
|Harrison, Nicholas R; Laroche, Fabrice J F; Gutierrez, Alejandro et al. (2016) Zebrafish Models of Human Leukemia: Technological Advances and Mechanistic Insights. Adv Exp Med Biol 916:335-69|
|Harrold, Itrat; Carbonneau, Seth; Moore, Bethany M et al. (2016) Efficient transgenesis mediated by pigmentation rescue in zebrafish. Biotechniques 60:13-20|
|Huiting, L N; Laroche, Fjf; Feng, H (2015) The Zebrafish as a Tool to Cancer Drug Discovery. Austin J Pharmacol Ther 3:1069|
|Shivanna, Sowmya; Harrold, Itrat; Shashar, Moshe et al. (2015) The c-Cbl ubiquitin ligase regulates nuclear ?-catenin and angiogenesis by its tyrosine phosphorylation mediated through the Wnt signaling pathway. J Biol Chem 290:12537-46|
|Anderson, N M; Harrold, I; Mansour, M R et al. (2014) BCL2-specific inhibitor ABT-199 synergizes strongly with cytarabine against the early immature LOUCY cell line but not more-differentiated T-ALL cell lines. Leukemia 28:1145-8|
|Zhu, Shizhen; Lee, Jeong-Soo; Guo, Feng et al. (2012) Activated ALK collaborates with MYCN in neuroblastoma pathogenesis. Cancer Cell 21:362-73|
|Blackburn, J S; Liu, S; Raiser, D M et al. (2012) Notch signaling expands a pre-malignant pool of T-cell acute lymphoblastic leukemia clones without affecting leukemia-propagating cell frequency. Leukemia 26:2069-78|
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