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 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 plan to conduct a dominant genetic modifier screen to identify and study """"""""oncorequisite"""""""" genes whose mutation delays the onset of leukemia (Aims 1 and 2) and then to clarify the importance of the human orthologs of these genes in T-ALL and neuroblastoma pathophysiology, including the consequences of their inhibition (Aim 3). The rationale and feasibility of this approach are well-illustrated by my recent preliminary data pinpointing a specific gene, encoding dihydrolipoamide S-succinyltransferase (DLST), whose heterozygous inactivation significantly delayed the onset of lymphoma/leukemia in zebrafish expressing the MYC oncogene. Small molecule inhibition of the cc- ketoglutatate dehydrogenase complex (DLST is an pound2 component) by a-keto-p-methyl-n valeric acid (KMV) promoted the rapid regression of zebrafish lymphoma/leukemia, and significantly decreased the viability of humanT-ALL cell lines. Hence, I consider the human ortholog of this Kreb's cycle transferase a promising candidate """"""""oncorequisite"""""""" protein for further characterization and testing with available inhibitors in human malignancies. The use of unbiased forward genetic strategies in the zebrafish will circumvent the need for a priori knowledge of contributing genes and pathways in MYC-induced cancer -an innovation that sets this application apart from others in the field - so that any suppressor mutant I identify will automatically qualify as a potentially useful target for inhibition with small molecules or monoclonal antibodies.
Many human cancers rely on expression of 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 molecules that could serve as useful targets for therapeutic intervention in human cancers.
| 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 |
| Zhu, Shizhen; Lee, Jeong-Soo; Guo, Feng et al. (2012) Activated ALK collaborates with MYCN in neuroblastoma pathogenesis. Cancer Cell 21:362-73 |
| Gutierrez, Alejandro; Grebliunaite, Ruta; Feng, Hui et al. (2011) Pten mediates Myc oncogene dependence in a conditional zebrafish model of T cell acute lymphoblastic leukemia. J Exp Med 208:1595-603 |
| Feng, Hui; Stachura, David L; White, Richard M et al. (2010) T-lymphoblastic lymphoma cells express high levels of BCL2, S1P1, and ICAM1, leading to a blockade of tumor cell intravasation. Cancer Cell 18:353-66 |
