Bcl2 Accelerates Onset but Not Progression of MYC-Induced T-Cell Leukemia in Transgenic Zebrafish.

MYC is a potent proto-oncogene aberrantly expressed in over 70% of human cancers. Our laboratory has previously generated transgenic zebrafish models that overexpress the mouse c-Myc gene fused to green fluorescent protein and develop T-cell Acute Lymphoblastic Leukemia (T-ALL) that recapitulates the human disease both molecularly and pathologically. These previous models have been limited by the inability to breed non-conditional transgenic animals due to disease onset prior to sexual maturity and by the low disease penetrance when conditional transgenic embryos are injected with Cre RNA. In order to improve these zebrafish T-ALL models to make modifier screens feasible, we have generated a new stable Cre transgenic line in which Cre expression is regulated by a heat-shock promoter, and have established a conditional compound transgenic zebrafish model by breeding this pzhsp70-Cre line with conditional rag2-lox-dsRED2-lox-EGFP-mMyc transgenic fish. Upon heat-shock treatment, 81% of compound transgenic fish developed tumor by 197 days of life (mean latency: 120 ± 43 days). Using this model, we showed that overexpression of zebrafish Bcl-2 strikingly accelerates the disease onset, suggesting that suppression of apoptosis is critical for zebrafish Myc-induced tumorigenesis and serving as a proof of principle for subsequent modifier screens. Paradoxically, overexpression of Bcl-2 delays the progression of T-ALL, implying functional roles for Bcl-2 in addition to the inhibition of apoptosis.