Abstract PR-010: Asc1lb progenitor-specific RB conditional inactivation in zebrafish models rare CNS primitive neuroectodermal tumors

Abstract We generated a new zebrafish model of human brain cancer by Cre/lox regulated conditional inactivation of the tumor suppressor RB in embryonic neural progenitors. An ascl1b progenitor Cre driver was used to inactivate RB by Cre recombination of an intronic floxed mRFP gene trap cassette, leading to mRFP expression and lineage labeling of RB mutated cells. Beginning at 6 months of age adult fish developed poorly differentiated brain tumors, similar to our previous zebrafish brain tumor model generated by CRISPR targeting of RB in embryos. Tumor transcriptome analysis revealed a proneural transcription factor molecular signature of the olig2+/sox10+ human CNS primitive neuroectodermal tumor subtype. Overexpression of chromatin remodelers suggest epigenetic mechanisms may contribute to tumorigenesis. Our model will allow sorting of RB mutant cells from the earliest stage of mutagenesis in the embryo to induction of cellular transformation in juveniles. With this approach we can profile the epigenetic time course of cellular transformation and reveal new insight into the molecular mechanisms driving PNET oncogenesis. Our approach to model cancer in fish with Cre/lox conditional inactivation can be applied to other cell lineages and brain tumor types. Citation Format: Maura McGrail, Fang Liu, Sekhar Kambakam, Zhitao Ming. Asc1lb progenitor-specific RB conditional inactivation in zebrafish models rare CNS primitive neuroectodermal tumors abstract. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84 (5 Suppl₁): Abstract nr PR-010.