Molecularly distinct models of zebrafish Myc-induced B cell leukemia

Zebrafish models of T cell acute lymphoblastic leukemia (T-ALL) have been studied for over a decade, but curiously, robust zebrafish B cell ALL (B-ALL) models had not been described. Recently, our laboratories reported two seemingly closely-related models of zebrafish B-ALL. In these genetic lines, the primary difference is expression of either murine or human transgenic c-MYC, each controlled by the zebrafish rag2 promoter. Here, we compare ALL gene expression in both models. Surprisingly, we find that B-ALL arise in different B cell lineages, with ighm+ vs. ighz+ B-ALL driven by murine Myc vs. human MYC, respectively. Moreover, these B-ALL types exhibit signatures of distinct molecular pathways, further unexpected dissimilarity. Thus, despite sharing analogous genetic makeup, the ALL types in each model are markedly different, proving subtle genetic changes can profoundly impact model organism phenotypes. Investigating the mechanistic differences between mouse and human c-MYC in these contexts may reveal key functional aspects governing MYC-driven oncogenesis in human malignancies.