Abstract
Acute lymphoblastic leukemia (ALL) is the most common pediatric, and ninth most common adult, cancer. ALL can develop in either B or T lymphocytes, but B-lineage ALL (B-ALL) exceeds T-ALL clinically. As for other cancers, animal models allow study of the molecular mechanisms driving ALL. Several zebrafish (Danio rerio) T-ALL models have been reported, but until recently, robust D. rerio B-ALL models were not described. Then, D. rerio B-ALL was discovered in two related zebrafish transgenic lines; both were already known to develop T-ALL. Here, we report new B-ALL findings in one of these models, fish expressing transgenic human MYC (hMYC). We describe B-ALL incidence in a large cohort of hMYC fish, and show B-ALL in two new lines where T-ALL does not interfere with B-ALL detection. We also demonstrate B-ALL responses to steroid and radiation treatments, which effect ALL remissions, but are usually followed by prompt relapses. Finally, we report gene expression in zebrafish B lymphocytes and B-ALL, in both bulk samples and single B- and T-ALL cells. Using these gene expression profiles, we compare differences between the two new D. rerio B-ALL models, which are both driven by transgenic mammalian MYC oncoproteins. Collectively, these new data expand the utility of this new vertebrate B-ALL model.
Highlights
Acute lymphoblastic leukemia (ALL) and the related malignancy lymphoblastic lymphoma (LBL) dominate pediatric oncology, together representing over one third of all childhood cancer [1,2,3]
We previously analyzed more than 50 unique human MYC (hMYC) B-lineage ALL (B-ALL) [58, 60], demonstrating these fish are a robust model, but latency and incidence rates for B- and T-ALL have not been reported in the hMYC line
Recent discoveries of B-ALL in D. rerio lines previously-known to develop T-ALL were unexpected, but in retrospect, are not surprising. Both B and T lymphoblasts express rag2, so it is predictable that the transgenic promoters used in hMYC and mMyc fish would be active in both lymphocyte lineages
Summary
Acute lymphoblastic leukemia (ALL) and the related malignancy lymphoblastic lymphoma (LBL) dominate pediatric oncology, together representing over one third of all childhood cancer [1,2,3]. These diseases afflict even more adults in absolute terms, and are more often fatal in them [4, 5]. ALL and LBL can develop in lymphoblasts of either the B or T cell lineage; B-ALL exceeds T-ALL, but T-LBL is more prevalent than B-LBL Despite treatments for these diseases improving considerably over the past several decades, relapsed ALL is the 4th most-frequent pediatric cancer diagnosis and second most lethal childhood malignancy, accounting for ~25% of all deaths [6,7,8]. Zebrafish (Danio rerio) offer flexible genetic tools, powerful live imaging, high fecundity, rapid development, shared oncogenic pathways, affordability, and other favorable traits that have allowed them to quickly gain traction as a cancer model [11,12,13,14,15,16,17]
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