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Oncotarget Zebrafish B cell acute lymphoblastic leukemia: new findings in an old model


FOR IMMEDIATE RELEASE
2020-04-15

Oncotarget Volume 11 Issue 15 reported that several zebrafish T-ALL models have been reported, but until recently, robust D. rerio B-ALL models were not described.

Here, the Research Team has shown new B-ALL findings in one of these models, fish expressing transgenic human MYC.

They 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.

Dr. J. Kimble Frazer from the Department of Cell Biology and the Department of Pediatrics, Section of Pediatric Hematology-Oncology, as well as the Department of Microbiology & Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA said, "Acute lymphoblastic leukemia (ALL) and the related malignancy lymphoblastic lymphoma (LBL) dominate pediatric oncology, together representing over one third of all childhood cancer."

"Acute lymphoblastic leukemia (ALL) and the related malignancy lymphoblastic lymphoma (LBL) dominate pediatric oncology, together representing over one third of all childhood cancer"

- Dr. J. Kimble Frazer, Department of Cell Biology and the Department of Pediatrics, Section of Pediatric Hematology-Oncology, as well as the Department of Microbiology & Immunology, University of Oklahoma Health Sciences Center

For T-ALL in particular, zebrafish models have been highly informative, advancing our understanding of T-ALL genetics, pro- and anti-oncogenic interactions between different genes and pathways, tumor heterogeneity, leukemia stem cells, and in screens for new therapeutics.

However, despite the fact that zebrafish T-ALL models had proven to be fertile grounds for study, B-ALL modeling in D. rerio had not been fruitful, with only one low penetrance and long latency line reported.

This was curious because zebrafish recombination activating gene 2 promoters active in both immature T and B cells was used to regulate most of these transgenic oncoproteins in the various T-ALL lines, yet D. rerio B-ALL had not been reported in them.

Figure 1: B-ALL in hMYC zebrafish. (A) Curves displaying B- and T-ALL incidence by 184 dpf, as determined by fluorescence microscopy. (B) Fluorescence microscopy images of fish with B-ALL (left), both B- and T-ALL (center), or T-ALL (right). Flow cytometry plots of ALL samples from these fish are shown beneath them. (C) B-ALL appearance in fish with rag2:hMYC and different transgenic markers: cd79a:GFP (left), cd79b:GFP (center), or lck:GFP (right). WT cd79a:GFP or cd79b:GFP fish without B-ALL are shown beneath for comparison. Images are representative of > 50 animals examined for each genotype.

In 2018, the zebrafish ALL field advanced suddenly with reports of B-ALL in two closely-related transgenic lines where T-ALL was already known to occur.

Here, the authors present new results in the hMYC model, including B- and T-ALL latency and penetrance data in a cohort of over 600 animals, in vivo glucocorticoid and radiation treatment of B-ALL, and expression profiles from single B- and T-ALL cells.

The Frazer Research Team concluded in their Oncotarget Research Perspective, "We postulate these and other differences may explain the apparently disparate oncogenic mechanisms employed by hMYC and mMyc in the B lymphoblasts of these closely-related lines. Pathway analysis of differentially-regulated genes predicted differing activation of several biologic pathways (e.g., cell differentiation, immune system process, lymphocyte activation, RNA binding, etc.; Figure 6B panels and Supplementary Table 4). These markedly different pathway signatures further demonstrate that human and murine MYC are far from synonymous in terms of their oncogenic effects upon zebrafish B lymphoblasts."

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DOI - https://doi.org/10.18632/oncotarget.27555

Full text - https://www.oncotarget.com/article/27555/text/

Correspondence to - J. Kimble Frazer - Kimble-Frazer@ouhsc.edu

Keywords - acute lymphoblastic leukemia, ALL, zebrafish, lymphocyte, MYC

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