Simultaneous B and T cell acute lymphoblastic leukemias in zebrafish driven by transgenic MYC: implications for oncogenesis and lymphopoiesis

Borga, Chiara; Park, Gilseung; Foster, Clay A.; Burroughs‐Garcia, Jessica; Marchesin, Matteo; Ahmed, Syed Talha; Bresolin, Silvia; Batchelor, Lance A.; Scordino, Teresa; Miles, Rodney R.; Kronnie, Geertruy te; Regens, James L.; Frazer, J. Kimble

doi:10.1101/281469

Cited by 3 publications

(9 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1B), with B-ALLs expressing cd79b , syk , pax5 , blnk and efb1 , while T-ALLs expressed cd8b , lck , runx3 and gata3 . As previously reported, the biphenotypic B/T-ALL and mixed hMYC -induced ALLs expressed both T- and B-cell lineage genes 1, 2 . PC2 up-regulated genes were enriched for B cell signaling pathways when independently assessed by GSEAsig (Supplemental Tables 1 and 2).…”

supporting

confidence: 80%

“…Zebrafish are a valuable leukemia model due to highly conserved hematopoietic and oncogenic pathways, facile genetics, and ease of use in chemical genetic screens. However, until recently, robust zebrafish B-cell leukemia models had not been described 1, 2 . The first transgenic zebrafish leukemia model was created 15 years ago and targeted murine c- Myc ( mMyc ) to thymocytes of AB strain zebrafish, leading to the rapid development of T-cell acute lymphoblastic leukemia (T-ALL) 3 .…”

mentioning

confidence: 99%

“…In two recent reports published in Leukemia , our groups independently demonstrated the development of zebrafish B-ALL using transgenic expression of mMyc or human c- MYC ( hMYC ) controlled by the zebrafish recombination activating gene 2 ( rag2 ) promoter 1, 2 . Both models shared genetic and phenotypic features, but there were also key differences including strain background and species differences in the MYC transgene that was used to generate each model.…”

mentioning

confidence: 99%

“…Thirteen ALLs were purified from rag2:hMYC;lck:eGFP double-transgenic fish 2 . As previously reported, these leukemias had heterogeneous GFP expression, with T-ALL being exclusively GFP hi , B-ALL exclusively GFP lo , and other fish harboring mixed-ALL with both GFP hi and GFP lo cells, representing simultaneous T- and B-ALL, respectively 2 . Leukemias were subjected to RNA-seq transcriptomic profiling and compared with transplanted leukemias generated from single ALL clones described by Garcia et al, 2018 1 .…”

mentioning

confidence: 99%

mentioning

confidence: 99%

See 4 more Smart Citations

Molecularly distinct models of zebrafishMyc-induced B cell leukemia

Borga

Foster

Iyer

et al. 2018

Preprint

Self Cite

View full text Add to dashboard Cite

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.

show abstract

supporting

confidence: 80%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Molecularly distinct models of zebrafishMyc-induced B cell leukemia

Borga

Foster

Iyer

et al. 2018

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

Pediatric Cancer Models in Zebrafish

Casey

Stewart

2020

Trends in Cancer

View full text Add to dashboard Cite

Pediatric cancer is a leading cause of death idraw n children and adolescents. Improvements in pediatric cancer treatment that include the alleviation of longterm adverse effects require a deeper understanding of the genetic, epigenetic, and developmental factors driving these cancers. Here, we review how the unique attributes of the zebrafish model system in embryology, imaging, and scalability have been used to identify new mechanisms of tumor initiation, progression, and relapse and for drug discovery. We focus on zebrafish models of leukemias, neural tumors and sarcomasthe most common and difficult childhood cancers to treat. Childhood and Adolescent CancerPediatric cancer is one of the leading causes of death in children and adolescents (age 0-19 years) and is mainly comprised of leukemias, cancers of the nervous system, and sarcomas [1]. Recent genomic profiling efforts to better understand the etiology of this group of diseases have enabled the stratification of tumor types based on molecular signatures and have led to the identification of potential genetic drivers and cooperating molecular events that underlie the development of different pediatric cancers. Most pediatric malignancies are mutationally quiet and are thought to be driven by a single driver gene, a fusion oncoprotein, or structural/copy number alterations [2,3]. In contrast, adult tumors frequently exhibit high mutational burdens, likely due to a longer period of mutational acquisition under selective pressure [2,3]. Despite these differences, however, pediatric cancer treatments are still largely modeled after treatments designed for the adult version of the disease and can cause debilitating, long-term side effects when administered to children. The development of robust preclinical pediatric cancer models that accurately recapitulate these diseases will ultimately be necessary for the design of more precise, targeted therapies to improve outcomes for pediatric cancer patients. Here, we discuss how the use of zebrafish has advanced the pediatric cancer field as a preclinical model for gene and drug discovery. HighlightsZebrafish develop tumors that are histologically and genetically similar to human tumors. Zebrafish enable the rapid identification of molecular drivers of tumor development and can be used to model cancers with unknown cells of origin using heatshock and β-actin promoters.Zebrafish models are amenable to highthroughput drug screening through larval drug submersion approaches, as well as transplantation of primary patient tumors into immunocompromised lines.Tumor-cell dynamics can be visualized in vivo throughout the lifetime of the animal by coupling oncogenes to fluorescent markers.

show abstract