Molecularly distinct models of zebrafish Myc-induced B cell leukemia

Borga, Chiara; Foster, Clay A.; Iyer, Sowmya; Garcia, Sara P.; Langenau, David M.; Frazer, J. Kimble

doi:10.1038/s41375-018-0328-1

Cited by 16 publications

(31 citation statements)

References 10 publications

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“…Analysis of over one hundred animals demonstrated that many develop B-ALL, others develop T-ALL (as previously known), and still other fish acquire both ALL types concommitantly [58]. A followup report by these groups further showed that despite high similarity between the mMyc and hMYC transgenes used, these B-ALL are actually quite different, occurring in distinct B cell lineages and with dissimilar expression patterns [60]. Here, we 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.…”

Section: Introductionmentioning

confidence: 72%

“…Counts were processed and normalized within DESeq2 (v.1.22.1) [68], and pairwise differential expression testing was used to compare hMYC and mMyc B-ALL (adjusted p-value < 0.05, absolute fold-change > 1.5). Additional filtering steps were as described previously [60]. Putative human orthologues were mapped to corresponding D. rerio genes using BEAGLE (update 090718; retrieved from http://chgr.mgh.harvard.edu/ genomesrus/index.php).…”

Section: Rna-seq and Gene Expression Comparisons Of Hmyc And Mmyc B-allmentioning

confidence: 99%

“…We previously analyzed more than 50 unique hMYC 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. To determine these, beginning at 3 months of age, we monitored fish by serial fluorescent microscopy to detect GFP lo B-ALL and GFP hi T-ALL, as we described previously ( Figure 1A) [58].…”

Section: B-all Is Early Onset and Highly Penetrant In Hmyc Zebrafishmentioning

confidence: 99%

“…In addition, select genes (e. g., foxo1b, skap1) occasionally were mis-expressed by cells of the 'wrong' lineage. The significance of these findings remain to be determined, as malignant cells express aberrant markers on occasion [88], but biphenotypic ALL was demonstrated in mMyc fish, so what has previously been termed gene 'mis-expression' may actually represent an intriguing finding [57,60]. Future single-cell studies hold promise as a means to address these and other unanswered questions about the cellular heterogeneity amongst lymphocytes, and within individual cancers, so as to define the precise gene expression differences that underlie their differing cellular phenotypes in vivo.…”

Section: Defining B-all and B Cell Gene Expression Patternsmentioning

confidence: 99%

“…MYC acts oncogenically in many ALL cases, and MYC is hyperactive in several other forms of cancer also [89], so it is not surprising that hMYC and mMyc can induce ALL in several types of lymphocytes [60]. However, the human and mouse MYC oncoproteins in these transgenic fish are highly conserved (435 amino acids, ~92% identical, ~94% similar; Figure 5), and both lines regulate MYC using the same zebrafish rag2 promoter, so it was surprising to discover that B-ALL in hMYC and mMyc fish are quite different.…”

Section: Distinct Types Of B-all Driven By Hmyc and Mmycmentioning

confidence: 99%

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2020

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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.

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Section: Introductionmentioning

confidence: 72%

Section: Rna-seq and Gene Expression Comparisons Of Hmyc And Mmyc B-allmentioning

confidence: 99%

Section: B-all Is Early Onset and Highly Penetrant In Hmyc Zebrafishmentioning

confidence: 99%

Section: Defining B-all and B Cell Gene Expression Patternsmentioning

confidence: 99%

Section: Distinct Types Of B-all Driven By Hmyc and Mmycmentioning

confidence: 99%

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2020

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Zebrafish models of acute leukemias: Current models and future directions

Molina

Chavez

Grainger

2020

WIREs Developmental Biology

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Acute myeloid leukemias (AML) and acute lymphoid leukemias (ALL) are heterogenous diseases encompassing a wide array of genetic mutations with both loss and gain of function phenotypes. Ultimately, these both result in the clonal overgrowth of blast cells in the bone marrow, peripheral blood, and other tissues. As a consequence of this, normal hematopoietic stem cell function is severely hampered. Technologies allowing for the early detection of genetic alterations and understanding of these varied molecular pathologies have helped to advance our treatment regimens toward personalized targeted therapies. In spite of this, both AML and ALL continue to be a major cause of morbidity and mortality worldwide, in part because molecular therapies for the plethora of genetic abnormalities have not been developed. This underscores the current need for better model systems for therapy development. This article reviews the current zebrafish models of AML and ALL and discusses how novel gene editing tools can be implemented to generate better models of acute leukemias.

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PRL3 enhances T-cell acute lymphoblastic leukemia growth through suppressing T-cell signaling pathways and apoptosis

et al. 2020

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T cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of thymocytes and is largely driven by the NOTCH/MYC pathway. Yet, additional oncogenic drivers are required for transformation. Here, we identify protein tyrosine phosphatase type 4 A3 (PRL3) as a collaborating oncogenic driver in T-ALL. PRL3 is expressed in a large fraction of primary human T-ALLs and is commonly co-amplified with MYC. PRL3 also synergized with MYC to initiate early-onset ALL in transgenic zebrafish and was required for human T-ALL growth and maintenance. Mass spectrometry phosphoproteomic analysis and mechanistic studies uncovered that PRL3 suppresses downstream T cell phosphorylation signaling pathways, including those modulated by VAV1, and subsequently suppresses apoptosis in leukemia cells. Taken together, our studies have identified new roles for PRL3 as a collaborating oncogenic driver in human T-ALL and suggest that therapeutic targeting of the PRL3 phosphatase will likely be a useful treatment strategy for T-ALL.

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Molecularly distinct models of zebrafish Myc-induced B cell leukemia

Cited by 16 publications

References 10 publications

Untitled

Untitled

Zebrafish models of acute leukemias: Current models and future directions

PRL3 enhances T-cell acute lymphoblastic leukemia growth through suppressing T-cell signaling pathways and apoptosis

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