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; Shah, Rikin; Hasan, Ameera; Ahmed, Syed Talha; Bresolin, Silvia; Batchelor, Lance A.; Scordino, Teresa; Miles, Rodney R.; Kronnie, Geertruy te; Regens, James L.; Frazer, J. Kimble

doi:10.1038/s41375-018-0226-6

Cited by 32 publications

(41 citation statements)

References 38 publications

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“…In the other, a rag2:hMYC (human MYC) transgene was utilized [32], as well as a transgenic marker, lck:eGFP [59], differentially expressed by B and T cells. 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].…”

Section: Introductionmentioning

confidence: 70%

“…Zebrafish care was provided as previously reported [58]. Animals were housed in an aquatic colony at 28.5°C on a 14:10 hour light:dark circadian cycle and experiments performed according to protocols approved by the University of Oklahoma Health Sciences Center IACUC (12-066 and 15-046).…”

Section: Zebrafish Carementioning

confidence: 99%

“…As previously described [58], cells from whole fish were dissociated using a pestle, and then passed through 35 μm filters. GFP hi , GFP lo , and/or GFPcells were collected from the lymphoid and precursor gates using a BD-FACSJazz Instrument (Becton Dickinson, San Jose, CA, USA).…”

Section: Fluorescence-activated Cell Sorting (Facs) and Flow Cytometrmentioning

confidence: 99%

“…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 [57,58]. In one, a rag2:mMyc (murine Myc) transgene was used [29], with ALL purified as single clones by allo-transplantation.…”

Section: Introductionmentioning

confidence: 99%

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2020

Oncotarget

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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: 70%

Section: Zebrafish Carementioning

confidence: 99%

Section: Fluorescence-activated Cell Sorting (Facs) and Flow Cytometrmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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2020

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“…Instead, leukemogenesis appears to happen in a sequential and directional manner that was consistent in all animals that we observed. Myc-derived zebrafish T cell leukemias are known to have heterogenous mutations and differential gene expression profiles, between individual leukemias and between clones within the same leukemia [14,25,26]. Yet, our data that leukemias consistently follow the same dissemination pattern suggest that initial leukemia onset is not reliant on acquisition of certain mutations or gene expression, and instead may be heavily influenced by either normal routes of T cell emigration from the thymus and/or external factors such as the thymic microenvironment.…”

Section: Resultsmentioning

confidence: 99%

In vivo imaging defines vascular interplay in the development of lymphocytic leukemia in zebrafish models

Revskoy

Blair

Powell

et al. 2019

Preprint

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The vascular microenvironment at the primary tumor site is represented by 12 functionally diverse types of vessels that contribute to metabolic supply, trafficking/dissemination of 13 tumor cells, and delivery of chemotherapeutics. However, the role of leukemia-associated vascular 14 networks in leukemia progression remains poorly understood. We utilized a MYC-induced T cell 15 leukemia model in zebrafish to assess the involvement of vascular endothelial growth factor 16 A-dependent (VEGFR2+), VEGFA-independent vasculature (VEGFR2-), and lymphatics in the initial 17 stages of leukemia cell dissemination using intravital microscopy. Leukemogenesis underwent 18 sequential progression, from initial successive emigration of single leukemic cells from the thymus 19 towards the kidney marrow, followed by collective migration in a dorsal-lateral direction with 20 scattered migration from the ventral thymus towards the aortic arches, before streaming towards the 21 rostral kidney area. Trafficking appeared independent of VEGFR2+ vasculature but was closely 22 associated with VEGFR2-microvessels, and, interestingly, leukemic cells did not utilize lymphatics 23 during initial dissemination. Overall, leukemic cells appeared to utilize the same routes as normal T 24 cell progenitors during development but in a reverse order, and primarily recruited VEGFR2-25 microvessels during the initial stages of progression. Ultimately, interfering with leukemia cell 26 migration by targeting vascular networks may represent a new therapeutic strategy to control 27 leukemia progression. 28 30 34 activating gene 2 (Rag2)-expressing lymphocyte precursors constitutes a critical step in the 35 development of immunocompetency, the intensive V(D)J recombination can result in Rag2-induced 36 off-target effects that may drive diverse leukemogenesis [4-6]. These types of genetic events might 37 significantly modify and diversify the behavior of the MYC-transformed leukemia cells, and the 38 molecular events accompanying Myc-induced cell transformation in leukemia and other cancers 39 have been extensively delineated. However, the microenvironmental and developmental contexts of 40 leukemogenesis remain largely unknown. 41 Normal Rag2+ T cell progenitors that colonize the thymus undergo a well-established life 42 cycle, including migration into the primordial thymus, homing to specific compartments within 43 thymus, and either apoptosis or clonal expansion followed by further lineage-directed 44 differentiation and emigration away from the thymus. In T cell leukemia, with high Myc expression 45 in particular, normal Rag2-expressing lymphocyte differentiation is blocked and cells are prompted 46 towards uncontrolled proliferation [7-9]. In addition to intrinsic changes in the transformed cells, 47 Myc overexpression in other types of cancers causes inflammatory remodeling of the tumor 48 microenvironment, angiogenesis, and ultimately, promotes metastatic behavior [10,11]. Unlike the 49 metastatic spread of epithelial cancers, lymphocytic leukemia di...

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Animal Models of Lymphoid Malignancies

Mishra

2023

Precision Cancer Therapies, Volume 1 ‐ Targeting Oncogenic Drivers and Signaling Pathways in Lymphoid Malignancies

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

Cited by 32 publications

References 38 publications

Untitled

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In vivo imaging defines vascular interplay in the development of lymphocytic leukemia in zebrafish models

Animal Models of Lymphoid Malignancies

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