Cell of origin dictates aggression and stem cell number in acute lymphoblastic leukemia

Garcia, Elaine G.; Iyer, Sowmya; Garcia, Sara P.; Loontiens, Siebe; Sadreyev, Ruslan I.; Speleman, Franki; Langenau, David M.

doi:10.1038/s41375-018-0130-0

Cited by 24 publications

(43 citation statements)

References 24 publications

(30 reference statements)

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“…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: 79%

“…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%

“…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 . Principal Component Analysis clearly distinguished mMyc- induced T-ALL from B-ALL, with the single mMyc- induced biphenotypic B/T-ALL clustering between these samples (Fig.…”

mentioning

confidence: 99%

“…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 .…”

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confidence: 99%

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Molecularly distinct models of zebrafishMyc-induced B cell leukemia

Borga

Foster

Iyer

et al. 2018

Preprint

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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.

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supporting

confidence: 79%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Molecularly distinct models of zebrafishMyc-induced B cell leukemia

Borga

Foster

Iyer

et al. 2018

Preprint

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“…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.…”

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confidence: 99%

Untitled

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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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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Cell of origin dictates aggression and stem cell number in acute lymphoblastic leukemia

Cited by 24 publications

References 24 publications

Molecularly distinct models of zebrafishMyc-induced B cell leukemia

Molecularly distinct models of zebrafishMyc-induced B cell leukemia

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Animal Models of Lymphoid Malignancies

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