Somatic drivers of B-ALL in a model of ETV6-RUNX1; Pax5 +/− leukemia
Authors
van, der Weyden Louise
Wong, Kim
Rust, Alistair G
Robles-Espinoza, Carla D
Osaki, Hikari
Adams, David J
Publication Date
2015-08-13ISSN
1471-2407
Type
Article
Metadata
Show full item recordCitation
van, d. W. L., Giotopoulos, G., Wong, K., Rust, A. G., Robles-Espinoza, C. D., Osaki, H., Huntly, B., & et al. (2015). Somatic drivers of B-ALL in a model of ETV6-RUNX1; Pax5 +/− leukemia. https://doi.org/10.1186/s12885-015-1586-1
Abstract
Abstract
Background
B-cell precursor acute lymphoblastic leukemia (B-ALL) is amongst the leading causes of childhood cancer-related mortality. Its most common chromosomal aberration is the ETV6-RUNX1 fusion gene, with ~25 % of ETV6-RUNX1 patients also carrying PAX5 alterations.
Methods
We have recreated this mutation background by inter-crossing Etv6-RUNX1 (Etv6
RUNX1-SB
) and Pax5
+/−
mice and performed an in vivo analysis to find driver genes using Sleeping Beauty transposon-mediated mutagenesis and also exome sequencing.
Results
Combination of Etv6-RUNX1 and Pax5
+/−
alleles generated a transplantable B220 + CD19+ B-ALL with a significant disease incidence. RNA-seq analysis showed a gene expression pattern consistent with arrest at the pre-B stage. Analysis of the transposon common insertion sites identified genes involved in B-cell development (Zfp423) and the JAK/STAT signaling pathway (Jak1, Stat5 and Il2rb), while exome sequencing revealed somatic hotspot mutations in Jak1 and Jak3 at residues analogous to those mutated in human leukemias, and also mutation of Trp53.
Conclusions
Powerful synergies exists in our model suggesting STAT pathway activation and mutation of Trp53 are potent drivers of B-ALL in the context of Etv6-RUNX1;Pax5
+/−
.
Sponsorship
Medical Research Council (MR/M010392/1)
ECH2020 EUROPEAN RESEARCH COUNCIL (ERC) (647685)
Worldwide Cancer Research (14-1069)
Identifiers
External DOI: https://doi.org/10.1186/s12885-015-1586-1
This record's URL: https://www.repository.cam.ac.uk/handle/1810/260536
Rights
Rights Holder: van der Weyden et al.
Licence:
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