Somatic drivers of B-ALL in a model of ETV6-RUNX1; Pax5(+/-) leukemia.
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(+/-).
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1HH, UK. lvdw@sanger.ac.uk.
Louise
L
van der Weyden
Cambridge Institute for Medical Research and Wellcome Trust/MRC Cambridge Stem Cell Institute, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0XY, UK. gg320@cam.ac.uk.
George
G
Giotopoulos
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1HH, UK. kw10@sanger.ac.uk.
Kim
K
Wong
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1HH, UK. ar12@sanger.ac.uk.
Alistair G
AG
Rust
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1HH, UK. cdre@sanger.ac.uk.
Carla Daniela
CD
Robles-Espinoza
Cambridge Institute for Medical Research and Wellcome Trust/MRC Cambridge Stem Cell Institute, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0XY, UK. ho265@cam.ac.uk.
Hikari
H
Osaki
Cambridge Institute for Medical Research and Wellcome Trust/MRC Cambridge Stem Cell Institute, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0XY, UK. bjph2@cam.ac.uk.
Brian J
BJ
Huntly
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1HH, UK. da1@sanger.ac.uk.|Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1HH, UK. da1@sanger.ac.uk.
David J
DJ
Adams
D000818:Animals; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics*; D004195:Disease Models, Animal; D053612:Janus Kinases / Q000235:genetics; D051379:Mice; D016296:Mutagenesis; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D051757:PAX5 Transcription Factor / Q000235:genetics; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D000097764:ETS Translocation Variant 6 Protein
D050676:Core Binding Factor Alpha 2 Subunit; D053612:Janus Kinases; D015514:Oncogene Proteins, Fusion; D051757:PAX5 Transcription Factor; D050783:Proto-Oncogene Proteins c-ets; D012097:Repressor Proteins; D000097764:ETS Translocation Variant 6 Protein; C497282:Pax5 protein, mouse; C493726:Runx1 protein, mouse; C102421:TEL-AML1 fusion protein