Dynamic clonal progression in xenografts of acute lymphoblastic leukemia with intrachromosomal amplification of chromosome 21

Sinclair, P. B. et al. (2018) Dynamic clonal progression in xenografts of acute lymphoblastic leukemia with intrachromosomal amplification of chromosome 21. Haematologica, 103(4), pp. 634-644. (doi: 10.3324/haematol.2017.172304) (PMID:29449437) (PMCID:PMC5865429)

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Abstract

Intrachromosomal amplification of chromosome 21 is a heterogeneous chromosomal rearrangement occurring in 2% of childhood precursor B-cell acute lymphoblastic leukemia. There are no cell lines with iAMP21 and these abnormalities are too complex to faithfully engineer in animal models. As a resource for future functional and pre-clinical studies, we have created xenografts from intrachromosomal amplification of chromosome 21 leukemia patient blasts and characterised them by in-vivo and ex-vivo luminescent imaging, FLOW immunophenotyping, and histological and ultrastructural analysis of bone marrow and the central nervous system. Investigation of up to three generations of xenografts revealed phenotypic evolution, branching genomic architecture and, compared with other B-cell acute lymphoblastic leukemia genetic subtypes, greater clonal diversity of leukemia initiating cells. In support of intrachromosomal amplification of chromosome 21 as a primary genetic abnormality, it was always retained through generations of xenografts, although we also observed the first example of structural evolution of this rearrangement. Clonal segregation in xenografts revealed convergent evolution of different secondary genomic abnormalities implicating several known tumour suppressor genes and a region, containing the B-cell adaptor, PIK3AP1, and nuclear receptor co-repressor, LCOR, in the progression of B-ALL. Tracking of mutations in patients and derived xenografts provided evidence for co-operation between abnormalities activating the RAS pathway in B-ALL and for their aggressive clonal expansion in the xeno-environment. Bi-allelic loss of the CDKN2A/B locus was recurrently maintained or emergent in xenografts and also strongly selected as RNA sequencing demonstrated a complete absence of reads for genes associated with the deletions.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Halsey, Professor Chris
Authors: Sinclair, P. B., Blair, H. H., Ryan, S. L., Buechler, L., Cheng, J., Clayton, J., Hanna, R., Hollern, S., Hawking, Z., Bashton, M., Schwab, C. J., Jones, L., Russell, L. J., Marr, H., Carey, P., Halsey, C., Heidenreich, O., Moorman, A. V., and Harrison, C. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Haematologica
Publisher:Ferrata Storti Foundation
ISSN:0390-6078
ISSN (Online):1592-8721
Published Online:15 February 2018
Copyright Holders:Copyright © 2018 Ferrata Storti Foundation
First Published:First published in Haematologica 103(4): 634-644
Publisher Policy:Reproduced under a Creative Commons License

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