Toggle Main Menu Toggle Search

Open Access padlockePrints

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

Lookup NU author(s): Dr Paul Sinclair, Dr Helen Blair, Dr Sarra Ryan, Dr Lars Buechler, Joanna Cheng, Jake Clayton, Rebecca Hanna, Shaun Hollern, Zoe Hawking, Dr Matthew Bashton, Claire Schwab, Lisa Jones, Dr Lisa Russell, Dr Helen Marr, Dr Peter Carey, Professor Olaf Heidenreich, Professor Anthony Moorman, Professor Christine Harrison

Downloads


Licence

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).


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.


Publication metadata

Author(s): Sinclair PB, Blair HH, Ryan SL, Buechler L, Cheng J, Clayton J, Hanna R, Hollern S, Hawking Z, Bashton M, Schwab CJ, Jones L, Russell LJ, Marr H, Carey P, Halsey C, Heidenreich O, Moorman AV, Harrison CJ

Publication type: Article

Publication status: Published

Journal: Haematologica

Year: 2018

Volume: 103

Pages: 634-644

Print publication date: 01/04/2018

Online publication date: 15/02/2018

Acceptance date: 08/02/2018

Date deposited: 20/03/2018

ISSN (print): 0390-6078

ISSN (electronic): 1592-8721

Publisher: Ferrata Storti Foundation

URL: https://doi.org/10.3324/haematol.2017.172304

DOI: 10.3324/haematol.2017.172304

PubMed id: 29449437


Altmetrics

Altmetrics provided by Altmetric


Actions

Find at Newcastle University icon    Link to this publication


Share