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Dynamic changes in clonal cytogenetic architecture during progression of chronic lymphocytic leukemia in patients and patient-derived murine xenografts

2017; Impact Journals LLC; Volume: 8; Issue: 27 Linguagem: Inglês

10.18632/oncotarget.17432

1949-2553

Nicholas Davies, Marwan Kwok, Clive Gould, Ceri Oldreive, Jingwen Mao, Helen Parry, Edward Smith, Angelo Agathanggelou, Guy Pratt, A. Malcolm R. Taylor, Paul Moss, Mike Griffiths, Tatjana Stanković,

Lymphoma Diagnosis and Treatment

// Nicholas J. Davies 1 , Marwan Kwok 1 , Clive Gould 2 , Ceri E. Oldreive 1 , Jingwen Mao 1 , Helen Parry 3 , Edward Smith 1 , Angelo Agathanggelou 1 , Guy Pratt 1 , Alexander Malcolm R. Taylor 1 , Paul Moss 3 , Mike Griffiths 1, 2 and Tatjana Stankovic 1 1 Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK 2 West Midlands Regional Genetics Laboratory, Birmingham Women's NHS Foundation Trust, Birmingham, UK 3 Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK Correspondence to: Tatjana Stankovic, email: t.stankovic@bham.ac.uk Keywords: chronic lymphocytic leukemia, xenograft, clonal evolution, multiplexed-FISH, cytogenetics Received: March 15, 2017 Accepted: March 29, 2017 Published: April 26, 2017 ABSTRACT Subclonal heterogeneity and clonal selection influences disease progression in chronic lymphocytic leukemia (CLL). It is therefore important that therapeutic decisions are made based on an understanding of the CLL clonal architecture and its dynamics in individual patients. Identification of cytogenetic abnormalities by FISH remains the cornerstone of contemporary clinical practice and provides a simple means for prognostic stratification. Here, we demonstrate that multiplexed-FISH can enhance recognition of CLL subclonal repertoire and its dynamics during disease progression, both in patients and CLL patient-derived xenografts (PDX). We applied a combination of patient-specific FISH probes to 24 CLL cases before treatment and at relapse, and determined putative ancestral relationships between subpopulations with different cytogenetic features. We subsequently established 7 CLL PDX models in NOD/Shi-SCID/IL-2Rγc tm1sug /Jic (NOG) mice. Application of multiplexed-FISH to these models demonstrated that all of the identified cytogenetic subpopulations had leukemia propagating activity and that changes in their representation during disease progression could be spontaneous, accelerated by treatment or treatment-induced. We conclude that multiplexed-FISH in combination with PDX models have the potential to distinguish between spontaneous and treatment-induced clonal selection, and therefore provide a valuable tool for the pre-clinical evaluation of novel therapies.