Dynamic changes in clonal cytogenetic architecture during progression of chronic lymphocytic leukemia in patients and patient-derived murine xenografts
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Nicholas J. Davies1, Marwan Kwok1, Clive Gould2, Ceri E. Oldreive1, Jingwen Mao1, Helen Parry3, Edward Smith1, Angelo Agathanggelou1, Guy Pratt1, Alexander Malcolm R. Taylor1, Paul Moss3, Mike Griffiths1,2 and Tatjana Stankovic1
1Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
2West Midlands Regional Genetics Laboratory, Birmingham Women’s NHS Foundation Trust, Birmingham, UK
3Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
Tatjana Stankovic, email: [email protected]
Keywords: chronic lymphocytic leukemia, xenograft, clonal evolution, multiplexed-FISH, cytogenetics
Received: March 15, 2017 Accepted: March 29, 2017 Published: April 26, 2017
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-2Rγctm1sug/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.
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