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Leukemia. 2017 Apr;31(4):837-845. doi: 10.1038/leu.2016.307. Epub 2016 Oct 31.

Targeted deep sequencing reveals clinically relevant subclonal IgHV rearrangements in chronic lymphocytic leukemia.

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Oxford NIHR BRC Molecular Diagnostic Centre, John Radcliffe Site, Oxford University Hospitals, Oxford, UK.
Laboratory of Clinical Cell Therapy, Jules Bordet Institute, Université Libre de Bruxelles (ULB), Brussels, Belgium.
Nuffield Department of Laboratory Sciences, University of Oxford, Oxford, UK.
Department of Physiology, Anatomy and Genetics, Computational Genomics Analysis and Training Programme, MRC Functional Genomics Unit, University of Oxford, Oxford, UK.
Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Trust, Oxford, UK.
Department of Oncology, Translational Molecular Diagnostics Centre, University of Oxford, Oxford, UK.


The immunoglobulin heavy-chain variable region gene (IgHV) mutational status is considered the gold standard of prognostication in chronic lymphocytic leukemia (CLL) and is currently determined by Sanger sequencing that allows the analysis of the major clone. Using next-generation sequencing (NGS), we sequenced the IgHV gene from two independent cohorts: (A) 270 consecutive patient samples obtained at diagnosis and (B) 227 patients from the UK ARCTIC-AdMIRe clinical trials. Using complementary DNA from purified CD19+CD5+ cells, we demonstrate the presence of multiple rearrangements in independent experiments and showed that 24.4% of CLL patients express multiple productive clonally unrelated IgHV rearrangements. On the basis of IgHV-NGS subclonal profiles, we defined five different categories: patients with (a) multiple hypermutated (M) clones, (b) 1 M clone, (c) a mix of M-unmutated (UM) clones, (d) 1 UM clone and (e) multiple UM clones. In population A, IgHV-NGS classification stratified patients into five different subgroups with median treatment-free survival (TFS) of >280(a), 131(b), 94(c), 29(d), 15(e) months (P<0.0001) and a median OS of >397(a), 292(b), 196(c), 137(d) and 100(e) months (P<0.0001). In population B, the poor prognosis of multiple UM patients was confirmed with a median TFS of 2 months (P=0.0038). In conclusion, IgHV-NGS highlighted one quarter of CLL patients with multiple productive IgHV subclones and improves disease stratification and raises important questions concerning the pre-leukemic cellular origin of CLL.

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