Dynamic variation of CD5 surface expression levels within individual chronic lymphocytic leukemia clones.
Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of clonally derived mature CD5highB cells; however, the cellular origin of CLL is still unknown. Patients with CLL also harbor variable numbers of CD5lowB cells, but the clonal relationship of these cells to the bulk disease is unknown and can have important implications for monitoring, treating, and understanding the biology of CLL. Here, we use B-cell receptors (BCRs) as molecular barcodes to first show by single-cell BCR sequencing that the great majority of CD5lowB cells in the blood of CLL patients are clonally related to CD5highCLL B cells. We investigate whether CD5 state switching was likely to occur continuously as a common event or as a rare event in CLL by tracking somatic BCR mutations in bulk CLL B cells and using them to reconstruct the phylogenetic relationships and evolutionary history of the CLL in four patients. Using statistical methods, we show that there is no parsimonious route from a single or low number of CD5lowswitch events to the CD5highpopulation, but rather, large-scale and/or dynamic switching between these CD5 states is the most likely explanation. The overlapping BCR repertoires between CD5highand CD5lowcells from CLL patient peripheral blood reveal that CLL exists in a continuum of CD5 expression. The major proportion of CD5lowB cells in patients are leukemic, thus identifying CD5lowB cells as an important component of CLL, with implications for CLL pathogenesis, clinical monitoring, and the development of anti-CD5-directed therapies.
Department of Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
Rachael J M
RJ
Bashford-Rogers
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
Anne L
AL
Palser
Cambridge Blood and Stem Cell Biobank, University of Cambridge, Department of Haematology, National Health Service Blood and Transplant Cambridge Centre, Cambridge, UK.
Clare
C
Hodkinson
Cambridge Blood and Stem Cell Biobank, University of Cambridge, Department of Haematology, National Health Service Blood and Transplant Cambridge Centre, Cambridge, UK.
Joanna
J
Baxter
Department of Haematology, Addenbrooke's Hospital, Cambridge, UK.
George A
GA
Follows
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
George S
GS
Vassiliou
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK; Research Department of Infection, Division of Infection and Immunity, University College London, London, UK. Electronic address: pk5@sanger.ac.uk.
Paul
P
Kellam
D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D015415:Biomarkers; D018956:CD5 Antigens / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D016130:Immunophenotyping; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism*; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D017422:Sequence Analysis, DNA
D015703:Antigens, CD; D015415:Biomarkers; D018956:CD5 Antigens; D011947:Receptors, Antigen, B-Cell
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