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Dynamic variation of CD5 surface expression levels within individual chronic lymphocytic leukemia clones.

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Bashford-Rogers, Rachael JM 
Palser, Anne L 
Baxter, Joanna 
Follows, George A 


Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of clonally derived mature CD5high B cells; however, the cellular origin of CLL is still unknown. Patients with CLL also harbor variable numbers of CD5low B 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 CD5low B cells in the blood of CLL patients are clonally related to CD5high CLL 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 CD5low switch events to the CD5high population, but rather, large-scale and/or dynamic switching between these CD5 states is the most likely explanation. The overlapping BCR repertoires between CD5high and CD5low cells from CLL patient peripheral blood reveal that CLL exists in a continuum of CD5 expression. The major proportion of CD5low B cells in patients are leukemic, thus identifying CD5low B cells as an important component of CLL, with implications for CLL pathogenesis, clinical monitoring, and the development of anti-CD5-directed therapies.



Antigens, CD, B-Lymphocytes, Biomarkers, CD5 Antigens, Cell Membrane, Gene Expression, Humans, Immunophenotyping, Leukemia, Lymphocytic, Chronic, B-Cell, Receptors, Antigen, B-Cell, Sequence Analysis, DNA

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Exp Hematol

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Elsevier BV
Medical Research Council (MC_PC_12009)
Wellcome Trust (106068/Z/14/Z)