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

Title: Dynamic variation of CD5 surface expression levels within individual chronic lymphocytic leukemia clones
Authors: Bashford-Rogers, RJM
Palser, AL
Hodkinson, C
Baxter, J
Follows, GA
Vassiliou, GS
Kellam, P
Item Type: Journal Article
Abstract: 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.
Issue Date: 1-Feb-2017
Date of Acceptance: 17-Sep-2016
URI: http://hdl.handle.net/10044/1/69586
DOI: https://dx.doi.org/10.1016/j.exphem.2016.09.010
ISSN: 0301-472X
Publisher: Elsevier
Start Page: 31
End Page: 37.e10
Journal / Book Title: Experimental Hematology
Volume: 46
Copyright Statement: © 2016 ISEH - International Society for Experimental Hematology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Keywords: Science & Technology
Life Sciences & Biomedicine
Hematology
Medicine, Research & Experimental
Research & Experimental Medicine
B-CELLS
DOWN-REGULATION
APOPTOSIS
LINKING
RNA
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
Antigens, CD5
Immunology
1102 Cardiorespiratory Medicine and Haematology
Publication Status: Published
Online Publication Date: 2016-09-28
Appears in Collections:Department of Medicine



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