Defining origins of malignant B cells: a new circulating normal human IgM + D + B-cell subset lacking CD27 expression and displaying somatically mutated IGHV genes as a relevant memory population

In probing the cell of origin in malignant B cells, an imprint of somatic hypermutation (SHM) in immunoglobulin (Ig) variable (V) region genes delineates antigen encounter, and identifying the precise pathway generating SHM in the normal B-cell counterpart becomes relevant. SHM remains the definitive memory imprint in normal human B cells, but CD27 expression also delineates memory. Recently, dye extrusion adenosine triphosphate-binding transporter assays identified circulating isotype-switched memory B cells that lacked CD27, yet exhibited low levels of SHM. To extend findings, we report a pre-switched CD27-ve circulating memory B-cell population in normal blood using comparable assays, and isolated CD19+IgM+D+CD27-ve cells (>99% purity) for the analysis of IGHV5/IGHV3-IGHM transcripts. Of these (n=334), 78% were germ line and naive B cell derived. Strikingly, 21.9% of the transcripts were mutated. They showed 3–5 mutations (13.5% of sequences) and >5 mutations (8.4% of sequences) per transcript. Accrual of mutations in a subset of CD19+IgM+D+CD27-ve cells define a new circulating pre-switched memory B-cell pool, present in substantial numbers in the population harboring naive B cells. These CD19+IgM+D+CD27-ve memory B cells may have a distinct lineage and function, and seem relevant to understanding origins of malignant B cells, in particular those of hairy cell leukemia cells, which display mutated V genes yet lack CD27 expression.