Single cell analysis reveals oligoclonality among “low count” monoclonal B cell lymphocytosis

Monoclonal B cell lymphocytosis (MBL) is a pre-clinical hematologic syndrome characterized by small accumulations of CD5(+) B lymphocytes. Most MBL share phenotypic characteristics with chronic lymphocytic leukemia (CLL). While some MBL progress to CLL, most MBL have apparently limited potential for progression to CLL, particularly those MBL with normal absolute B cell counts (“low count” MBL). Most CLL are monoclonal and it is not known whether MBL are monoclonal or oligoclonal; this is important because it is unclear whether MBL represent indolent CLL or represent a distinct pre-malignant precursor prior to the development of CLL. We used flow cytometry analysis and sorting to determine immunophenotypic characteristics, clonality, and molecular features of MBL from familial CLL kindreds. Single cell analysis indicated 4 of 6 low count MBL consisted of two or more unrelated clones; the other 2 MBL were monoclonal. 87% of low count MBL clones had mutated immunoglobulin genes, and no immunoglobulin heavy chain rearrangements of V(H) family 1 were observed. Some MBL were diversified, clonally related populations with evidence of antigen-drive. We conclude that while low count MBL share many phenotypic characteristics with CLL, many MBL are oligoclonal. This supports a model for step-wise development of MBL into CLL.