Project Summary Our proposal addresses the important issue of defining the clinical consequences of low count Monoclonal B cell lymphocytosis (LC MBL) and providing insight into why 5-10% of U.S. adults over the age of 40 develop this condition. MBL - the precursor state to chronic lymphocytic leukemia (CLL), is one of the most common premalignant conditions in humans. Individuals with MBL have a circulating clonal B cell population, an absolute B cell count <5x109/L and no other features of a lymphoproliferative disorder. Studies have found that the prevalence of MBL increases with age, affecting <0.5% of individuals under age 40, 5% of those age 40-60, and over 10% of those over age 60. MBL is now subdivided into low count (LC) MBL and high count (HC) MBL depending on whether the absolute B cell count is above or below 1x109/L. The overwhelming majority (i.e. >98%) of individuals with MBL have LC MBL and never come to clinical attention. The clinical consequences of LC MBL are largely unknown. Despite the low risk of progression to CLL, individuals with LC MBL are likely to have other important clinical consequences. In a preliminary study of 1001 adults age >40, we found that individuals with LC MBL have reduced overall survival and increased risk of life-threatening infections. This suggests that 5-10% of adults over age 40 have a largely unstudied, acquired, asymptomatic condition with potentially important clinical implications. Currently little to no information is known about the risk factors for developing MBL. We are now poised via this proposal to determine the critical clinical consequences of LC MBL with respect to risk of infection and non-hematologic malignancy and to identify the risk factors for developing LC MBL. This is because of our unique opportunity to study MBL using the Mayo Clinic Biobank, the only tissue repository in the USA we are aware of that stores peripheral blood mononuclear cells in a manner that permits testing for the presence of LC MBL. This Biobank is linked to the Mayo Clinic Medical record and provides exceptionally well annotated prospective follow-up to evaluate clinical outcomes. Participants in the Biobank also provided detailed information on epidemiologic, health and behavioral risk factors at the time of blood collection which allows evaluation of how these factors relate to MBL risk. In this proposal, we will harness this unique platform to robustly define the clinical outcomes associated with LC MBL and the risk factors for developing this age related clinical condition which affects 5-10% of adults over the age of 40.