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Monoclonal B-cell lymphocytosis (MBL) is an asymptomatic condition of monoclonal B-cell expansions in the blood of healthy, mostly elderly, individuals. MBL is classified into three distinct subtypes: (i) “chronic lymphocytic leukemia (CLL)-like” MBL (CD5CD23), which accounts for the vast majority of cases; (ii) “atypical CLLlike” MBL (CD5CD23-CD20; and (iii) “non CLL-like” MBL (CD5). “CLL-like” MBL is subdivided into two different categories based on clonal size; cases with 0.55x10 cells/L are categorized as “high-count MBL” (HCMBL), whereas those with <0.5x10 cells/L as ”low-count MBL” (LC-MBL). HC-MBL progresses to CLL requiring treatment at a rate of 1-2% per year, whereas the risk of progression for “CLL-like” LC-MBL is negligible despite persisting over time. Recently, we reported that the genomic profiles of LCMBL, HC-MBL and ‘ultra-stable’ CLL (no disease progression for ≥10 years) are very similar. On these grounds, we proposed that cross-talk between CLL progenitor cells and the microenvironment might represent a major driver in early stages of the disease. Relevant microenvironmental triggers might be provided by T cells, considering ample evidence for their implication in CLL pathogenesis and the existence of T-cell expansions. Such clonal expansions were also evident in HCMBL and LC-MBL, however, the relevant studies had important limitations, such as limited coverage of the expressed repertoire and sequencing depth, thus precluding firm conclusions from being drawn. In order to overcome these limitations, we characterized the T-cell receptor beta (TRB) chain gene repertoire using a high-throughput sequencing approach. Blood samples were collected from individuals from Val Borbera, Italy, where a LC-MBL cohort is regularly followed up (Online Supplementary Material). Samples from aged-matched, healthy individuals without MBL from the same region were analyzed as controls; comparisons to CLL were also performed. The research protocol was approved by the Ethics Committee of the San Raffaele Institute and all participants gave written informed consent in accordance with the Declaration of Helsinki. Samples of blood (5 mL) were obtained from all individuals and processed within 24 h. LC-MBL was diagnosed following a standardized flow cytometry approach (Online Supplementary Methods). We analyzed 48 samples from individuals with LC-MBL (“CLL -like” LC-MBL, n=41; “other” LC-MBL subtypes, n=7), and 17 samples from healthy controls (Online Supplementary Table S1). TRBV-TRBD-TRBJ gene rearrangements were amplified by polymerase chain reaction, sequenced on a MiSeq Sequencer and bioinformatically processed, as previously described. Overall, 2,357,648 distinct TRB clonotypes were identified. Of these, 1,006,126 (42.7%) were expanded (>1 read), whereas the remainder (1,351,522, 57.3%) concerned singletons (=1 read). The relevance of age in shaping the TRB repertoire, reported in a recent next-generation sequencing study, was also evident in our cohort; clonal expansions were present in all sample categories, including healthy donors. However, significantly different mean relative frequencies of expanded clonotypes were evident between sample categories [analysis of variance (ANOVA), P<0.05]. In more detail, expanded clonotypes were larger in “CLL-like” LC-MBL (0.018%; range, 0.0030.14%) than in “other” LC-MBL (0.007%; range, 0.0010.04%) or in the “healthy” category (0.01%; range, 0.002-0.012%) (Table 1, Online Supplementary Figure S1). Two different approaches were followed to assess clonality in each sample: (i) the ten “major” (most expanded) clonotypes; and (ii) all expanded clonotypes with an individual frequency of >1%. The first approach led to the identification of slightly higher clonality levels in LC-MBL than in healthy individuals, yet lower than those reported in CLL (ANOVA, P=0.3) (Figure 1, Online Supplementary Table S2). When considering clonotypes with a relative frequency >1%, the average number of expanded clonotypes for the “CLL-like” LC-MBL, “other” LC-MBL and healthy groups was five (range, 0-27), four (range, 2-6) and four (range, 1-11), respectively. The average sum of relative frequencies was 20% in “CLL-like” LC-MBL, 17% in “other” LC-MBL and 15% in the

haematologica

High-throughput analysis of the T cell receptor gene repertoire in low-count monoclonal B cell lymphocytosis reveals a distinct profile from chronic lymphocytic leukemia