High-risk subtypes of chronic lymphocytic leukemia are detectable as early as 16 years prior to diagnosis

Abstract

Chronic lymphocytic leukemia (CLL) is preceded by monoclonal B-cell lymphocytosis (MBL), a CLL precursor state with a prevalence of up to 12% in aged individuals; however, the duration of MBL and the mechanisms of its evolution to CLL remain largely unknown. In this study, we sequenced the B-cell receptor (BcR) immunoglobulin heavy chain (IGH) gene repertoire of 124 patients with CLL and 118 matched controls in blood samples taken up to 22 years prior to diagnosis. Significant skewing in the BcR IGH gene repertoire was detected in the majority of patients, even before the occurrence of lymphocytosis and irrespective of the clonotypic IGH variable gene somatic hypermutation status. Furthermore, we identified dominant clonotypes belonging to major stereotyped subsets associated with poor prognosis up to 16 years before diagnosis in 14 patients with CLL. In 22 patients with longitudinal samples, the skewing of the BcR IGH gene repertoire increased significantly over time to diagnosis or remained stable at high levels. For 14 of 16 patients with available samples at diagnosis, the CLL clonotype was already present in the prediagnostic samples. Overall, our data indicate that the preclinical phase of CLL could be longer than previously thought, even in adverse-prognostic cases.

Characterizing Features of Human Circulating B Cells Carrying CLL-Like Stereotyped Immunoglobulin Rearrangements

“…The above interpretations may not be mutually exclusive. In addition, it is possible that the leukemogenic process can be accompanied by immunophenotypic changes that encompass an elevated expression of CD5 typically observed in CLL and MBL cells and presumably the pre-monoclonal B-cell lymphocytosis described by Kolijn, P. et al (32) In this context, B-cell immune-genotype appears to be a relevant factor in the quest to identify the CLL clones' cell of origin, adding additional elements useful for understanding CLL emergence routes.…”

“…Blood samples were collected from donors with a median age of 58.8 (range 56-67), which is in the range of possible identification of clonotypes ascribable to CLL clones that became clinically evident later. Indeed, it has been reported that clonotypes attributable to the leukemic clone can be identified in the PB up to 16 years before CLL diagnosis ( 32 ). It is, however, unknown whether phenotypic changes were present in the PB B lymphocytes at this early stage.…”

T and NK Cells in IL2RG-Deficient Patient 50 Years After Hematopoietic Stem Cell Transplantation

“…4A-B, S7). Similarly, a gradient of CD8 expression was observed on a fraction of all TCR Vβ dominant subclusters (5,22,21,26,13,1,12,16), except for the TCR Vβ17 + family, ranging from 38% of TCR Vβ2 + cells to 92% of TCR Vβ13.2 + cells (Figs. 4A-B, S7).…”

“…75-100 ng of DNA was amplified through multiplex PCR of TRBV-TRBD-TRBJ gene rearrangements following the BIOMED-2 protocol [10]. Purification of PCR products and library preparation were performed as described previously [11,12]. Paired-end sequencing was performed using the MiSeq Reagent Kit v2 (2 × 250 bp) on the MiSeq Benchtop Sequencer (Illumina, San Diego, CA, USA).…”

“…4A-B, S7). In contrast, some subclusters with TCR Vβ4 (11,12,16,18), Vβ2 (9) and TCR Vβ17 (7,17) dominance expressed a gradient of CD45RA, suggesting the presence of a differentiation gradient (Figs. 4A-B, S7).…”