The chronic lymphocytic leukemia (CLL) immunoglobulin repertoire is biased and characterized by the existence of subsets of cases with closely homologous ("stereotyped") complementarity-determining region 3 (CDR3) sequences. In the present series, 201 (21.9%) of 916 patients with CLL expressed IGHV genes that belonged to 1 of 48 different subsets of sequences with stereotyped heavy chain (H) CDR3. Twenty-six subsets comprised 3 or more sequences and were considered "confirmed." The remaining subsets comprised pairs of sequences and were considered "potential"; public database CLL sequences were found to be members of 9 of 22 "potential" subsets, thereby allowing us to consider them also "confirmed.

This study establishes that allogeneic BCT results in quicker hematologic recovery but is associated with a higher occurrence of chronic graft-versus-host disease.

Chronic lymphocytic leukemia (CLL) immunoglobulin repertoire is biased. Furthermore, subsets of closely homologous (“stereotyped”) complementarity-determining region 3 (CDR3) sequences were recently described in CLL patients. In the present study, we evaluated the frequency and characteristics of these homologous subsets in a cohort of 916 CLL patients. We report that 201 cases (21.9%) expressed IGHV genes which belonged to one of 48 different subsets of sequences with stereotyped heavy chain (H) CDR3, of which only ten have been reported previously. Within each stereotyped HCDR3 subset, the IG sequences might show the usage of identical or different IGHV genes. In the latter case, the IGHV genes most often belonged to the same IGHV subgroup or clan or carried homologous HCDR1. Each subset included up to 20 cases. A similar proportion of HCDR3 restriction (80/462 cases; 17.3%) was found among public-database CLL sequences; comparison to 6430 non-CLL public database IGHV-D-J sequences showed that this is a “CLL-related” feature. In our series, the chance of belonging to a subset was even (p<0.001) higher for unmutated IGHV sequences (35%); furthermore, it exceeded 30% in cases using selected IGHV genes (e.g., IGHV3-21/1-69/1-2/1-3/4-39/3-48). Database and literature searches revealed that 64/916 CLL cases belonging to seven different subsets displayed HCDR3 homology with various autoantibodies, including rheumatoid factors and anti-cardiolipin antibodies. In our series, CLL cases with selected stereotyped IGs were also found to share unique biological and clinical features. In particular, cases expressing stereotyped IGHV4-34/IGKV2-30 B cell receptors (BCRs) were of significantly younger age and followed a strikingly indolent disease, whereas those expressing, IGHV3-21/IGLV3-21 BCRs experienced an aggressive disease, regardless of IGHV mutation status. Furthermore, among patients expressing unmutated IGHV1-69 genes, we identified a subset (IGHV1-69/IGHD3-10/IGHJ6) with higher overall survival (OS) compared to another subset (IGHV1-69/IGHD2-2/IGHJ6) with significantly shorter OS (log Rank test=0.05). In conclusion, the unique, “CLL-biased” molecular features of stereotyped HCDR3 sequences suggest a role for antigen not only in driving the cell of origin but also in determining the clinical features and outcome for at least some CLL patients. Considering the clinical-biological associations with certain subsets, it is conceivable that future therapeutic decisions should be based not only on mutational status of IGHV genes but also on individual HCDR3 characteristics.

EBV-negative PTLD may be a late serious complication of organ transplantation. Half the tumors observed after kidney transplantation in our center were not associated with EBV and emerged after more than 5 years, which suggests the number of EBV-negative PTLDs in organ recipients might increase with time.

Appropriate cancer care requires a thorough understanding of the natural history of the disease, including the cell of origin, the pattern of clonal evolution, and the functional consequences of the mutations. Using deep sequencing of flow-sorted cell populations from patients with chronic lymphocytic leukemia (CLL), we established the presence of acquired mutations in multipotent hematopoietic progenitors. Mutations affected known lymphoid oncogenes, including BRAF, NOTCH1, and SF3B1. NFKBIE and EGR2 mutations were observed at unexpectedly high frequencies, 10.7% and 8.3% of 168 advanced-stage patients, respectively. EGR2 mutations were associated with a shorter time to treatment and poor overall survival. Analyses of BRAF and EGR2 mutations suggest that they result in deregulation of B-cell receptor (BCR) intracellular signaling. Our data propose disruption of hematopoietic and early B-cell differentiation through the deregulation of pre-BCR signaling as a phenotypic outcome of CLL mutations and show that CLL develops from a pre-leukemic phase. SIGNIFICANCE:The origin and pathogenic mechanisms of CLL are not fully understood. The current work indicates that CLL develops from pre-leukemic multipotent hematopoietic progenitors carrying somatic mutations. It advocates for abnormalities in early B-cell differentiation as a phenotypic convergence of the diverse acquired mutations observed in CLL. Cancer Discov; 4(9); 1088-1101