Over 20% of patients with chronic lymphocytic leukemia carry stereotyped receptors: pathogenetic implications and clinical correlations

Abstract

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.

Next generation RNA‐sequencing in prognostic subsets of chronic lymphocytic leukemia

“…All patients were diagnosed according to recently revised criteria and displayed the typical CLL immunophenotype (CD5 1 /CD19 1 /CD23 1 ) [21]. Subsets were defined according to previously described criteria [3,22] (Supporting Information Table 8S). All samples were collected at follow-up (median 82 and range 6-167 months after diagnosis) and contained 90% (average 93%) tumor cells.…”

“…Enoxaparin is a low-molecular weight heparin (LMWH) that effectively reduces the risk of VTE in both medically ill and surgical patients [3,4]. However, patients with extreme obesity (i.e., BMI >40 kg/m 2 ), a major risk factor for VTE [1,5,6], were under-represented in VTE prophylaxis trials of enoxaparin (40 mg once daily (QDay)) in medically ill patients [3,7].…”

“…Moreover, CLL is characterized by multiple subsets carrying quasi-identical or ''stereotyped'' B-cell receptors which imply a role for antigen selection in leukemogenesis [3]. Recently, certain subsets have also been shown to share clinico-biological features [3,4]; for instance, subset #1 patients, which uniformly express unmutated IGHV1/5/7 together with IGKV1(D)-39 genes and a stereotyped heavy complementarity determining region 3 (VH CDR3) of 13-14 amino acids, have a significantly inferior outcome compared to patients expressing the same IGHV genes but without stereotypy [3,5]. In contrast, subset #4 patients (IGHV4-34/IGKV2-30 usage and VH CDR3 of 20 amino acids), have a low median age at diagnosis, express surface IgG and have an indolent disease [3].…”

“…Recently, certain subsets have also been shown to share clinico-biological features [3,4]; for instance, subset #1 patients, which uniformly express unmutated IGHV1/5/7 together with IGKV1(D)-39 genes and a stereotyped heavy complementarity determining region 3 (VH CDR3) of 13-14 amino acids, have a significantly inferior outcome compared to patients expressing the same IGHV genes but without stereotypy [3,5]. In contrast, subset #4 patients (IGHV4-34/IGKV2-30 usage and VH CDR3 of 20 amino acids), have a low median age at diagnosis, express surface IgG and have an indolent disease [3]. Furthermore, we have previously shown that stereotyped subsets can carry a different spectrum of genomic alterations as well as diverse gene expression profiles [6,7].…”

“…The mutation status of the immunoglobulin heavy variable (IGHV) genes divides CLL into two clinically relevant subgroups, where unmutated IGHV genes ( 40% of patients) are associated with a considerably worse prognosis compared to mutated IGHV genes [1,2]. Moreover, CLL is characterized by multiple subsets carrying quasi-identical or ''stereotyped'' B-cell receptors which imply a role for antigen selection in leukemogenesis [3]. Recently, certain subsets have also been shown to share clinico-biological features [3,4]; for instance, subset #1 patients, which uniformly express unmutated IGHV1/5/7 together with IGKV1(D)-39 genes and a stereotyped heavy complementarity determining region 3 (VH CDR3) of 13-14 amino acids, have a significantly inferior outcome compared to patients expressing the same IGHV genes but without stereotypy [3,5].…”