Multiple Distinct Sets of Stereotyped Antigen Receptors Indicate a Role for Antigen in Promoting Chronic Lymphocytic Leukemia

Previous studies suggest that the diversity of the expressed variable (V) region repertoire of the immunoglobulin (Ig)H chain of B-CLL cells is restricted. Although limited examples of marked constraint in the primary structure of the H and L chain V regions exist, the possibility that this level of restriction is a general principle in this disease has not been accepted. This report describes five sets of patients, mostly with unmutated or minimally mutated IgV genes, with strikingly similar B cell antigen receptors (BCRs) arising from the use of common H and L chain V region gene segments that share CDR3 structural features such as length, amino acid composition, and unique amino acid residues at recombination junctions. Thus, a much more striking degree of structural restriction of the entire BCR and a much higher frequency of receptor sharing exists among patients than appreciated previously. The data imply that either a significant fraction of B-CLL cells was selected by a limited set of antigenic epitopes at some point in their development and/or that they derive from a distinct B cell subpopulation with limited Ig V region diversity. These shared, stereotyped Ig molecules may be valuable probes for antigen identification and important targets for cross-reactive idiotypic therapy

The CD38 Ectoenzyme Family: Advances in Basic Science and Clinical Practice

One aim of this session given at the Torino CD38 Meeting in June, 2006 was to review the role of CD38 in B-cell Chronic Lymphocytic Leukemia (B-CLL), and its potential as a therapeutic target. CD38(high) B-CLL cases show activated phenotypic features as compared with CD38(low) cases. Moreover, a greater percentage of Ki-67 and telomerase activity is documented among CD38(high) cases. Also, CD38 is not merely a negative prognostic marker in B-CLL, but also a key element in the pathogenetic network underlying the disease. A large series of B-CLL cases investigating the CD38 expression on bone marrow B-cells identified CD38 value <10% as the cut-off predicting a longer time to treatment. However, neither CD38 nor ZAP-70 by themselves or in combination were able to anticipate IgVH mutational status. Transferring these findings into clinical ground, 3 groups of B-CLL cases were identified with significantly different clinical courses: i.e., low-risk (no negative prognostic factor), intermediate-risk (1 negative prognostic factor) and high-risk (2-3 negative prognostic factors) patients. Altogether these results suggest that: i) CD38-expressing cells present not only an activation status, but also a different stage differentiation with a more repeated turnover; ii) CD38 contributes to controlling a signaling pathway that confers to B-CLL cells an increased proliferative potential, enhancing aggressiveness of this variant; iii) different CD38 cut off values should be considered for peripheral blood and bone marrow; iv) CD38 seems to independently contribute to prognostic stratification of B-CLL

Rewiring of sIgM-mediated intracellular signaling through the CD180 toll-like receptor

Chronic Lymphocytic Leukaemia (CLL) development and progression is thought to be driven by unknown antigens/autoantigens through the B cell receptor (BCR), and environmental signals for survival and expansion including Toll-like receptor (TLR) ligands. CD180/RP105, a membrane-associated orphan receptor of the TLR family, induces normal B cell activation and proliferation and is expressed by approximately 60% of CLL samples. Half of these respond to ligation with anti-CD180 antibody by increased activation/phosphorylation of protein kinases associated with BCR signaling. Hence CLL cells expressing both CD180 and the BCR could receive signals via both receptors. Here we investigated cross-talk between BCR and CD180-mediated signaling on CLL cell survival and apoptosis. Our data indicate that ligation of CD180 on responsive CLL cells leads to activation of either pro-survival BTK/PI3K/AKT-mediated, or pro-apoptotic p38MAPK-mediated signaling pathways, whilst sIgM ligation predominantly engages the BTK/PI3K/AKT pathway. Furthermore, pre-treatment of CLL cells with anti-CD180 redirects IgM-mediated signaling from the pro-survival BTK/PI3K/AKT towards the pro-apoptotic p38MAPK pathway. Thus pre-engaging CD180 could prevent further pro-survival signaling mediated via the BCR and, instead, induce CLL cell apoptosis, opening the door to therapeutic profiling and new strategies for the treatment of a substantial cohort of CLL patients

In vivo intraclonal and interclonal kinetic heterogeneity in B-cell chronic lymphocytic leukemia

Clonal evolution and outgrowth of cellular variants with additional chromosomal abnormalities are major causes of disease progression in chronic lymphocytic leukemia (CLL). Because new DNA lesions occur during S phase, proliferating cells are at the core of this problem. In this study, we used in vivo deuterium (2H) labeling of CLL cells to better understand the phenotype of proliferating cells in 13 leukemic clones. In each case, there was heterogeneity in cellular proliferation, with a higher fraction of newly produced CD38+ cells compared with CD38− counterparts. On average, there were 2-fold higher percentages of newly born cells in the CD38+ fraction than in CD38− cells; when analyzed on an individual patient basis, CD38+ 2H-labeled cells ranged from 6.6% to 73%. Based on distinct kinetic patterns, interclonal heterogeneity was also observed. Specifically, 4 patients exhibited a delayed appearance of newly produced CD38+ cells in the blood, higher leukemic cell CXC chemokine receptor 4 (CXCR4) levels, and increased risk for lymphoid organ infiltration and poor outcome. Our data refine the proliferative compartment in CLL based on CD38 expression and suggest a relationship between in vivo kinetics, expression of a protein involved in CLL cell retention and trafficking to solid tissues, and clinical outcome