Bi‐directional activation between mesenchymal stem cells and CLL B‐cells: implication for CLL disease progression

Abstract

SummaryIt was hypothesized that contact between chronic lymphocytic leukaemia (CLL) B-cells and marrow stromal cells impact both cell types. To test this hypothesis, we utilized a long-term primary culture system from bone biopsies that reliably generates a mesenchymal stem cell (MSC). Co-culture of MSC with CLL B-cells protected the latter from both spontaneous apoptosis and drug-induced apoptosis. The CD38 expression in previously CD38 positive CLL B-cells was up-regulated with MSC co-culture. Upregulation of CD71, CD25, CD69 and CD70 in CLL B-cells was found in the co-culture. CD71 upregulation was more significantly associated with high-risk CLL, implicating CD71 regulation in the microenvironment predicting disease progression. In MSC, rapid ERK and AKT phosphorylation (within 30 min) were detected when CLL B-cells and MSC were separated by transwell; indicating that activation of MSC was mediated by soluble factors. These findings support a bi-directional activation between bone marrow stromal cells and CLL B-cells.

Study of the Quantitative, Functional, Cytogenetic, and Immunoregulatory Properties of Bone Marrow Mesenchymal Stem Cells in Patients with B-Cell Chronic Lymphocytic Leukemia

“…Their morphology and immunophenotype met the established criteria [34], and they were actually indistinguishable from MSCs derived from healthy individuals. These observations are in line with previously reported data [8]. However, in our study, even though MSC cultures could be established and serially replated from all CLL patients, their growth rate over passages was significantly reduced compared with cultures generated from normal individuals.…”

“…Previous reports have shown that CLL cells can also influence MSCs within the BM and that reciprocal interactions eventually activate both cell populations [8,35]. In view of the established bi-directional cross-talk between CLL cells and their microenvironnment, we further investigated whether malignant B-cells might also affect patient-derived MSC survival.…”

“…Given that soluble factors from CLL cells have been shown to activate patient-derived MSCs and induce their proliferation [8,35], we investigated whether CLL cells night also influence MSC apoptosis. In this context, MSCs from (n = 5) CLL patients (n = 5) were cultured for 4 days in the presence or absence of (n = 5) allogeneic patient-derived PBMCs (n = 5).…”

“…Data on the possible role of human BM MSCs in the pathophysiology of CLL are rather limited [8,9,23,24], and the question as to whether patient MSCs differ from their normal counterparts has not been properly answered. In the current study, we investigate whether intrinsic defects might exist within the BM MSC compartment of CLL patients by evaluating the reserves and qualitative characteristics in terms of their proliferative potential, differentiation capacity, and immunoregulatory effects on B-cells and T-cell proliferation, in comparison to normal individuals.…”

“…The dependence of leukemic Bcells on microenvironment signals is further highlighted by the observation that despite their prolonged survival in vivo [2], they undergo spontaneous apoptosis when cultured ex vivo [2]. Interestingly, a variety of stromal cell lines have been shown to enhance the survival of CLL cells in co-culture experiments [3][4][5][6][7][8][9][10] and even protect them from drug-induced apoptosis [9,[11][12][13][14].…”