Abstract
Leukemic cells from Chronic Lymphocytic Leukemia (CLL) patients interact with stromal cells of the surrounding microenvironment. Mesenchymal Stromal Cells (MSCs) represent the main population in CLL marrow stroma, which may play a key role for disease support and progression. In this study we evaluated whether MSCs influence in vitro CLL cell survival. MSCs were isolated from the bone marrow of 46 CLL patients and were characterized by flow cytometry analysis. Following co-culture of MSCs and leukemic B cells, we demonstrated that MSCs were able to improve leukemic B cell viability, this latter being differently dependent from the signals coming from MSCs. In addition, we found that the co-culture of MSCs with leukemic B cells induced an increased production of IL-8, CCL4, CCL11, and CXCL10 chemokines.As far as drug resistance is concerned, MSCs counteract the cytotoxic effect of Fludarabine/Cyclophosphamide administration in vivo, whereas they do not protect CLL cells from the apoptosis induced by the kinase inhibitors Bafetinib and Ibrutinib. The evidence that leukemic clones are conditioned by environmental stimuli suggest new putative targets for therapy in CLL patients.
Highlights
The accumulation of CD19+/CD5+/CD23+ B cells is a peculiar hallmark of B cell chronic lymphocytic leukemia (CLL) [1]
Since CD49d plays a critical role in cell adhesion and increases the ability of malignant cells to access to protective niches [35], we addressed the effect of the two kinase inhibitors on its expression on CLL B cell surface, demonstrating that the treatment with Bafetinib and Ibrutinib significantly decreases CD49d expression in co-culture with mesenchymal stromal cells (MSCs) (MFI ratio 0.87±0.12 Bafetinib, p < 0.05, and 0.89±0.05 Ibrutinib, p < 0.01) (Figure 9C)
We demonstrated that MSCs support in vitro leukemic B cell survival more efficiently than the stromal cell line HS-5 [36]
Summary
The accumulation of CD19+/CD5+/CD23+ B cells is a peculiar hallmark of B cell chronic lymphocytic leukemia (CLL) [1]. Despite a remarkable phenotypic and cytological homogeneity, CLL is characterized by extremely variable clinical course related to different prognostic factors including the mutational status of the immunoglobulin heavy-chain variable region (IgVH) [24], expression of CD38 and ZAP70 markers [5, 6] and specific cytogenetic alterations [7,8,9]. CLL B cells reside in close contact with T lymphocytes, stromal cells, mesenchymal stromal cells (MSCs), endothelial cells, follicular dendritic cells and macrophages. Interactions among these components of the microenvironment regulate the trafficking, survival, and proliferation of leukemic B cells in a way that depends both on direct cell-cell contact and/or on the exchange of soluble factors [12]. Once resident in stromal environment, CLL cells are protected from different therapeutic interventions [13,14,15]
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