Abstract
B-cell chronic lymphocytic leukemia (B-CLL) is one of the most common leukemias among the elderly and, despite many efforts, still stays incurable. Recent studies point to the microenvironment as the critical factor providing leukemic lymphocytes with pro-survival signals. Thus, the neighboring cells appear to be a perfect target for antileukemic therapy. Nurse-like cells (NLCs) largely contribute to CLL microenvironmental support. We developed the CLL lymphocyte/NLC co-culture model for the investigation of microenvironmental interactions. Viability and apoptosis were investigated in CLL lymphocytes treated with dexamethasone (DEX) and chlorambucil (CLB), with and without NLCs’ support. For the first time, the capacity of DEX and CLB to affect NLCs viability was also evaluated. Apoptosis-associated gene expression profiles of leukemic lymphocytes ex vivo and cultured with NLCs were assessed by expression arrays. CLL lymphocytes escaped spontaneous apoptosis for several months when cultured with NLCs. The presence of NLCs significantly reduced apoptosis induced with DEX and CLB (p < 0.001; p = 0.012, respectively), and their protective effect was more evident than the effect of recombinant SDF1. Both DEX and CLB also decreased NLCs viability, but to a lesser extent (mean viability in DEX-treated cultures was 37.79 % in NLCs compared to 29.24 % in lymphocytes). NLCs induced the expression of important anti-apoptotic genes in cultured CLL lymphocytes; median expression of BCL2, SURVIVIN, BCL2A1, and XIAP was significantly higher as compared to ex vivo status. The CLL lymphocyte/NLC co-culture makes up the convenient and close to the natural-state model for studying the relationship between leukemic cells and the microenvironment. Direct cell-to-cell contact with NLCs increases the expression of anti-apoptotic genes in CLL lymphocytes, thus protecting them against induced apoptosis. As the effect of antileukemic drugs is not so apparent in NLCs, the combined therapy targeted at both lymphocytes and the microenvironment should be considered for CLL patients. Simultaneous aiming at the disruption of several different signaling pathways and/or anti-apoptotic proteins may further improve treatment efficiency.Electronic supplementary materialThe online version of this article (doi:10.1007/s10238-013-0268-z) contains supplementary material, which is available to authorized users.
Highlights
B-cell chronic lymphocytic leukemia (B-CLL) is characterized by an accumulation of leukemic lymphocytes in peripheral blood, bone marrow, and lymphatic organs [1]
Apoptosis-associated gene expression profiles of leukemic lymphocytes ex vivo and cultured with nurse-like cells (NLCs) were assessed by expression arrays
We developed the natural model for investigation, which utilizes NLCs grown from peripheral blood of CLL patients, and we compared it with non-cell model of culture supplemented with SDF1, which is considered as the most important NLC-derived chemokine [5]
Summary
B-cell chronic lymphocytic leukemia (B-CLL) is characterized by an accumulation of leukemic lymphocytes in peripheral blood, bone marrow, and lymphatic organs [1]. CLL microenvironment is composed of cells of different origin, including activated T lymphocytes, dendritic cells, stromal cells, endothelial cells, and nurse-like cells (NLCs) [3]. The latter were named after thymic nurse cells, which were found to be necessary for proper maturation and differentiation of thymocytes [4]. CLL nurse-like cells were first described by Burger et al in 2000 [5] They differentiate from peripheral blood monocytes of CLL patients in in vitro cultures, but were found in vivo, within pseudo follicles present in tissue infiltrates [6]. We characterized the gene expression pattern of NLCs and stated that they resemble tumor-associated macrophages (TAMs), which support growth of solid tumor cells and may influence the prognosis [9]
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