Protein Kinase C-β-Dependent Activation of NF-κB in Stromal Cells Is Indispensable for the Survival of Chronic Lymphocytic Leukemia B Cells In Vivo

Abstract

SummaryTumor cell survival critically depends on heterotypic communication with benign cells in the microenvironment. Here, we describe a survival signaling pathway activated in stromal cells by contact to B cells from patients with chronic lymphocytic leukemia (CLL). The expression of protein kinase C (PKC)-βII and the subsequent activation of NF-κB in bone marrow stromal cells are prerequisites to support the survival of malignant B cells. PKC-β knockout mice are insusceptible to CLL transplantations, underscoring the in vivo significance of the PKC-βII-NF-κB signaling pathway in the tumor microenvironment. Upregulated stromal PKC-βII in biopsies from patients with CLL, acute lymphoblastic leukemia, and mantle cell lymphoma suggests that this pathway may commonly be activated in a variety of hematological malignancies.

Exosomes released by chronic lymphocytic leukemia cells induce the transition of stromal cells into cancer-associated fibroblasts

“…The latter was defined by the formation of stress fibers and a-smooth muscle actin (a-SMA) accumulation ( Figure 6C), a characteristic of activated stroma and CAFs. 22,36 A similar formation of stress fibers was observed in stromal cells and fibroblasts, together with an increased expression of RhoA, a GTP-binding protein necessary for this actin skeleton remodeling (supplemental Figure 6A-C) when cells were incubated with exosomes. Exosomes produced by healthy donor B cells did not induce a-SMA expression ( Figure 6C).…”

“…Because CAF-mediated functions are strictly dependent on NF-kB signaling, we evaluated our transcriptome data set for changes in genes associated with CAF phenotype and performed unsupervised hierarchical clustering. A previously described, CAF gene expression signature 22,35 was observed in BM-MSCs treated with CLL exosomes ( Figure 5B). Unsupervised clustering also identified expression changes in gene signatures related to cell growth, survival, movement, and inflammation in BM-MSCs (supplemental Figure 4A).…”

“…15 Exosomes released by acute myeloid leukemia cells affect the proliferation and migration of bone marrow (BM) stromal cells, 16,17 multiple myeloma exosomes enhance angiogenesis, 18 melanoma-derived exosomes reprogram the BM niche to support metastasis, 19 and miR-105 conveyed by breast cancer-derived exosomes destroys the endothelial barrier to promote metastasis. 20 In CLL, circulating exosomes may affect mesenchymal stem cells (MSCs) and endothelial cells (ECs), which are both present in the BM and lymphatic tissues, where they support leukemic cell survival 21,22 and are possible sources of cancerassociated fibroblast (CAF). 23,24 Here, we report a comprehensive analysis of exosomes derived from CLL cells and their role in the dialogue between leukemic cells and their microenvironment.…”

Generation of a poor prognostic chronic lymphocytic leukemia-like disease model: PKC subversion induces up-regulation of PKC II expression in B lymphocytes

“…50 Targeting PKC, and in particular PKCb, is especially pertinent given the recent findings of Lutzny et al, who demonstrated that PKCbII expression in bone marrow stromal cells is essential for the survival and development of CLL cells. 51 Therefore, inhibition of PKCb may modify the tumor microenvironment, which has been established to play a critical role in supporting CLL survival, proliferation and chemoresistance. 52 Collectively, our results demonstrate the potential for therapeutic agents targeting PI3K/PKCb−related signaling pathways, and highlight the translational applicability of the PKCa-KR mouse model as a pre-clinical model for the development of poor prognostic CLL.…”

Extracellular vesicles released from chronic lymphocytic leukemia cells exhibit a disease relevant mRNA signature and transfer mRNA to bystander cells

“…This data set complements studies on proteins and microRNA transferred by CLL-vesicles 5-7 and might finally contribute to a detailed understanding of tumor-related aberrant gene expression in stromal cells, known to be crucial for CLL survival. 15 Interestingly, the disease-related mRNA signature was pronounced upon TLR engagement used as a milieu-mimic. Moreover, the transfer of enriched mRNA to monocytes and fibroblasts was demonstrated and the otherwise strictly lymphocyte-restricted protein expression of TCL1A was detectable in fibroblasts upon vesicle uptake.…”