Bone Marrow Lymphoid Niche Adaptation to Mature B Cell Neoplasms

Abstract

B-cell non-Hodgkin lymphoma (B-NHL) evolution and treatment are complicated by a high prevalence of relapses primarily due to the ability of malignant B cells to interact with tumor-supportive lymph node (LN) and bone marrow (BM) microenvironments. In particular, progressive alterations of BM stromal cells sustain the survival, proliferation, and drug resistance of tumor B cells during diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and chronic lymphocytic leukemia (CLL). The current review describes how the crosstalk between BM stromal cells and lymphoma tumor cells triggers the establishment of the tumor supportive niche. DLBCL, FL, and CLL display distinct patterns of BM involvement, but in each case tumor-infiltrating stromal cells, corresponding to cancer-associated fibroblasts, exhibit specific phenotypic and functional features promoting the recruitment, adhesion, and survival of tumor cells. Tumor cell-derived extracellular vesicles have been recently proposed as playing a central role in triggering initial induction of tumor-supportive niches, notably within the BM. Finally, the disruption of the BM stroma reprogramming emerges as a promising therapeutic option in B-cell lymphomas. Targeting the crosstalk between BM stromal cells and malignant B cells, either through the inhibition of stroma-derived B-cell growth factors or through the mobilization of clonal B cells outside their supportive BM niche, should in particular be further evaluated as a way to avoid relapses by abrogating resistance niches.

Stromal cells support the survival of human primary chronic lymphocytic leukemia (CLL) cells through Lyn-driven extracellular vesicles

“…Additionally, they are influenced by the tumor cells themselves to develop an improved supportive phenotype, the so-called CAF phenotype. The survival signaling is mainly facilitated by cell contact, with multiple interactions, including adhesion molecules, receptorligand interactions and soluble growth factors (7). EVs also contribute to the mutual activation.…”

“…Except for the 96 h-time point, the reduction was statistically significant, i.e., P = 0.0436, P = 0.0069, P = 0.0379, and P = 0.1438 after 24, 48, 72, and 96 h, respectively. To show the overall influence of the HS-5 variants on CLL cell survival we determined the AUC as follows: wt HS-5 cells (7,488), scr control (6,912), CD248-deficient HS-5 cells (5,472), and the CLL monoculture (4,668) confirming that CD248 from HS-5 cells contributes at least in part to the survival support of primary CLL cells. In contrast to Lyn (Figure 4), CD248 showed no significant influence on the particle release (Figure 7C), the filopodia count (Figure 7D) and the filopodia length (Figure 7E).…”

“…The infiltration of stromal cells in the TME of CLL tissue is an essential contribution to the survival of primary CLL cells. CLL cells are able to differentiate stromal cells to CAFs, which in turn directly support CLL cells and cause angiogenesis by stimulation of endothelial cells (7). Stromal cells also release fibrogenic factors, such as fibroblast growth factor (FGF), transforming growth factor beta1 (TGFB1), collagen, and lysyl oxidase (LOX), the latter enzyme increases the stiffness of the matrix by crosslinking collagen fibers and elastin (8).…”

Advances in the multi-omics landscape of follicular lymphoma

“…Together, these results indicate that the heterogeneity of microenvironment cells lies far beyond our understanding and remains to be further functionally explored. The cellular components of TME in the bone marrow are very different from those in lymph nodes (reviewed in separate articles 108 , 109 ). FL subclones with different gene expression profiles are detected between bone marrow and lymph nodes 109 , 110 .…”

A bone-based 3D scaffold as an in-vitro model of microenvironment–DLBCL lymphoma cell interaction

“…The presence of bone marrow (BM) involvement has been consistently identified among negative prognostic factors ( 3 ). In this regard, the interaction of tumor cells with the tumor microenvironment (TME) is a key determinant of intratumor heterogeneity in DLBCL, potentially affecting prognostically relevant features ( 4 , 5 ).…”