Impact of the reactive microenvironment on the bone marrow involvement of follicular lymphoma

Abstract

Our study showed that different tumour cell growth in the LN and BM may generate different microenvironments, and suggested that the reduced number of cytotoxic T lymphocytes and macrophages in LNs favours BM infiltration of neoplastic cells in FL.

Stromal Cell Contribution to Human Follicular Lymphoma Pathogenesis

“…Even if BM malignant B cells retain their main follicular features, several morphologic, phenotypic, and genetic differences have been reported among tumor cells found within LN and BM. In particular, BM FL cells are characterized by a lower cytological grade and proliferation (Bognar et al, 2005; Rajnai et al, 2012), and exhibit a distinct transcriptomic profile revealing a downregulation of genes involved in cell proliferation and DNA repair (our unpublished data). In addition, despite a common clonal origin, analysis of intraclonal evolution reveals that a significant part of the BM infiltration evolves independently from the tumor clones detected in the LN indicating that BM provides a specific non-lymphoid malignant cell niche (Bognar et al, 2005; Ruminy et al, 2008).…”

“…In addition, despite a common clonal origin, analysis of intraclonal evolution reveals that a significant part of the BM infiltration evolves independently from the tumor clones detected in the LN indicating that BM provides a specific non-lymphoid malignant cell niche (Bognar et al, 2005; Ruminy et al, 2008). Recently, major differences in the cell composition of BM and LN microenvironments have been highlighted (Rajnai et al, 2012; Wahlin et al, 2012) thus paving the way for dedicated studies evaluating the impact of these variations on the behavior of malignant FL cell clones.…”

Impact of B cell/lymphoid stromal cell crosstalk in B-cell physiology and malignancy

“…Predominantly diffuse FLs are usually BCL2-negative and often carry a 1p36 deletion including HVEM but tumor B cells produce very low amounts of LT and mature FDCs are poorly detectable [62]. Another important issue is the level of tumor cell intratumoral their localization with LN versus BM, suggesting that trafficking within various microenvironments could differentially impact FL pathogenesis and clonal selection [76][77][78][79]. In this context, the nature of the specific stromal niches supporting FL proliferative cells versus the FL ancestral common precursor clone responsible for disease relapse and transformation remains to be explored.…”

IL-4/CXCL12 loop is a key regulator of lymphoid stroma function in follicular lymphoma

“…54 In addition, TNF-induced classical nuclear factor kB signaling was already shown to inhibit CXCL12 expression in human umbilical vein endothelial cells 55,56 and in a BM stromal cell line. 52,53 The demonstration that TNF/LT-primed stromal cells became more For personal use only. on June 7, 2019. by guest www.bloodjournal.org From sensitive to IL-4-dependent CXCL12 upregulation, at least in part through an increased expression of STAT6 signaling molecules, deserves further investigation.…”

“…The source of IL-4 within FL BM cells remains unknown, but even if their number is reduced compared with that in the LN niche, programmed cell death protein 1-positive T cells could be detected in FL BM together with an increase of the CD4/CD8 T-cell ratio, and these T FH /T FH -like cells are likely to be involved. 19,53 In addition, IL-4 is also involved in the polarization of FL-infiltrating macrophages. 16 Altogether, these results highlight IL-4 as a key mediator and FL pathogenesis and T FH -stroma crosstalk as a new B-cell extrinsic mechanism that supports FL cell growth (supplemental Figure 11).…”