The splenic marginal zone shapes the phenotype of leukemia B cells and facilitates their niche-specific retention and survival

Abstract

Microenvironmental regulation in lymphoid tissues is essential for the development of chronic lymphocytic leukemia. We identified cellular and molecular factors provided by the splenic marginal zone (MZ), which alter the migratory and adhesive behavior of leukemic cells. We used the Cxcr5 ¡/¡ Em-Tcl1 leukemia mouse model, in which tumor cells are excluded from B cell follicles and instead accumulate within the MZ. Genes involved in MZ B cell development and genes encoding for adhesion molecules were upregulated in MZ-localized Cxcr5 ¡/¡ Em-Tcl1 cells. Likewise, surface expression of the adhesion and homing molecules, CD49d/VLA-4 and CXCR7, and of NOTCH2 was increased. In vitro, exposing Em-Tcl1 cells or human CLL cells to niche-specific stimuli, like B cell receptor-or Toll-like receptor ligands, caused surface expression of these molecules characteristic for a follicular or MZ-like microenvironment, respectively. In vivo, inhibition of VLA-4-mediated adhesion and CXCL13-mediated follicular homing displaced leukemic cells not only from the follicle, but also from the MZ and reduced leukemia progression. We conclude that MZ-specific factors shape the phenotype of leukemic cells and facilitate their niche-specific retention. This strong microenvironmental influence gains pathogenic significance independent from tumor-specific genetic aberrations.

CXCL13 in Cancer and Other Diseases: Biological Functions, Clinical Significance, and Therapeutic Opportunities

“…Most lymphoid neoplasms are not remediable and eventually relapse after conventional treatment, a phenomenon in which the interaction between malignant lymphocytic cells and resident stromal cells exert a dominant influence [142]. The CXCL13/CXCR5 axis plays pivotal roles in the dissemination and accumulation of malignant lymphocytic cells and in shaping such a tumor-stromal cell microenvironment interaction network [147][148][149]. The expression level of CXCL13 and CXCR5 are dramatically elevated in NHL [150][151][152][153][154].…”

VLA-4 Expression and Activation in B Cell Malignancies: Functional and Clinical Aspects

“…The importance of integrins in mediating the precise localization of B cells within the different splenic compartments is also evident under pathologic conditions. In a murine chronic lymphocytic leukemia (CLL) model, which is driven by the proliferation of malignant B cells in follicles, the inhibition of VLA-4-mediated adhesion and CXCL13-mediated follicular homing displaced leukemic cells not only from the follicle, but also the marginal zone, and reduced leukemia progression [26,27]. Consistently, in B and T cell lymphoma 3D models, VLA-4 was critical for maintaining the adhesion of the lymphoma cells to follicular dendritic cells.…”

Targeting Nuclear NOTCH2 by Gliotoxin Recovers a Tumor-Suppressor NOTCH3 Activity in CLL

“…Under physiological conditions, NOTCH2 signaling might be induced by ligand-expressing surrounding cells in order to protect the proliferative/regenerative reservoir of CD5+ B-cells from NR4A1-mediated activation-induced cell death (AICD) [32,52,60]. This scenario might take place in the marginal zone (MZ) of the spleen [61], where DLL1-expressing bystander cells have been identified [62]. In contrast, apoptotic NOTCH3 signaling might counteract the uncontrolled expansion of CD5+ B-cells in the periphery.…”