Common stromal motifs between primary and secondary lymphoid tissues control genesis and progression of B-cell lymphomas

Progetto: Research project

Description

BackgroundAlong B-cell lymphomagenesis, lymphoid clone-intrinsic events may not be sufficient for full-blown transformation andoutgrowth of the lymphomatous clone. Microenvironment stromal signals may provide a crucial complement to such malignanttransformation. Mechanisms necessary for central B cell lymphopoiesis or for B-cell expansion upon immune challnges can bediverted toward malignancy.HypothesisIn this project we explore the existence of common stromal programs regulating specific microenvironments of the bonemarrow and secondary lymphoid organs deputed to the nurturing of B lymphoid precursors and to functional plasticity ofimmature B-cells, within the bone marrow (BM) osteoblastic niche and the secondary lymphoid organ (SLO) germinal centre,respectively. We hypothesized that stroma-dependent pathways active during early B-cell development in the BM and duringAg-triggered B-cell expansion in the SLO follicle, can be mimicked during early B-cell lymphomagenesis and in lymphomatouscolonization of the BM.AimsThe project is structured in two AIMS. In the first AIM we will test the hypothesis that the stromal composition of BM and SLOlymphopoietic niches, specifically: the BM endosteal/osteoblastic niche and the SLO follicle GC, may share common elementsrelevant to B-NHL behavior, considering that B-NHL of GC or of extra-follicular derivation in SLO display a different affinityfor the endosteal or vascular niches when reaching the BM. In the second AIM we will perform functional experiments todemonstrate whether the common mesenchymal programs within BM and SLO candidated by the analyses of AIM1 are relevantfor the development and nurturing of normal and malignant B-cells in both microenvironments.Experimental DesignIn AIM-1 innovative in situ software-aided quantitative immuno-localization analyses and gene expression profiling with genesetenrichment analyses will be used the identity the shared stromal programs and investigate their modulation along differenttypes and phases of peripheral B-cell lymphomagenesis and BM metastatic colonization. In AIM-2, in vivo experimental modelsof spontaneous lymphomagenesis in p53-/- transgenic mice also deficient for key stromal factors that are known to regulate themesenchymal composition of BM and SLO, namely SPARC and Osteopontin, will be developed to test the reqirement for intactcommon stromal features by B-cell lymphomas arising in SLO and eventually colonizing the BM. Within the project, specificemphasis will be given to mesenchymal stem-cell populations as primary players of stromal remodeling in BM and SLOfunctional to B-cell clones. In particular, the mechanisms potentially regulating B-cell clone-induced modifications of themesenchymal precursors towards induction of specialized phenotypes, such as follicular dendritic cells, will be explored in vitrothrough specific co-culture experiments.Expected ResultsOverall, the accomplishment of this project will likely produce an in depth characterization of the key mechanisms acting ascommon mesenchymal regulators of lymphopoietic homeostasis in the BM and SLO and highlight those crucial to theengendering of a permissive stromal microenvironment for B-cell lymphoma establishment and progression. The identificationof such common regulators might also prompt investigation of novel stroma-targeted treatments.

Layman's description

AimsThe project is structured in two AIMS. In the first AIM we will test the hypothesis that the stromal composition of BM and SLOlymphopoietic niches, specifically: the BM endosteal/osteoblastic niche and the SLO follicle GC, may share common elementsrelevant to B-NHL behavior, considering that B-NHL of GC or of extra-follicular derivation in SLO display a different affinityfor the endosteal or vascular niches when reaching the BM. In the second AIM we will perform functional experiments todemonstrate whether the common mesenchymal programs within BM and SLO candidated by the analyses of AIM1 are relevantfor the development and nurturing of normal and malignant B-cells in both microenvironments.Experimental DesignIn AIM-1 innovative in situ software-aided quantitative immuno-localization analyses and gene expression profiling with genesetenrichment analyses will be used the identity the shared stromal programs and investigate their modulation along differenttypes and phases of peripheral B-cell lymphomagenesis and BM metastatic colonization. In AIM-2, in vivo experimental modelsof spontaneous lymphomagenesis in p53-/- transgenic mice also deficient for key stromal factors that are known to regulate themesenchymal composition of BM and SLO, namely SPARC and Osteopontin, will be developed to test the reqirement for intactcommon stromal features by B-cell lymphomas arising in SLO and eventually colonizing the BM. Within the project, specificemphasis will be given to mesenchymal stem-cell populations as primary players of stromal remodeling in BM and SLOfunctional to B-cell clones. In particular, the mechanisms potentially regulating B-cell clone-induced modifications of themesenchymal precursors towards induction of specialized phenotypes, such as follicular dendritic cells, will be explored in vitrothrough specific co-culture experiments.

Key findings

Salute
StatoFinito
Data di inizio/fine effettiva1/1/1512/31/17