From Graft-Versus-Host Disease to Lymphoma Pathogenesis: Emerging Roles for Stromal Notch Ligands in Hematology

Notch signaling is a highly conserved signaling pathway with multiple functions in health and disease. Notch ligands of the Delta-like and Jagged families interact with Notch1-4 on adjacent cells to trigger proteolytic activation of the Notch receptors, followed by context-dependent transcriptional activation of Notch target genes. In the hematopoietic system, Notch was first identified for its oncogenic role in T cell acute lymphoblastic leukemia (T-ALL). More recently, Notch has been recognized as a recurrent oncogenic pathway in multiple B cell lymphoproliferative disorders, including CLL/SLL, mantle cell lymphoma and marginal zone lymphoma. In parallel, essential functions of Notch signaling have been identified in early T cell development and B cell homeostasis, as well as in regulating T and B cell immune responses in secondary lymphoid organs. We have discovered a conserved pathogenic function of Notch signaling in the control of graft-versus-host disease (GVHD), both in mouse and non-human primate models of hematopoietic cell transplantation. Within days after allogeneic hematopoietic cell transplantation, donor-derived T cells interact with Delta-like Notch ligands expressed by specialized subsets of non-hematopoietic fibroblastic stromal cells in spleen and lymph nodes. In turn, Notch signaling programs alloreactive T cells to become pathogenic effector cells that mediate long-term damage in GVHD target tissues, while suppressing the expansion of regulatory T cells. Emerging evidence suggests the existence of an active crosstalk between T cells, B cells and well-defined specialized immunological stromal niches expressing Notch ligands in secondary lymphoid organs, both in GVHD and in other types of immune responses. Moreover, many B cell lymphomas demonstrate oncogenic Notch activation as a result of gain-of-function mutations that increase the persistence of intracellular Notch after proteolytic cleavage, thus requiring the presence of Notch ligands in the microenvironment to trigger oncogenic Notch signals. New evidence suggests that key Notch ligands in human lymphomas are present in the lymph node microenvironment, and that oncogenic Notch activation can happen even in the absence of mutations in a substantial fraction of lymphoma patients, including the majority of patients with CLL/SLL. In these cases, lymphoma cells appear to interact with microenvironmental Notch ligands in secondary lymphoid organs through unmutated Notch receptors, borrowing from the playbook of normal lymphocytes. Furthermore, the expression of Notch ligands by defined subsets of fibroblastic stromal cells illustrates a new paradigm through which microenvironmental signals can profoundly influence the differentiation and function of adjacent lymphoid cells. We speculate that better understanding the regulation of Notch signaling and fibroblastic stromal cells in secondary lymphoid organs will provide valuable new information with translational potential both in immunobiology and in malignant hematology.