Role of Notch2 pathway in mature B cell malignancies

Abstract

In recent decades, the Notch pathway has been characterized as a key regulatory signaling of cell-fate decisions evolutionarily conserved in many organisms and different tissues during lifespan. At the same time, many studies suggest a link between alterations of this signaling and tumor genesis or progression. In lymphopoiesis, the Notch pathway plays a fundamental role in the correct differentiation of T and B cells, but its deregulated activity leads to leukemic onset and evolution. Notch and its ligands Delta/Jagged exhibit a pivotal role in the crosstalk between leukemic cells and their environment. This review is focused in particular on Notch2 receptor activity. Members of Notch2 pathway have been reported to be mutated in Chronic Lymphocytic Leukemia (CLL), Splenic Marginal Zone Lymphoma (SMZL) and Nodal Marginal Zone Lymphoma (NMZL). CLL is a B cell malignancy in which leukemic clones establish supportive crosstalk with non-malignant cells of the tumor microenvironment to grow, survive, and resist even the new generation of drugs. SMZL and NMZL are indolent B cell neoplasms distinguished by a distinct pattern of dissemination. In SMZL leukemic cells affect mainly the spleen, bone marrow, and peripheral blood, while NMZL has a leading nodal distribution. Since Notch2 is involved in the commitment of leukemic cells to the marginal zone as a major regulator of B cell physiological differentiation, it is predominantly affected by the molecular lesions found in both SMZL and NMZL. In light of these findings, a better understanding of the Notch receptor family pathogenic role, in particular Notch2, is desirable because it is still incomplete, not only in the physiological development of B lymphocytes but also in leukemia progression and resistance. Several therapeutic strategies capable of interfering with Notch signaling, such as monoclonal antibodies, enzyme or complex inhibitors, are being analyzed. To avoid the unwanted multiple “on target” toxicity encountered during the systemic inhibition of Notch signaling, the study of an appropriate pharmaceutical formulation is a pressing need. This is why, to date, there are still no Notch-targeted therapies approved. An accurate analysis of the Notch pathway could be useful to drive the discovery of new therapeutic targets and the development of more effective therapies.

Progression of Notch signaling regulation of B cells under radiation exposure

“…Bone marrow transplantation of irradiated mice with recombinant ADAM10 revealed that the lymph nodes of the transplanted mice had normal lymphoid structure and the MZB in the cortical area were restored to normal (143). The study demonstrated that Notch-mediated ADAM10 expression restored secondary lymphoid structures and promoted the neogenesis of splenic germinal centers in irradiated mice (84,144). In the spleen, the Notch2 ligand (delta-like 1, DL1) is present at high concentrations in the small splenic veins which is considered a key activator of MZB development (82, 84).…”

“…Indeed, a commitment of HSPCs into the B lineage needs to inhibit the Notch1 signal (163). For instance, when Pro-B cells undergo maturation in the BM, bone marrow stromal cells secrete the cytokine CXCL12, which effectively suppresses the expression of Notch ligands (144). With the Pro-B cells continuing to develop, Notch signaling plays an increasingly important role in subsequent developmental processes (134).…”

“…The differentiation of HSPCs into the B-cell lineage is influenced by distinct Notch ligands and receptors, each playing specific roles (162, 164, 165). For example, Delta-like ligands-1 (Delta 1), as the important Notch2 ligand, induces immature B cells homing to the spleen, where Notch2 activation DLL1-mediated induces immature B2 cells to differentiate into MZB (144). However, the lower densities of Delta 1 in BM is inhibited B lineage development because the induced Notch signaling was not sufficient (162).…”

“…Based on the above studies, we speculate that the depletion effect of radiation on early B cells in BM may be related to the insufficient number of Delta 1 ligands and the silencing of Notch signaling in early B cells. With the continuous differentiation of B cell lineages (134) and the activation of Notch signaling (144,162), subsequent developing B cells become increasingly resistant to radiation, such as plasma cells (30).…”

Exosomes Derived from Human Palatal Mesenchymal Cells Mediate Intercellular Communication During Palatal Fusion by Promoting Oral Epithelial Cell Migration

“…The top 10 proteins which were significantly up-regulated in HEPM-EXO showed a high intercorrelation and were reported to be associated with cell growth, cell communication and signal transduction. [25][26][27][28][29][30][31][32][33][34] HEPM-EXO may rely on some of these proteins to regulate the proliferation and migration of HIOEC. Among these proteins, THBS1 was frequently associated with exosomal regulation of cell migration.…”