Notch2, a Key Player in Chronic Lymphocytic Leukemia: Mechanism, Microenvironment Interactions, and Therapeutic Implications

<b>Background/Objectives</b>: Tissue niches, such as those in the spleen, bone marrow, and lymph nodes, are crucial for the survival and growth of leukemic cells in chronic lymphocytic leukemia (CLL). <b>Methods</b>: A growing amount of research over the last 20 years has shown how important the tumor microenvironment (TME) is to the pathophysiology, development, and resistance to treatment of CLL. This protective environment, which is made up of various cell types (including stromal and immune cells), extracellular matrix components, and soluble factors, supports CLL cells and encourages their survival, growth, and drug resistance. Even in the absence of mutations, Notch2 is functionally activated in the CLL system, in addition to the well-known Notch1. This occurs because leukemic cells aberrantly express the ligand Jagged1/2, which activates the Notch2 receptor on both stromal and CLL cells themselves. Notch2 activation on stromal cells leads to the triggering of the Wnt/β-catenin program in CLL cells, whereas the activation of Notch2 in CLL cells promotes the expression of Mcl-1, which confers drug tolerance (especially in cases with trisomy 12). <b>Results</b>: In addition to these mechanisms, Notch2 acts as a transcription factor that directly controls the expression of key targets, such as CD23 and Hes1, that are fundamental for B cell proliferation, differentiation, and survival in CLL. <b>Conclusions</b>: All of these circuits represent important therapeutic targets and help explain the cells' dependence on their niche, the formation of proliferation centers, and resistance to modern targeted agents.