Notch in Leukemia.

Notch in Leukemia. Adv Exp Med Biol. 2018;1066:355-394 Authors: McCarter AC, Wang Q, Chiang M Abstract Notch is commonly activated in lymphoid malignancies through ligand-independent and ligand-dependent mechanisms. In T-cell acute lymphoblastic leukemia/lymphoma (T-ALL), ligand-independent activation predominates. Negative Regulatory Region (NRR) mutations trigger supraphysiological Notch1 activation by exposing the S2 site to proteolytic cleavage in the absence of ligand. Subsequently, cleavage at the S3 site generates the activated form of Notch, intracellular Notch (ICN). In contrast to T-ALL, in mature lymphoid neoplasms such as chronic lymphocytic leukemia (CLL), the S2 cleavage site is exposed through ligand-receptor interactions. Thus, agents that disrupt ligand-receptor interactions might be useful for treating these malignancies. Notch activation can be enhanced by mutations that delete the C-terminal proline (P), glutamic acid (E), serine (S), and threonine (T) (PEST) domain. These mutations do not activate the Notch pathway per se, but rather impair degradation of ICN. In this chapter, we review the mechanisms of Notch activation and the importance of Notch for the genesis and maintenance of lymphoid malignancies. Unfortunately, targeting the Notch pathway with pan-Notch inhibitors in clinical trials has proven challenging. These clinical trials have encountered dose-limiting on-target toxicities and primary resistance. S...
Source: Advances in Experimental Medicine and Biology - Category: Research Tags: Adv Exp Med Biol Source Type: research