Notch in Leukemia

Advances in Experimental Medicine and Biology
Anna C McCarterMark Chiang

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 chall...Continue Reading

Citations

Jan 31, 2020·Journal of Cardiovascular Translational Research·Wenbin LuQiming Dai
Dec 12, 2018·Frontiers in Oncology·Francesca ArrugaSilvia Deaglio
Sep 15, 2020·Blood Cancer Discovery·Anna C McCarterMark Y Chiang
Sep 23, 2020·The Journal of Clinical Investigation·Ke JinCornelia M Weyand
May 1, 2021·Cancers·Benedetto Daniele GiaimoTilman Borggrefe

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