Notch in Leukemia

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. Strategies to overcome these challenges have emerged from the identification and improved understanding of direct oncogenic Notch target genes. Other strategies have arisen from new insights into the "nuclear context" that selectively directs Notch functions in lymphoid cancers. This nuclear context is created by factors that co-bind ICN at cell-type specific transcriptional regulatory elements. Disrupting the functions of these proteins or inhibiting downstream oncogenic pathways might combat cancer without the intolerable side effects of pan-Notch inhibition.

Combinatorial ETS1-Dependent Control of Oncogenic NOTCH1 Enhancers in T-cell Leukemia

“…S5A and S5B). These results reinforce the well-established roles for Myc and mTOR as major oncogenic effector pathways in Notch1-induced T-ALL (2).…”

“…tors, such as gamma-secretase inhibitors (GSI), for the treatment of human cancers (1,2). Notch receptors (Notch1-4) are activated by ligands in normal cells or additionally by activating mutations in cancer via cleavage by the gammasecretase complex, which releases IntraCellular Notch (ICN).…”

Making sense out of missense mutations: Mechanistic dissection of Notch receptors through structure‐function studies inDrosophila

“…In addition to the involvement in a handful of genetic diseases, somatic mutations in human NOTCH genes as well as alterations in their expression are found in different types of cancer (Aster, Pear, & Blacklow, 2017;McCarter, Wang, & Chiang, 2018;Nowell & Radtke, 2017). Similar to variants linked to rare diseases, in vitro and in vivo studies of cancer-associated NOTCH alleles have led to the classification of some mutations as LOF or GOF (Table 1).…”

The NOTCH Pathway and Its Mutations in Mature B Cell Malignancies

“…In adult tissues, NOTCH-mediated signals are important regulators in the maintenance of self-renewal, contributing for example to myogenesis, neurogenesis and lymphocyte development ( 5 ). Considering its multiple roles in a wide range of processes and tissues, aberrations resulting in gain or loss of NOTCH signaling components and functions have been linked to a variety of disorders including solid cancers ( 6 ) and hematological malignancies ( 7 ), where NOTCH can act either as an oncogene or as a tumor suppressor. In the past decade an increasing number of reports described recurrent gain-of-function mutations of NOTCH1 and NOTCH2 in lymphoproliferative disorders of the B series, including chronic lymphocytic leukemia (CLL), mantle cell (MCL), splenic marginal zone (SMZL), diffuse large B cell (DLBCL) and follicular (FL), Burkitt's (BL) and Hodgkin's (HL) lymphomas.…”