Therapeutic targeting of NOTCH1 signaling in T-cell acute lymphoblastic leukemia

Abstract

The recent identification of activating mutations in NOTCH1 in the majority of T-cell acute lymphoblastic leukemias (T-ALLs) has brought major interest toward targeting the NOTCH signaling pathway in this disease. Small-molecule gamma-secretase inhibitors (GSIs), which block a critical proteolytic step required for NOTCH1 activation, can effectively block the activity of NOTCH1 mutant alleles. However, the clinical development of GSIs has been hampered by their low cytotoxicity against human T-ALL and the development of significant gastrointestinal toxicity derived from the inhibition of NOTCH signaling in the gut. Improved understanding of the oncogenic mechanisms of NOTCH1 and the effects of NOTCH inhibition in leukemic cells and the intestinal epithelium are required for the design of effective anti-NOTCH1 therapies in T-ALL.

FIGURE 1. THE NOTCH1 SIGNALING PATHWAY

The NOTCH1 receptor is activated upon interaction with Delta-like and Jagged ligands expressed the surface of a neighbor cell. This ligand-receptor interaction results in a conformational change in the LNR repeats of NOTCH1 and the dissociation of the two subunits of the HD domain, which is followed by cleavage of the receptor, first by an ADAM metalloprotease (S2 cleavage) and subsequently by the γ-secretase complex (S3 cleavage). This latter proteolytic processing releases the intracellular domains of NOTCH1 (ICN1) from the membrane. ICN1 interacts with DNA via the CSL DNA binding protein and recruits the MAML1 coactivator to activate the expression of NOTCH1 target genes.

FIGURE 2. STRUCTURE AND MECHANISM OF ACTION OF ONCOGENIC FORMS OF NOTCH1

NOTCH1 mutations located in the HD domain of the receptor increase ICN1 levels by inducing ligand independent NOTCH1 signaling. Truncations of the PEST domain of NOTCH1 (ΔPEST mutations) result in accumulation of ICN1 in the nucleus by impairing the degradation of activated NOTCH1.

FIGURE 3. PREVALENCE OF ACTIVATING MUTATIONS IN NOTCH1 IN T-ALL

HD and ΔPEST mutations account for the majority of activating mutations in NOTCH1 in T-ALL. An additional 1% of patients harbor translocations involving NOTCH1 and the TCR loci. NOTCH1 JME mutations related to HD mutant alleles are found in 3% of all T-ALLs. Finally about 15% of T-ALL cases harbor deletions or mutations in FBXW7, which are functionally related to NOTCH1 ΔPEST mutant alleles.