The role of NOTCH1 signaling in T-ALL

Abstract

The identification of activating mutations in NOTCH1 in over 50% of T-cell acute lymphoblastic leukemias (T-ALL) has generated major interest in the elucidation of the mechanisms of transformation downstream of oncogenic NOTCH and in the targeting of the NOTCH signaling pathway in this disease. Small molecule gamma-secretase inhibitors (GSIs) block NOTCH1 signaling in T-ALL lymphoblasts, yet the clinical development of GSIs has been held back by the development of gastrointestinal toxicity and their weak antileukemic effects against human T-ALL. However, new therapeutic strategies aiming to optimize the use of anti-NOTCH1 therapies for T-ALL, including combination therapies with molecularly targeted drugs and glucocorticoids, have started to emerge as a result of improved understanding of the molecular mechanisms that mediate the effects of GSIs in leukemic cells and the intestinal epithelium. This review focuses on the molecular basis of NOTCH1-induced transformation, the mechanisms of action of oncogenic NOTCH1 and clinical significance of NOTCH1 mutations in T-ALL.

Figure 1. The NOTCH1 signaling pathway

Interaction of the NOTCH1 receptor with Delta-like and Jagged ligands expressed on the surface of a neighbor cells triggers the proteolytic cleavage of the receptor, first by an ADAM metalloprotease (S2 cleavage) and subsequently by the γ-secretase complex (S3 cleavage), which releases the intracellular domains of NOTCH1 (ICN1) from the membrane. ICN1 translocates to the nucleus and interacts with DNA via the RBPJ/CSL DNA binding protein and recruits the MAML1 coactivator to activate the expression of NOTCH1 target genes.

Figure 2. Oncogenic forms of NOTCH1 in T-ALL

Aberrant activation of NOTCH signaling can be triggered by mutations in the NOTCH1 gene. (a) Structure of the wild type NOTCH1 receptor. Functional domains of NOTCH1 are annotated. EGF-like: EGF-like repeats. HD: heterodimerization domain. LNR: LNR repeats. RAM: RAM domain. Ankyrin: ankyrin repeats. TAD: transactivation domain. PEST: PEST domain. S2: metalloprotease cleavage site (green). S3: γ-secretase cleavage site (yellow). (b) Translocations of NOTCH1 to the TCR loci induce the expression of truncated forms of NOTCH1. (c) NOTCH1 HD class1 mutations destabilize the structure of the HD-LNR repeats responsible for maintaining the receptor in resting configuration. (d) The NOTCH1 H1545P mutation impairs the protection of the S2 cleavage site by the HD-LNR repeat complex. (e) NOTCH1 HD class2 mutations displace the S2 metalloprotease cleavage site outside the HD-LNR complex. (f) NOTCH1 JME alleles increase the separation of the HD-LNR repeat complex from the membrane. (g) NOTCH1 ΔPEST mutations delete the C-terminal part of the receptor and impairing the degradation of activated NOTCH1 in the nucleus. Sequences altered by the different NOTCH1 mutations are highlighted in red.

Figure 3. Prevalence of activating mutations in NOTCH1 in T-ALL

NOTCH1 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 alleles are found in 3% of all T-ALLs. In total about 15% of T-ALL cases harbor deletions or mutations in FBXW7, which impair the degradation of activated NOTCH1 in the nucleus and are functionally related to NOTCH1 ΔPEST mutant alleles.