Challenges and Opportunities for Effective NOTCH1 Targeting in T-ALL.

The NOTCH pathway is an evolutionarily conserved mechanism responsible for the direct transduction of developmental signals at the cell surface into changes in gene expression in the nucleus. In the hematopoietic system, the NOTCH1 signaling pathway is required for the commitment of multipotent hematopoietic progenitors to the T cell lineage and, later on, to support cell growth, proliferation, and survival at multiple stages of thymocyte development. These physiological functions are disrupted by activating mutations in the NOTCH1 gene in over 50% of T-cell acute lymphoblastic leukemias (T-ALL). NOTCH1 mutations result in ligand-independent activation or increased protein stability, leading to deregulated cell proliferation and survival in T cell progenitors and T cell transformation. Importantly, small molecule inhibitors of the γ-secretase complex (GSIs) effectively abrogate NOTCH1 signaling, making NOTCH1 a promising therapeutic target for the treatment of T-ALL. However, the clinical development of GSIs has been hampered by our incomplete understanding of the effector pathways controlled by NOTCH1, the lack of clinical responses to GSI therapy, and the development of gastrointestinal toxicity secondary to inhibition of NOTCH signaling in the gut. Recent progress in the identification of the transcriptional regulatory networks that control T cell transformation downstream of NOTCH1 has shown a close relationship between oncogenic NOTCH1 signaling and the transcriptional control of cell growth and metabolism. Thus, NOTCH1 directly controls multiple genes involved in anabolic pathways and further promotes cell growth via direct transcriptional upregulation of MYC and indirect upregulation of the PI3K-AKT signaling pathway via HES1-mediated downregulation of PTEN. Moreover, oncogenic NOTCH1 signaling promotes activation of the NFKB pathway and interacts with the function of p53. Although the specific mechanisms mediating some of these interactions have not been elucidated yet, these results suggest that combinations of GSIs with chemotherapy or drugs targeting the PI3K-AKT and NFKB pathways may have a synergistic effect in the treatment of T-ALL. Moreover, inhibitory antibodies capable of selectively blocking the activation of NOTCH1 and inhibitors of the nuclear transcriptional complex mediating the activation of NOTCH1 target genes offer alternative approaches for the inhibition of oncogenic NOTCH1 signaling. Each of these strategies offers the promise to induce potent antileukemic effects and/or to ameliorate the gastrointestinal toxicity associated with systemic inhibition of NOTCH signaling and may ultimately lead to the development of rationally-designed and highly effective anti-NOTCH1 therapies for T-ALL.