Oncogenic NOTCH1 control of MYC and PI3K: challenges and opportunities for anti-NOTCH1 therapy in T-cell acute lymphoblastic leukemias and lymphomas

Abstract

The identification of activating mutations in NOTCH1 in the majority of T-cell acute lymphoblastic leukemias and lymphomas (T-ALL) has brought much interest in inhibiting NOTCH1 signaling as therapeutic target in this disease. Small-molecule inhibitors of the gamma-secretase complex, which mediates a critical proteolytic cleavage required for NOTCH1 activation, hold the promise of becoming an effective molecular therapy against relapsed and refractory T-ALL. Recent progress in the elucidation of the transcriptional regulatory networks downstream of oncogenic NOTCH1 has uncovered a central role of NOTCH1 signaling in promoting leukemic cell growth and revealed an intricate circuitry that connects NOTCH1 signaling with MYC and the PI3K-AKT signaling pathway. The identification of the downstream effector pathways controlled by NOTCH1 should pave the way for the rational design of anti-NOTCH1 therapies for the treatment of T-ALL.

Figure 1. Schematic representation of the NOTCH1 signaling pathway and transcriptional networks promoting leukemic cell growth downstream of oncogenic NOTCH1

The two subunits of the mature NOTCH1 receptor are generated by cleavage by a furin protease in the trans-Golgi network soon after translation of NOTCH1 precursor protein. The extracellular subunit responsible for ligand-receptor interaction and the transmembrane subunit responsible for triggering transcription activation interact by their respective heterodimerization (HD) domains. Upon binding to its ligands –Delta-like 1, 3 and 4; Jagged 1 and 2– the transmembrane portion of NOTCH1 is sequentially cleaved by ADAM proteases and then by the γ-secretase complex. This final proteolytic cleavage liberates the active intracellular fragment of NOTCH1 (ICN1), which translocates to the nucleus and activates the expression of target genes by forming a ternary complex with the CSL DNA binding protein and the MAML1 transcriptional coactivator. Small molecule inhibitors of the γ-secretase block NOTCH1 activation by retaining the receptor at the membrane. NOTCH1 promotes cell growth by transcriptional upregulation of genes involved in anabolic pathways and also by transcriptional upregulation of MYC. In addition NOTCH1 induces the expression of HES1, a transcriptional repressor that promotes the upregulation of the PI3K-AKT signaling pathway by transcriptional downregulation of PTEN. Termination of NOTCH1 signaling is mediated by phosphorylated-coupled degradation of the activated receptor in the proteasome via FBXW7-SCF.