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

Clin Cancer Res. 2008 Sep 1;14(17):5314-7. doi: 10.1158/1078-0432.CCR-07-4864.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Drug Delivery Systems
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Leukemia-Lymphoma, Adult T-Cell / genetics*
  • Lymphoma / genetics*
  • Models, Biological
  • Mutation
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Receptor, Notch1 / antagonists & inhibitors
  • Receptor, Notch1 / genetics*
  • Signal Transduction / genetics


  • Proto-Oncogene Proteins c-myc
  • Receptor, Notch1
  • Phosphatidylinositol 3-Kinases