Inhibition of Notch Signaling Enhances Chemosensitivity in B-cell Precursor Acute Lymphoblastic Leukemia

Cancer Res. 2019 Feb 1;79(3):639-649. doi: 10.1158/0008-5472.CAN-18-1617. Epub 2018 Dec 18.


Notch3 and Notch4 support survival of primary B-cell acute lymphoblastic leukemia (B-ALL) cells, suggesting a role for Notch signaling in drug response. Here we used in vitro, in silico, and in vivo mouse xenograft model-based approaches to define the role of the Notch pathway in B-ALL chemosensitivity. We observed significant Notch receptor and ligand expression in B-ALL primary cells and cell lines. Primary leukemia cells from high-risk patients overexpressed Notch3, Notch4, and Jagged2 while displaying a reduction in expression levels of Notch1-4 following chemotherapy. We then analyzed in vitro cell survival of B-ALL cells treated with conventional chemotherapeutic agents alone or in combination with Notch signaling inhibitors. Gamma-secretase inhibitors (GSI) and anti-Notch4 were all capable of potentiating drug-induced cell death in B-ALL cells by upregulating intracellular levels of reactive oxygen species, which in turn modulated mTOR, NF-κB, and ERK expression. In NOG-mouse-based xenograft models of B-ALL, co-administration of the Notch inhibitor GSI-XII with the chemotherapeutic agent Ara-C lowered bone marrow leukemic burden compared with DMSO or Ara-C alone, thus prolonging mouse survival. Overall, our results support the potential effectiveness of Notch inhibitors in patients with B-ALL.Significance: Inhibition of Notch signaling enhances the chemosensitivity of B-ALL cells, suggesting Notch inhibition as a potential therapeutic strategy to improve the outcome of patients with B-ALL.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Cytarabine / administration & dosage
  • Cytarabine / pharmacology*
  • Dipeptides / administration & dosage
  • Dipeptides / pharmacology*
  • Drug Resistance, Neoplasm
  • Drug Synergism
  • HEK293 Cells
  • Humans
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / metabolism
  • Receptors, Notch / antagonists & inhibitors*
  • Receptors, Notch / metabolism
  • Signal Transduction
  • Xenograft Model Antitumor Assays


  • Dipeptides
  • Receptors, Notch
  • benzyloxycarbonyl-isoleucyl-leucinal
  • Cytarabine