NOTCH inhibition and glucocorticoid therapy in T-cell acute lymphoblastic leukemia

Leukemia. 2009 Aug;23(8):1374-7. doi: 10.1038/leu.2009.75. Epub 2009 Apr 9.

Abstract

Inhibition of NOTCH1 signaling with gamma-secretase inhibitors (GSIs) has been proposed as a molecularly targeted therapy in T-cell acute lymphoblastic leukemia (T-ALL). However, GSIs seem to have limited antileukemic activity in human T-ALL and are associated with severe gastrointestinal toxicity resulting from inhibition of NOTCH signaling in the gut. Inhibition of NOTCH1 signaling in glucocorticoid-resistant T-ALL restored glucocorticoid sensitivity and co-treatment with glucocorticoids inhibited GSI-induced gut toxicity. Thus, combination therapies with GSIs plus glucocorticoids may offer a new opportunity for the use of anti-NOTCH1 therapies in human T-ALL.

Publication types

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

MeSH terms

  • Adult
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Basic Helix-Loop-Helix Transcription Factors / physiology
  • Child
  • Drug Resistance, Neoplasm / drug effects
  • Drug Synergism
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / adverse effects
  • Enzyme Inhibitors / pharmacology
  • Gastrointestinal Diseases / chemically induced
  • Gastrointestinal Diseases / prevention & control
  • Gene Expression Regulation, Neoplastic / drug effects
  • Glucocorticoids / administration & dosage
  • Glucocorticoids / pharmacology*
  • Homeodomain Proteins / physiology
  • Humans
  • Intestinal Mucosa / metabolism
  • Intestines / drug effects
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / physiology
  • Mice
  • Mice, Knockout
  • Neoplasm Proteins / antagonists & inhibitors*
  • Neoplasm Proteins / genetics
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
  • Protein Processing, Post-Translational
  • Receptor, Notch1 / antagonists & inhibitors*
  • Receptor, Notch1 / genetics
  • Transcription Factor HES-1

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Enzyme Inhibitors
  • GKLF protein
  • Glucocorticoids
  • Hes1 protein, mouse
  • Homeodomain Proteins
  • Kruppel-Like Transcription Factors
  • NOTCH1 protein, human
  • Neoplasm Proteins
  • Notch1 protein, mouse
  • Receptor, Notch1
  • Transcription Factor HES-1
  • HES1 protein, human
  • Amyloid Precursor Protein Secretases