Targeting acute myeloid leukemia with a small molecule inhibitor of the Myb/p300 interaction

Research output: Contribution to journalArticle

Authors

  • Sagar Uttarkar
  • Anna Coulibaly
  • Simone Steinmann
  • Anke Jakobs
  • Caroline Schomburg
  • Amke Trentmann
  • Joachim Jose
  • Peter Schlenke
  • Wolfgang E Berdel
  • Thomas J Schmidt
  • Carsten Müller-Tidow
  • Karl-Heinz Klempnauer

Colleges, School and Institutes

Abstract

The transcription factor Myb plays a key role in the hematopoietic system and has been implicated in the development of leukemia and other human cancers. Inhibition of Myb is therefore emerging as a potential therapeutic strategy for these diseases. However, due to lack of suitable inhibitors the feasibility of therapeutic approaches based on Myb inhibition has not been explored. We have identified the triterpenoid Celastrol as a potent low-molecular weight inhibitor of the interaction of Myb with its cooperation partner p300. We demonstrate that Celastrol suppresses the proliferative potential of acute myeloid leukemia (AML) cells while not affecting normal hematopoietic progenitor cells. Furthermore, Celastrol prolongs the survival of mice in a model of an aggressive AML. Overall, our work demonstrates the therapeutic potential of a small-molecule inhibitor of the Myb/p300 interaction for the treatment of AML and provides a starting point for the further development of Myb-inhibitory compounds for the treatment of leukemia and, possibly, other tumors driven by deregulated Myb.

Details

Original languageEnglish
JournalBlood
Early online date2 Dec 2015
Publication statusE-pub ahead of print - 2 Dec 2015