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A novel molecular mechanism of primary resistance to FLT3-kinase inhibitors in AML

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Author

  • Frank Breitenbuecher
  • Boyka Markova
  • Stefan Kasper
  • Birgit Carius
  • Torsten Stauder
  • Frank D. Boehmer
  • Kristina Masson
  • Lars Rönnstrand
  • Christoph Huber
  • Thomas Kindler
  • Thomas Fischer
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Summary, in English

Currently, FLT3 tyrosine kinase inhibitors (TKIs) are emerging as the most promising drug therapy to overcome the dismal prognosis of acute myelogenous leukemia (AML) patients harboring internal tandem duplications (ITDs) of FLT3. However, up-front drug resistance occurs in approximately 30% of patients, and molecular mechanisms of resistance are poorly understood. Here, we have uncovered a novel mechanism of primary resistance to FLT3 TKIs in AML: an FLT3 receptor harboring a nonjuxtamembrane ITD atypically integrating into the beta-2 sheet of the first kinase domain (FLT3_ITD627E) induces dramatic up-regulation of the anti-apoptotic myeloid cell leukemia 1 protein (MCL-1). Using RNA interference technology, deregulated MCL-1 protein expression was shown to play a major role in conferring the resistance phenotype of 32D_ITD627E cells. Enhanced and sustained binding of the adaptor protein GRB-2 to the FLT3_ITD627E receptor is involved in MCL-1 up-regulation and is independent from TKI (PKC412)-induced inhibition of the receptor kinase. Thus, we describe a new mechanism of primary resistance to TKIs, which operates by reprogramming local and distant signal transduction events of the FLT3 tyrosine kinase. The data presented suggest that particular ITDs of FLT3 may be associated with rewired signaling and differential responsiveness to TKIs. (Blood. 2009; 113: 4063-4073)

Publishing year

2009

Language

English

Pages

4063-4073

Publication/Series

Blood

Volume

113

Issue

17

Document type

Journal article

Publisher

American Society of Hematology

Topic

  • Hematology

Status

Published

ISBN/ISSN/Other

  • ISSN: 1528-0020