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

Breitenbuecher, Frank; Markova, Boyka; Kasper, Stefan; Carius, Birgit; Stauder, Torsten; Boehmer, Frank D.; Masson, Kristina LU ; Rönnstrand, Lars LU ; Huber, Christoph and Kindler, Thomas, et al. (2009) In Blood 113(17). p.4063-4073
Abstract
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... (More)
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) (Less)
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published
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Blood
volume
113
issue
17
pages
4063 - 4073
publisher
American Society of Hematology
external identifiers
  • wos:000265447000026
  • scopus:65449158845
ISSN
1528-0020
DOI
10.1182/blood-2007-11-126664
language
English
LU publication?
yes
id
db9f1f38-e020-4f14-b601-7a13d287de25 (old id 1428045)
date added to LUP
2009-06-25 11:04:14
date last changed
2017-09-10 03:35:28
@article{db9f1f38-e020-4f14-b601-7a13d287de25,
  abstract     = {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)},
  author       = {Breitenbuecher, Frank and Markova, Boyka and Kasper, Stefan and Carius, Birgit and Stauder, Torsten and Boehmer, Frank D. and Masson, Kristina and Rönnstrand, Lars and Huber, Christoph and Kindler, Thomas and Fischer, Thomas},
  issn         = {1528-0020},
  language     = {eng},
  number       = {17},
  pages        = {4063--4073},
  publisher    = {American Society of Hematology},
  series       = {Blood},
  title        = {A novel molecular mechanism of primary resistance to FLT3-kinase inhibitors in AML},
  url          = {http://dx.doi.org/10.1182/blood-2007-11-126664},
  volume       = {113},
  year         = {2009},
}