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A novel molecular m...
A novel molecular mechanism of primary resistance to FLT3-kinase inhibitors in AML
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Breitenbuecher, Frank (author)
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Markova, Boyka (author)
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Kasper, Stefan (author)
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Carius, Birgit (author)
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Stauder, Torsten (author)
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Boehmer, Frank D. (author)
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- Masson, Kristina (author)
- Lund University,Lunds universitet,Institutionen för translationell medicin,Medicinska fakulteten,Department of Translational Medicine,Faculty of Medicine
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- Rönnstrand, Lars (author)
- Lund University,Lunds universitet,Institutionen för translationell medicin,Medicinska fakulteten,Department of Translational Medicine,Faculty of Medicine
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Huber, Christoph (author)
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Kindler, Thomas (author)
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Fischer, Thomas (author)
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(creator_code:org_t)
- American Society of Hematology, 2009
- 2009
- English.
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In: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 113:17, s. 4063-4073
- Related links:
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http://dx.doi.org/10...
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https://lup.lub.lu.s...
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https://doi.org/10.1...
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Abstract
Subject headings
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- 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)
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Hematologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Hematology (hsv//eng)
Publication and Content Type
- art (subject category)
- ref (subject category)
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Blood
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- By the author/editor
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Breitenbuecher, ...
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Markova, Boyka
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Kasper, Stefan
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Carius, Birgit
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Stauder, Torsten
-
Boehmer, Frank D ...
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show more...
-
Masson, Kristina
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Rönnstrand, Lars
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Huber, Christoph
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Kindler, Thomas
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Fischer, Thomas
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Hematology
- Articles in the publication
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Blood
- By the university
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Lund University