title: A novel molecular mechanism of primary resistance to FLT3-kinase inhibitors in AML.
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.
authors.affiliation: 3rd Medical Department, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Breitenbuecher
authors.forename: Boyka
authors.initials: B
authors.lastname: Markova
authors.forename: Stefan
authors.initials: S
authors.lastname: Kasper
authors.forename: Birgit
authors.initials: B
authors.lastname: Carius
authors.forename: Torsten
authors.initials: T
authors.lastname: Stauder
authors.forename: Frank D
authors.initials: FD
authors.lastname: Böhmer
authors.forename: Kristina
authors.initials: K
authors.lastname: Masson
authors.forename: Lars
authors.initials: L
authors.lastname: Rönnstrand
authors.forename: Christoph
authors.initials: C
authors.lastname: Huber
authors.forename: Thomas
authors.initials: T
authors.lastname: Kindler
authors.forename: Thomas
authors.initials: T
authors.lastname: Fischer
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D010641:Phenotype; D040081:Protein Array Analysis; D015398:Signal Transduction / Q000187:drug effects; D019311:Staurosporine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D013379:Substrate Specificity; D015854:Up-Regulation / Q000187:drug effects; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D019311:Staurosporine; C059539:midostaurin