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|Ref Type||Journal Article|
|Authors||Kindler T, Breitenbuecher F, Kasper S, Estey E, Giles F, Feldman E, Ehninger G, Schiller G, Klimek V, Nimer SD, Gratwohl A, Choudhary CR, Mueller-Tidow C, Serve H, Gschaidmeier H, Cohen PS, Huber C, Fischer T|
|Title||Identification of a novel activating mutation (Y842C) within the activation loop of FLT3 in patients with acute myeloid leukemia (AML).|
|Date||2005 Jan 1|
|Abstract Text||Fms-like tyrosine kinase 3 (FLT3) receptor mutations as internal tandem duplication (ITD) or within the kinase domain are detected in up to 35% of patients with acute myeloid leukemia (AML). N-benzoyl staurosporine (PKC412), a highly effective inhibitor of mutated FLT3 receptors, has significant antileukemic efficacy in patients with FLT3-mutated AML. Mutation screening of FLT3 exon 20 in AML patients (n = 110) revealed 2 patients with a novel mutation (Y842C) within the highly conserved activation loop of FLT3. FLT3-Y842C-transfected 32D cells showed constitutive FLT3 tyrosine phosphorylation and interleukin 3 (IL-3)-independent growth. Treatment with PKC412 led to inhibition of proliferation and apoptotic cell death. Primary AML blasts bearing FLT3-Y842C mutations showed constitutive FLT3 and signal transducer and activator of transcription 5 (STAT-5) tyrosine phosphorylation. Ex vivo PKC412 treatment of primary blasts resulted in suppression of constitutive FLT3 and STAT-5 activation and apoptotic cell death. Inspection of the FLT3 structure revealed that Y842 is the key residue in regulating the switch from the closed to the open (= active) conformation of the FLT3 activation loop. Overall, our data suggest that mutations at Y842 represent a significant new activating mutation in AML blasts. Since FLT3 tyrosine kinase inhibitors (TKIs) such as PKC412 are currently being investigated in clinical trials in AML, extended sequence analysis of FLT3 may be helpful in defining the spectrum of TKI-sensitive FLT3 mutations in AML.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|FLT3||Y842C||missense||gain of function||FLT3 Y842C lies within the protein kinase domain of the Flt3 protein (UniProt.org). Y842C results in constitutive phosphorylation of Flt3, activation of Stat5 signaling, is transforming in cell culture (PMID: 15345593), and has been demonstrated to promote secondary drug resistance in the context of FLT3 internal tandem duplication (FLT3-ITD) mutations (PMID: 22504184, PMID: 29187377).||Y|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|FLT3 Y842C||acute myeloid leukemia||resistant||Imatinib||Preclinical||Actionable||In a preclinical study, primary AML blasts expressing FLT3 Y842C were resistant to Gleevec (imatinib) as demonstrated by constitutively phosphorylated FLT3 and STAT-5 (PMID: 15345593).||15345593|
|FLT3 Y842C||acute myeloid leukemia||sensitive||Midostaurin||Preclinical - Cell culture||Actionable||In a preclinical study, Rydapt (midostaurin) induced cell death and inhibited FLT3 activation and downstream STAT5 activation in primary acute myeloid leukemic blasts harboring FLT3 Y842C in culture (PMID: 15345593).||15345593|