Reference Detail

Ref Type Journal Article
PMID (15345593)
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).
Journal Blood
Vol 105
Issue 1
Date 2005 Jan 1
URL
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.

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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
Variant Impact Protein Effect Variant Description Associated with drug Resistance
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 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
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