Identification of a novel activating mutation (Y842C) within the activation loop of FLT3 in patients with acute myeloid leukemia (AML) Journal Article
| Authors: | Kindler, T.; Breitenbuecher, F.; Kasper, S.; Estey, E.; Giles, F.; Feldman, E.; Ehninger, G.; Schiller, G.; Klimek, V.; Nimer, S. D.; Gratwohl, A.; Choudhary, C. R.; Mueller-Tidow, C.; Serve, H.; Gschaidmeier, H.; Cohen, P. S.; Huber, C.; Fischer, T. |
| Article Title: | Identification of a novel activating mutation (Y842C) within the activation loop of FLT3 in patients with acute myeloid leukemia (AML) |
| Abstract: | 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. (C) 2005 by The American Society of Hematology. |
| Keywords: | imatinib; cytogenetics; receptor tyrosine kinase; inhibitors; cell-lines; disease; malignancies; stat5; internal tandem duplication; minimal residual |
| Journal Title: | Blood |
| Volume: | 105 |
| Issue: | 1 |
| ISSN: | 0006-4971 |
| Publisher: | American Society of Hematology |
| Date Published: | 2005-01-01 |
| Start Page: | 335 |
| End Page: | 340 |
| Language: | English |
| DOI: | 10.1182/blood-2004-02-0660 |
| ACCESSION: | WOS:000225997100055 |
| PROVIDER: | wos |
| PUBMED: | 15345593 |
| Notes: | --- - Article; Proceedings Paper - 45th Annual Meeting of the American-Society-of-Hematology - DEC 06-09, 2003 - SAN DIEGO, CA - "Source: Wos" |
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