Activating FLT3 mutants show distinct gain-of-function phenotypes in vitro and a characteristic signaling pathway profile associated with prognosis in acute myeloid leukemia
About 30% of patients with acute myeloid leukemia (AML) harbour mutations of the receptor tyrosine kinase FLT3, mostly internal tandem duplications (ITD) and point mutations of the second tyrosine kinase domain (TKD). It was the aim of this study to comprehensively analyze clinical and functional pr...
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| creator | Janke, Hanna Pastore, Friederike Schumacher, Daniela Herold, Tobias Hopfner, Karl-Peter Schneider, Stephanie Berdel, Wolfgang E Büchner, Thomas Woermann, Bernhard J Subklewe, Marion Bohlander, Stefan K Hiddemann, Wolfgang Spiekermann, Karsten Polzer, Harald |
| description | About 30% of patients with acute myeloid leukemia (AML) harbour mutations of the receptor tyrosine kinase FLT3, mostly internal tandem duplications (ITD) and point mutations of the second tyrosine kinase domain (TKD). It was the aim of this study to comprehensively analyze clinical and functional properties of various FLT3 mutants. In 672 normal karyotype AML patients FLT3-ITD, but not FLT3-TKD mutations were associated with a worse relapse free and overall survival in multivariate analysis. In paired diagnosis-relapse samples FLT3-ITD showed higher stability (70%) compared to FLT3-TKD (30%). In vitro, FLT3-ITD induced a strong activating phenotype in Ba/F3 cells. In contrast, FLT3-TKD mutations and other point mutations--including two novel mutations--showed a weaker but clear gain-of-function phenotype with gradual increase in proliferation and protection from apoptosis. The pro-proliferative capacity of the investigated FLT3 mutants was associated with cell surface expression and tyrosine 591 phosphorylation of the FLT3 receptor. Western blot experiments revealed STAT5 activation only in FLT3-ITD positive cell lines, in contrast to FLT3-non-ITD mutants, which displayed an enhanced signal of AKT and MAPK activation. Gene expression analysis revealed distinct difference between FLT3-ITD and FLT3-TKD for STAT5 target gene expression as well as deregulation of SOCS2, ENPP2, PRUNE2 and ART3. FLT3-ITD and FLT3 point mutations show a gain-of-function phenotype with distinct signalling properties in vitro. Although poor prognosis in AML is only associated with FLT3-ITD, all activating FLT3 mutations can contribute to leukemogenesis and are thus potential targets for therapeutic interventions. |
| doi_str_mv | 10.1371/journal.pone.0089560 |
| format | Article |
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It was the aim of this study to comprehensively analyze clinical and functional properties of various FLT3 mutants. In 672 normal karyotype AML patients FLT3-ITD, but not FLT3-TKD mutations were associated with a worse relapse free and overall survival in multivariate analysis. In paired diagnosis-relapse samples FLT3-ITD showed higher stability (70%) compared to FLT3-TKD (30%). In vitro, FLT3-ITD induced a strong activating phenotype in Ba/F3 cells. In contrast, FLT3-TKD mutations and other point mutations--including two novel mutations--showed a weaker but clear gain-of-function phenotype with gradual increase in proliferation and protection from apoptosis. The pro-proliferative capacity of the investigated FLT3 mutants was associated with cell surface expression and tyrosine 591 phosphorylation of the FLT3 receptor. Western blot experiments revealed STAT5 activation only in FLT3-ITD positive cell lines, in contrast to FLT3-non-ITD mutants, which displayed an enhanced signal of AKT and MAPK activation. Gene expression analysis revealed distinct difference between FLT3-ITD and FLT3-TKD for STAT5 target gene expression as well as deregulation of SOCS2, ENPP2, PRUNE2 and ART3. FLT3-ITD and FLT3 point mutations show a gain-of-function phenotype with distinct signalling properties in vitro. Although poor prognosis in AML is only associated with FLT3-ITD, all activating FLT3 mutations can contribute to leukemogenesis and are thus potential targets for therapeutic interventions.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0089560</identifier><identifier>PMID: 24608088</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Acute myelocytic leukemia ; Animals ; Apoptosis ; Apoptosis - genetics ; Apoptosis - physiology ; Biology ; Blotting, Western ; Cell Line ; Cell Proliferation ; Chromosomes ; Comparative analysis ; fms-Like Tyrosine Kinase 3 - genetics ; Gene expression ; Gene mutation ; Genetic aspects ; Humans ; Leukemia, Myeloid, Acute - enzymology ; Leukemia, Myeloid, Acute - genetics ; Leukemia, Myeloid, Acute - metabolism ; Medical prognosis ; Medicine ; Mice ; Multivariate Analysis ; Mutation ; Mutation - genetics ; Prognosis ; Signal Transduction - genetics ; Signal Transduction - physiology ; Tyrosine</subject><ispartof>PloS one, 2014-03, Vol.9 (3), p.e89560-e89560</ispartof><rights>COPYRIGHT 2014 Public Library of Science</rights><rights>2014 Janke et al. 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It was the aim of this study to comprehensively analyze clinical and functional properties of various FLT3 mutants. In 672 normal karyotype AML patients FLT3-ITD, but not FLT3-TKD mutations were associated with a worse relapse free and overall survival in multivariate analysis. In paired diagnosis-relapse samples FLT3-ITD showed higher stability (70%) compared to FLT3-TKD (30%). In vitro, FLT3-ITD induced a strong activating phenotype in Ba/F3 cells. In contrast, FLT3-TKD mutations and other point mutations--including two novel mutations--showed a weaker but clear gain-of-function phenotype with gradual increase in proliferation and protection from apoptosis. The pro-proliferative capacity of the investigated FLT3 mutants was associated with cell surface expression and tyrosine 591 phosphorylation of the FLT3 receptor. Western blot experiments revealed STAT5 activation only in FLT3-ITD positive cell lines, in contrast to FLT3-non-ITD mutants, which displayed an enhanced signal of AKT and MAPK activation. Gene expression analysis revealed distinct difference between FLT3-ITD and FLT3-TKD for STAT5 target gene expression as well as deregulation of SOCS2, ENPP2, PRUNE2 and ART3. FLT3-ITD and FLT3 point mutations show a gain-of-function phenotype with distinct signalling properties in vitro. Although poor prognosis in AML is only associated with FLT3-ITD, all activating FLT3 mutations can contribute to leukemogenesis and are thus potential targets for therapeutic interventions.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24608088</pmid><doi>10.1371/journal.pone.0089560</doi><tpages>e89560</tpages><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_plos_journals_1504977490 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Acute myelocytic leukemia Animals Apoptosis Apoptosis - genetics Apoptosis - physiology Biology Blotting, Western Cell Line Cell Proliferation Chromosomes Comparative analysis fms-Like Tyrosine Kinase 3 - genetics Gene expression Gene mutation Genetic aspects Humans Leukemia, Myeloid, Acute - enzymology Leukemia, Myeloid, Acute - genetics Leukemia, Myeloid, Acute - metabolism Medical prognosis Medicine Mice Multivariate Analysis Mutation Mutation - genetics Prognosis Signal Transduction - genetics Signal Transduction - physiology Tyrosine |
| title | Activating FLT3 mutants show distinct gain-of-function phenotypes in vitro and a characteristic signaling pathway profile associated with prognosis in acute myeloid leukemia |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-02T06%3A42%3A56IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Activating%20FLT3%20mutants%20show%20distinct%20gain-of-function%20phenotypes%20in%20vitro%20and%20a%20characteristic%20signaling%20pathway%20profile%20associated%20with%20prognosis%20in%20acute%20myeloid%20leukemia&rft.jtitle=PloS%20one&rft.au=Janke,%20Hanna&rft.date=2014-03-07&rft.volume=9&rft.issue=3&rft.spage=e89560&rft.epage=e89560&rft.pages=e89560-e89560&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0089560&rft_dat=%3Cgale_plos_%3EA478773329%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1504977490&rft_id=info:pmid/24608088&rft_galeid=A478773329&rft_doaj_id=oai_doaj_org_article_b13bc09d27824706bc8cd843182112d3&rfr_iscdi=true |