Activation of Wnt signaling in cKit-ITD mediated transformation and imatinib sensitivity in acute myeloid leukemia.
The Wnt-signaling pathway plays a critical role in directing cell fate during embryogenesis and also in the pathogenesis of cancer. In leukemia, it is well described that activating internal tandem duplications (ITD) mutations in receptor tyrosine kinases like cKit or Flt3 confer to the pathogenesis of cancer. Here, we analyzed whether Wnt-signaling plays a role in cKit-ITD mediated transformation. Stably transfected 32D cells with cKit-ITD cells had higher beta-Catenin protein levels compared to the cKit-WT. Analysis of beta-Catenin mRNA and protein levels revealed that beta-Catenin was regulated at post-transcriptional level in cKit-ITD as well as Flt3-ITD compared to the wildtype. Signaling analyses revealed higher-phosphorylation of GSK3beta by oncogenic cKit-ITD. Moreover, activation of Wnt signaling was confirmed by constitutive activation of c-myc luciferase by cKit-ITD cells. Importantly, using dominant negative TCF4, we show that activation of Wnt signaling plays an important role in cKit mediated transformation of myeloid cells. Application of specific receptor tyrosine kinase inhibitors for Flt3 or cKit result in a decrease of beta-Catenin that underwent with a decrease of GSK3beta phosphorylation, suggesting an indirect mechanism of beta-Catenin regulation by oncogenic receptor tyrosine kinases in both ITD mutations. Our study shows the importance of activation of Wnt signaling in leukemia and suggests as attractive target for future therapeutical approaches.
Tickenbrock
Lara
L
Department of Medicine, Hematology and Oncology, University of Münster, Division of Hematology/Oncology, Domagkstr. 3, 48149, Münster, Germany. tickenbr@uni-muenster.de.
Hehn
Sina
S
Medizinische Klinik II, Klinikum der Johann-Wolfgang Goethe-Universität Frankfurt am Main, Frankfurt, Germany.
Sargin
Bülent
B
Department of Medicine, Hematology and Oncology, University of Münster, Division of Hematology/Oncology, Domagkstr. 3, 48149, Münster, Germany.
Evers
Georg
G
Department of Medicine, Hematology and Oncology, University of Münster, Division of Hematology/Oncology, Domagkstr. 3, 48149, Münster, Germany.
Ng
Pavankumar Reddy
PR
Medizinische Klinik II, Klinikum der Johann-Wolfgang Goethe-Universität Frankfurt am Main, Frankfurt, Germany.
Choudhary
Chunaram
C
Department of Medicine, Hematology and Oncology, University of Münster, Division of Hematology/Oncology, Domagkstr. 3, 48149, Münster, Germany.
Berdel
Wolfgang E
WE
Department of Medicine, Hematology and Oncology, University of Münster, Division of Hematology/Oncology, Domagkstr. 3, 48149, Münster, Germany.
Müller-Tidow
Carsten
C
Department of Medicine, Hematology and Oncology, University of Münster, Division of Hematology/Oncology, Domagkstr. 3, 48149, Münster, Germany.
Serve
Hubert
H
Medizinische Klinik II, Klinikum der Johann-Wolfgang Goethe-Universität Frankfurt am Main, Frankfurt, Germany.
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D020080:Tandem Repeat Sequences; D014162:Transfection; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D001549:Benzamides; C495267:CTNNB1 protein, mouse; D010879:Piperazines; D011743:Pyrimidines; D051153:Wnt Proteins; D051176:beta Catenin; D000068877:Imatinib Mesylate; C497971:Flt3 protein, mouse; D019009:Proto-Oncogene Proteins c-kit; D051941:fms-Like Tyrosine Kinase 3; D038362:Glycogen Synthase Kinase 3