Activation of Wnt signaling in cKit-ITD mediated transformation and imatinib sensitivity in acute myeloid leukemia

• Published in: International journal of hematology 2008-09, Vol.88 (2), p.174-180
• Main Authors: Tickenbrock, Lara, Hehn, Sina, Sargin, Bülent, Evers, Georg, NG, Pavankumar Reddy, Choudhary, Chunaram, Berdel, Wolfgang E., Müller-Tidow, Carsten, Serve, Hubert
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Benzamides; beta Catenin - genetics; beta Catenin - metabolism; Biological and medical sciences; Cell Line; Cell Transformation, Neoplastic - genetics; fms-Like Tyrosine Kinase 3 - genetics; fms-Like Tyrosine Kinase 3 - metabolism; Gene Expression Regulation, Leukemic; Glycogen Synthase Kinase 3 - metabolism; Hematologic and hematopoietic diseases; Hematology; Humans; Imatinib Mesylate; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - metabolism; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Medicine; Medicine & Public Health; Mice; Oncology; Original Article; Phosphorylation; Piperazines - pharmacology; Proto-Oncogene Proteins c-kit - genetics; Proto-Oncogene Proteins c-kit - metabolism; Pyrimidines - pharmacology; Signal Transduction - drug effects; Signal Transduction - physiology; Tandem Repeat Sequences; Transfection; Wnt Proteins - genetics; Wnt Proteins - metabolism
• ISSN: 0925-5710; 1865-3774
• DOI: 10.1007/s12185-008-0141-0

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 β-Catenin protein levels compared to the cKit-WT. Analysis of β-Catenin mRNA and protein levels revealed that β-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 GSK3β 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 β-Catenin that underwent with a decrease of GSK3β phosphorylation, suggesting an indirect mechanism of β-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.