Upregulation of FZ5 Results in Abberant Expression of Beta-Catenin and LEF/TCF Complex in Acute Myeloid Leukemia.

Wnt proteins form a family of secreted signalling proteins that play a key role in various developmental events such as cell differentiation, cell migration, cell polarity and cell proliferation. Activation of the Wnt/beta-catenin through canonical and non-canonical pathways has recently been shown to be crucial to the self-renewal of hematopoietic progenitors and stem cells. WNT proteins initiate the canonical (beta-catenin-regulated) signaling cascade by binding to seven-transmembrane spanning receptors of the Frizzled (FZ) family. WNT stimulation leads to beta-catenin accumulation, nuclear translocation and interaction with T-cell factor/lymphoid enhancer factor (TCF/LEF) to regulate genes important for embryonic development and proliferation. Also beta-catenin is thought to have a role in the self renewal potential of leukemic cells in AML. To determine the role of the WNT pathways in the development of acute myeloid leukaemia (AML), we studied seven WNT pathway genes (WNT10b, WNT5a, FZ5, Beta-catenin, APC, TCF1 and LEF1) in 34 AML patients by quantitative real-time PCR. Results were compared by peripheral blood samples from healthy donors by using Ct values. FZ5 gene expression showed 10 fold and LEF1gene expression showed 3 fold increase when compared to controls (p>0.01 and p=0.02 respectively). Beta-catenin was 5 fold higher in patients than normal peripheral blood samples. The WNT10b expression was slightly lower (1.5 fold) comparing to other genes. TCF1 expression level also seemed to be higher in AML patients (OR=4.2 95%CI=0.04–2.82, p=0.06). These results may represent that canonical WNT signaling takes place in AML development and provide the evidence for the involvement of FZ5 upregulation in the pathogenesis of AML through activation of the TCF/LEF mediated signaling.