Continuous activation of β-catenin through the interaction with T-cell factor/Lef transcription factors results in the aberrant transcription of c-myc, which promotes the differentiation of HSCs at the expense of self-renewal and blocks before the terminal maturation stage of blood cells, leading to the exhaustion of the HSC pool and peripheral cytopenia. β-catenin, which keeps a dynamic balance between the cadherin-β-catenin complex and the Wnt signal-regulated conformation, accumulates in the cytoplasm as the downregulation of cadherins occurs and is transported to the nucleus. These events lead to the inhibition of Axin-mediated β-catenin phosphorylation and therefore the stabilization of β-catenin. Dvl recruitment by Fz leads to LRP5/6 phosphorylation and Axin recruitment. In the presence of a Wnt ligand, a receptor complex forms between Fz and LRP5/6. Phosphorylated β-catenin is recognized by an E3 ubiquitin ligase, resulting in its ubiquitination and proteasomal degradation. In the absence of Wnt, cytoplasmic β-catenin forms a complex with Axin, APC, GSK3 and CK1, which is phosphorylated by CK1 and GSK3. Cadherin and Rap1 have a positive feedback-like interplay with each other. The two small G proteins, Rap1GAP and Rac2, may act as new molecular markers for the diagnosis of MDS.Ī possible mechanism for regulating the hematopoiesis of HSCs in MDS is shown. This study provides vital and new insights into the pathophysiology of MDS. The aberrant expression of Rho GTPases may also be responsible for the dysplasia characteristics observed in MDS. This pathway is strengthened by the upregulation of Rac2, which may allow the nuclear translocation of β-catenin. In addition, Ras-proximate-1 (Rap1), which is negatively regulated by Rap1GAP, may serve as an initiator of this axis through interplay with cadherin. We believe that the cadherin-β-catenin-c-myc signaling axis is crucial in the hematopoiesis of HSCs in the early stages of MDS. Only Rap1GAP and Rac2 showed higher expression levels when mononuclear cells were used from another group of patients with MDS-RA who also had normal karyotypes. The array results were confirmed by real-time quantitative polymerase chain reaction (RQ-PCR) using CD34(+) cells from a cohort of patients with MDS-refractory anemia (RA) who had normal karyotypes. However, no change in the expression of genes involved in the canonical Wnt signaling pathway, with the exception of β-catenin, was observed. These profiles showed that N-cadherin, E-cadherin and c-myc binding protein tended to be downregulated, whereas β-catenin, Ras-proximate-1 GTPase-activating protein (Rap1GAP), c-myc promoter binding protein, Rac1, Rac2 and CDC42 tended to be upregulated. To gain insight into the poorly understood pathophysiology of MDS, the present study focused on analyzing the gene expression profiles of these molecules with whole genomic array using CD34(+) cells from MDS patients. Adhesion molecules and the Wnt signaling pathway are mostly involved with the self-renewal, proliferation and differentiation of hematopoietic stem cells (HSCs) while Rho GTPases are closely correlated with the cytoskeleton and therefore cell morphology. Myelodysplastic syndrome (MDS) is a stem cell disease that has a characteristic morphological dysplasia.
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