Ras-proximate-1 GTPase-activating protein and Rac2 may play pivotal roles in the initial development of myelodysplastic syndrome

摘要

Myelodysplastic syndrome (MDS) is a stem cell disease that has a characteristic morphological dysplasia. 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. 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. 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. However, no change in the expression of genes involved in the canonical Wnt signaling pathway, with the exception of β-catenin, was observed. 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 (2008) RCUD, RCMD and MDS-U] who had normal karyotypes. Only Rap1GAP and Rac2 showed higher expression levels when mononuclear cells were used from another group of patients with MDS-RA [WHO (2008) RCUD, RCMD and MDS-U] who also had normal karyotypes. We believe that the cadherin-β-catenin-c-myc signaling axis is crucial in the hematopoiesis of HSCs in the early stages of MDS. In addition, Ras-proximate-1 (Rap1), which is negatively regulated by Rap1GAP, may serve as an initiator of this axis through interplay with cadherin. This pathway is strengthened by the upregulation of Rac2, which may allow the nuclear translocation of β-catenin. The aberrant expression of Rho GTPases may also be responsible for the dysplasia characteristics observed in MDS. This study provides vital and new insights into the pathophysiology of MDS. The two small G proteins, Rap1GAP and Rac2, may act as new molecular markers for the diagnosis of MDS.