Polycomb Group Proteins in Myelodysplastic Syndromes and Its Transformation Into Acute Myeloid Leukemia.

Abstract 1756

Poster Board I-782

The myelodysplastic syndrome (MDS) is a group of clonal blood disorders characterized by refractory cytopenia in peripheral blood, dysplastic cellular morphology in bone marrow, and a high risk of malignant transformation. Recently, expression of BMI1, a polycomb group protein, has been used as an important marker for predicting progression of MDS to acute myeloid leukemia(AML). However the function of BMI1 in MDS is remained unknown. Presently, we have analyzed the expression of SALL4, EZH2, P16 and BMI1 in bone marrow mononuclear cells from 48 newly diagnosed MDS patients and 40 treated MDS patients. Real-time polymerase chain reaction has shown that expression levels of these genes in MDS was frequently higher than that of non-MDS cytopenians (P<0.05). A high level of SALL4 expression in newly diagnosed MDS was always associated with high level of BMI1 expression. When MDS cases were divided into two groups based on their SALL4 mean level, The BMI1 expressed significantly higher in SALL4 higher group than that of SALL4 lower group (P<0.05). The BMI1 expression pattern showed an increasing tendency from MDS-RA moving to MDS-RAEB, without a statistically significance. On the contrary, the EZH2 expression level of MDS-RAEB is lower than that of MDS-RA (P<0.05). Although BMI1 expression level has been down-regulated when MDS patients are in morphological remission, the expression level of SALL4 and EZH2, P16 still remain abnormal (P<0.05). A significantly high level of BMI1 expression could usually be observed in MDS patients in progression, i.e. from RA to RAEB or from MDS to AML. To study whether BMI1 contributes to the MDS progression, we have transfected U937 and K562 cell line with BMI1 full-length cDNA mediated by MSCV retroviral vector and selected subclone cells. The viability of BMI1 transfected cell is much higher than the control cells cultured serum-free medium. Flow cytometry has shown that BMI1 transfected cell also inhibit apoptosis induced by As2O3. By real-time RT-PCR, it was found that BMI1 can repress the expression of EZH2, PTEN and P16 in BMI1 transfected U937 cell line, while only repress the expression of EZH2 in BMI1 transfected K562 cell line. These results suggest that the polycomb group family genes probably play a pivotal role in MDS progression, and BMI1 cooperated with EZH2 may act via an epigenetic mechanism in the pathogenesis of MDS.