Aberrant Cell Cycle and Expression Profiles of Cell Cycle Regulatory Genes in Myelodysplastic Syndrome.

Deregulation of the cell cycle machinery, especially G₁/S phase deregulation, is known to contribute to the uncontrolled cell proliferation and malignant transformation in haematological malignances. However, little is known about the aberrant bone marrow cell cycle and its molecular mechanisms in myelodysplastic syndromes (MDS). In this study, we conducted the cell cycle analysis of bone marrow mononuclear cells (BMMC) before and after exposure to haematopoietic growth factors (HGFs) cocktail, in combination with the analysis of the expression of Ki-67 antigen in BMMC and CD34⁺ cells in twenty-seven MDS patients. In addition, we examined the expression profiles of cell cycle regulatory genes. We found that MDS patients had higher percentage of BMMC in G₀/G₁ phase and lower ratio of cells in S+G₂/M, and higher proportion of CD34⁺ Ki-67⁺ cells. After exposure to HGFs cocktail in vitro, high proportion of G₀/G₁ phase cells decreased significantly in MDS. All types of four cyclins (cyclin D2, D3, E, and A1) were at higher level had high amount of mRNA transcripts in MDS, together with higher activation of CDK2, CDK6, and RB genes. Furthermore, we also demonstrated higher activation of p21 and p27 genes. These results demonstrated that G₁ arrest occurred in MDS Ki-67⁺ hematopoietic cells. High activation of cyclins, CDKs, and RB genes are the molecular bases of large proportion of Ki-67⁺ proliferate BMMC population. High activation of p21 and p27 genes in MDS blocked hematopoietic cells entry into the following cell cycle.