MDS骨髓细胞癌变的主要机制

Main mechanism of malignant transformation of MDS into leukemia

在内源性V-erbB基因突变和扩增导致MDS骨髓细胞克隆性增生基础上,随着机体免疫的弱化、代偿机制的参与和胸苷酸合成酶(TS)等增生和代偿相关基因的协同扩增,大大强化了上述骨髓干/祖细胞的增生力,以致无法控制。同时,由于TS(作为一个新认识的癌基因)扩增,细胞对叶酸需求的倍增,使其处于叶酸饥饿状态,导致脲苷酸(dUMP)未经甲基化而进入DNA合成,造成遗传不稳定和染色体异常。在缺叶酸培养条件下部分MDS患者骨髓细胞暂时地陷入细胞周期停滞状态即姐妹染色单体分化(SCD)阴性状态,而没有TS扩增仅有V-erbB扩增的MDS骨髓细胞则仅有超常增生而无上述反应。

Our studies had demonstrated that myelodysplassia of MDS was associated with C-erbB rearrangement/amplification. The endogenous V-erbB is its pathogenic gene. Its mutation and amplification cause clonal proliferation of BM stem cells. These preleukemic stem cells have got more and more strong proliferative ability in order to uncontrol,because of decreased immuno-ability, involvement of reproductive mechanism in this process and its related genes, such as TS and TK gene amplification, meanwhile since TS gene amplificates, stem cells need multiple serum folic acid for their DNA synthesis, but the body of patient with MDS do not provide so much.Under this condition the dUMT do not methylated and misincoperated into DNA. This lead to genetic unstability,chromosome alterations and longer cell cycle. V-erbB and TS gene both are oncogene. Conclusion： The main mechanism of malignant transformation of MDS into leukemia is that amplification of V-erbB and TS gene both sychronizes in same stem cells.