Shi Jun, Zhao Yan, Ishii Takefumi, Hu Wenyang, Sozer Selcuk, Zhang Wei, Bruno Edward, Lindgren Valerie, Xu Mingjiang, Hoffman Ronald
Section of Hematology/Oncology, Department of Medicine, University of Illinois College of Medicine, Chicago, Illinois 60612, USA.
Cancer Res. 2007 Jul 1;67(13):6417-24. doi: 10.1158/0008-5472.CAN-07-0572.
Idiopathic myelofibrosis (IM) is likely the consequence of both the acquisition of genetic mutations and epigenetic changes that silence critical genes that control cell proliferation, differentiation, and apoptosis. We have explored the effects of the sequential treatment with the DNA methyltransferase inhibitor, decitabine [5-aza-2'-deoxycytidine (5azaD)], followed by the histone deacetylase inhibitor, trichostatin A (TSA), on the behavior of IM CD34(+) cells. Unlike normal CD34(+) cells where 5azaD/TSA treatment leads to the expansion of CD34(+) cells and marrow-repopulating cells, treatment of IM CD34(+) cells results in a reduction of the number of total cells, CD34(+) cells, and assayable hematopoietic progenitor cells (HPC). In IM, HPCs are either heterozygous or homozygous for the JAK2V617F mutation or possess wild-type JAK2 in varying proportions. Exposure of IM CD34(+) cells to 5azaD/TSA resulted in a reduction of the proportion of JAK2V617F-positive HPCs in 83% of the patients studied and the reduction in the proportion of homozygous HPCs in 50% of the patients. 5azaD/TSA treatment led to a dramatic reduction in the number of HPCs that contained chromosomal abnormalities in two JAK2V617F-negative IM patients. IM is characterized by constitutive mobilization of HPCs, which has been partly attributed to decreased expression of the chemokine receptor CXCR4. Treatment of IM CD34(+) cells with 5azaD/TSA resulted in the up-regulation of CXCR4 expression by CD34(+) cells and restoration of their migration in response to SDF-1. These data provide a rationale for sequential therapy with chromatin-modifying agents for patients with IM.
特发性骨髓纤维化（IM）可能是基因突变和表观遗传变化共同作用的结果，这些变化使控制细胞增殖、分化和凋亡的关键基因沉默。我们探讨了先用DNA甲基转移酶抑制剂地西他滨[5-氮杂-2'-脱氧胞苷（5azaD）]，再用组蛋白去乙酰化酶抑制剂曲古抑菌素A（TSA）进行序贯治疗对IM CD34(+)细胞行为的影响。与正常CD34(+)细胞不同，5azaD/TSA处理正常CD34(+)细胞会导致CD34(+)细胞和骨髓重建细胞扩增，而处理IM CD34(+)细胞则会导致总细胞数、CD34(+)细胞数和可检测的造血祖细胞（HPC）数量减少。在IM中，HPCs对于JAK2V617F突变要么是杂合子，要么是纯合子，或者以不同比例拥有野生型JAK2。将IM CD34(+)细胞暴露于5azaD/TSA后，在83%的研究患者中，JAK2V617F阳性HPCs的比例降低，在50%的患者中，纯合HPCs的比例降低。在两名JAK2V617F阴性的IM患者中，5azaD/TSA治疗导致含有染色体异常的HPCs数量大幅减少。IM的特征是HPCs的持续动员，这部分归因于趋化因子受体CXCR4表达的降低。用5azaD/TSA处理IM CD34(+)细胞导致CD34(+)细胞CXCR4表达上调，并恢复其对SDF-1的迁移反应。这些数据为IM患者使用染色质修饰剂进行序贯治疗提供了理论依据。
