Abstract：
Growth Factor Independence 1 (GFI1) is a transcription factor with an important role in the regulation of development of myeloid and lymphoid cell lineages and was implicated in the development of myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). Reduced expression of GFI1 or presence of the GFI1-36N (serine replaced with asparagine) variant leads to epigenetic changes in human and murine AML blasts and accelerated the development of leukaemia in a murine model of human MDS and AML. We and other groups previously showed that the GFI1-36N allele or reduced expression of GFI1 in human AML blasts is associated with an inferior prognosis. Using GFI1-36S, -36N -KD, NUP98-HOXD13-tg mice and curcumin (a natural histone acetyltransferase inhibitor (HATi)), we now demonstrate that expansion of GFI1-36N or -KD, NUP98-HODXD13 leukaemic cells can be delayed. Curcumin treatment significantly reduced AML progression in GFI1-36N or -KD mice and prolonged AML-free survival. Of note, curcumin treatment had no effect in GFI1-36S, NUP98-HODXD13 expressing mice. On a molecular level, curcumin treatment negatively affected open chromatin structure in the GFI1-36N or -KD haematopoietic cells but not GFI1-36S cells. Taken together, our study thus identified a therapeutic role for curcumin treatment in the treatment of AML patients (homo or heterozygous for GFI1-36N or reduced GFI1 expression) and possibly improved therapy outcome.
摘要：
生长因子独立1（GFI1）是一种转录因子，在调节骨髓和淋巴细胞谱系的发育中起重要作用，并与骨髓增生异常综合征（MDS）和急性骨髓性白血病（AML）的发展有关。GFI1的表达降低或GFI1-36N(丝氨酸被天冬酰胺取代)变体的存在导致人和鼠AML母细胞的表观遗传变化,并加速人MDS和AML的鼠模型中白血病的发展。我们和其他小组先前表明，人AML母细胞中GFI1-36N等位基因或GFI1表达降低与预后较差有关。使用GFI1-36S，-36N-KD,NUP98-HOXD13-tg小鼠和姜黄素（一种天然组蛋白乙酰转移酶抑制剂（HATi）），我们现在证明了GFI1-36N或-KD的扩展，NUP98-HODXD13白血病细胞可以延迟。姜黄素治疗显著降低GFI1-36N或-KD小鼠的AML进展并延长无AML生存期。值得注意的是，姜黄素治疗对GFI1-36S没有影响，NUP98-HODXD13表达小鼠。在分子水平上,姜黄素处理对GFI1-36N或-KD造血细胞而不是GFI1-36S细胞中的开放染色质结构产生负面影响。一起来看,因此,我们的研究确定了姜黄素治疗在治疗AML患者中的治疗作用(GFI1-36N同源或杂合或GFI1表达降低),并可能改善治疗结果.
