UTX 在慢性粒细胞白血病伊马替尼耐药中的作用及其分子机制研究

Imatinib has been proved to be very effective in the clinical treatment of chronic myelogenous leukemia (CML) patients. However, about thirty percent of patients will eventually develop imatinib resistance and force to seek alternative therapy, such as bone marrow transplation. The molecular mechanism underlying imatinib resistance remains to be elusive and is complicated, therefore basic research concerning this is in urgent clinical needs. It has been reported that drug-resistance in leukemia treatment may be involved with epigenetic mechanism. As such, UTX, a well difined histone demethylase, has drawn much attention as a novel cancer drug target. We found in our preliminery studies that UTX might increase the reactivity of CML cultured cell to imatinib, possibly through increasing STAT5 expression and thereby inhibiting BCL6 function. Thess results suggest that undermined UTX function might be a novel mechanism for imatinib-resistance. We propose to study the role of UTX in imatinib-resistance in more detail by means of genetic and molecular stratagies in CML cells and in mouse model. We aim to present further theoretical basis for new targets of CML therapy.

伊马替尼作为治疗慢性粒细胞白血病（CML）的一线药物有着十分显著的疗效，但仍有约 30% 患者存在着原发或继发耐药，而其耐药机制复杂多样且尚未完全清楚。据文献报道，表观遗传学机制与多种白血病的耐药性关系密切。我们的前期研究发现，在CML细胞中，表观遗传学因子UTX表达下降可导致STAT5转录水平下降，而STAT5表达减少对BCL6表达起着促进作用，进而增强CML细胞对于伊马替尼的耐药性。因此我们推断UTX可能通过STAT5/BCL6通路参与CML细胞伊马替尼耐药的过程。本研究拟以CML细胞、患者以及模型鼠为研究对象，采用基因导入、基因沉默、基因敲除或特异性抑制剂等干预方法，研究UTX对CML细胞染色质结构的动态调控过程以及对相关信号分子表达的影响，以期探究UTX功能与CML细胞伊马替尼耐药的关系。对进一步阐明伊马替尼耐药的分子机制以及相关临床研究提供实验依据。