Study on mechanism and alteration of ATRA-resistance caused by mutant PML-RARα in acute promyelocytic leukemia

突变体PML-RAR α对atra抗性的研究在这项研究中，我们检测了人类APL细胞系UF-1的细胞和分子ra反应，该细胞系来自于一名具有atra抗性和PML-RAR α嵌合蛋白突变的患者。在细胞ra反应中，对类维生素a处理的UF-1细胞的分化和凋亡进行了评估。对于分子上的ra反应，我们检测了PML-RARa嵌合蛋白的ra依赖性转录活性以及PML-RAR α、RAR α、RAR β和RAR γ的RT-PCR。在100 nM或更低剂量的ATRA和Am80作用下，细胞和分子均未检测到ra反应。相比之下，在1□M ATRA和Am80的作用下，UF-1表现出全面的成熟和凋亡，而突变体PML-RARa的分子ra反应不足。这些发现表明，UF-1细胞的剂量依赖性改变可能是通过突变的PML-RARa与其他内在核RA受体之间的相互作用来确定的。

Study on ATRA-resistance caused by mutant PML-RAR α ; In this study, we examined the cellular and molecular RA-response of a human APL cell line, UF-1, established from a patient who had ATRA-resistance and a mutation in the PML-RAR α chimeric protein. For cellular RA-response, differentiation and apoptosis was evaluated in UF-1 cells treated with retinoids. For molecular RA-response, RA-dependent transcriptional activity of PML-RARa chimeric protein and RT-PCR of PML-RAR α, RAR α, RAR β, and RAR γ was determined. In response to ATRA and Am80 at 100 nM or lower doses, neither cellular nor molecular RA-response was detected. By contrast, in response to 1 □M ATRA and Am80, UF-1 showed a full-scaled maturation with apoptosis, whereas molecular RA-response of the mutant PML-RARa was insufficient. These findings suggest that the dose-dependently altered ATRA-response of UF-1 cells may be determined through the interaction between the mutant PML-RARa and other intrinsic nuclear RA receptors.