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

突变型PML-RARα引起急性早幼粒细胞白血病ATRA耐药机制及改变的研究

• 批准号: 15591081
• 负责人: FUJII Kunihiro
• 金额: $ 2.24万
• 依托单位: TOHOKU UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15591081/
• 关键词: Acute promyelocytic leukemia; mutant PML-RARa; ATRA-resistance; Am80; Am80; PML; MRDモニタリング; FLT3遺伝子; 急性前骨髄球性白血病; 変異PML-RARα; 分子標的療法; アポトーシス

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.

PML-RAR α突变体引起ATRA耐药的研究在这项研究中，我们研究了人APL细胞系UF-1的细胞和分子RA反应，该细胞系是从一名具有ATRA耐药和PML-RAR α嵌合蛋白突变的患者中建立的。对于细胞RA反应，在用类维生素A处理的UF-1细胞中评价分化和凋亡。对于分子RA应答，测定PML-RAR α嵌合蛋白的RA依赖性转录活性和PML-RAR α、RAR α、RAR β和RAR γ的RT-PCR。在100 nM或更低剂量的ATRA和Am 80的反应中，既没有检测到细胞也没有检测到分子RA反应。相比之下，在响应于1 □M ATRA和Am 80时，UF-1显示出具有凋亡的完全成熟，而突变体PML-RAR α的分子RA响应是不足的。这些发现表明，UF-1细胞的ATRA反应的剂量依赖性改变可能是通过突变PML-RARa与其他内在核RA受体之间的相互作用来确定的。

项目成果

Alteration in the cellular response to retinoic acid of a human acute promyelocytic leukemia cell line, UF-1, carrying a patient-derived mutant PML-RARalpha chimeric gene.

携带源自患者的突变 PML-RARα 嵌合基因的人急性早幼粒细胞白血病细胞系 UF-1 对视黄酸的细胞反应发生变化。

• 发表时间: 2004
• 期刊: Leukemia Research 28(9)
• 作者: Atsushi Sato

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