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早幼粒细胞白血病PML/RARα蛋白对分化的影响取决于PML蛋白二聚化结构域与RARα DNA结合结构域的融合。

Effects on differentiation by the promyelocytic leukemia PML/RARalpha protein depend on the fusion of the PML protein dimerization and RARalpha DNA binding domains.

作者信息

Grignani F, Testa U, Rogaia D, Ferrucci P F, Samoggia P, Pinto A, Aldinucci D, Gelmetti V, Fagioli M, Alcalay M, Seeler J, Grignani F, Nicoletti I, Peschle C, Pelicci P G

机构信息

Istituto di Clinica Medica I, Policlinico Monteluce, Perugia University, Italy.

出版信息

EMBO J. 1996 Sep 16;15(18):4949-58.

PMID:8890168
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC452232/
Abstract

The block of terminal differentiation is a prominent feature of acute promyelocytic leukemia (APL) and its release by retinoic acid correlates with disease remission. Expression of the APL-specific PML/RARalpha fusion protein in hematopoietic precursor cell lines blocks terminal differentiation, suggesting that PML/ RARalpha may have the same activity in APL blasts. We expressed different PML/RARalpha mutants in U937 and TF-1 cells and demonstrated that the integrity of the PML protein dimerization and RARalpha DNA binding domains is crucial for the differentiation block induced by PML/RARalpha, and that these domains exert their functions only within the context of the fusion protein. Analysis of the in vivo dimerization and cell localization properties of the PML/RARalpha mutants revealed that PML/RARalpha--PML and PML/RARalpha--RXR heterodimers are not necessary for PML/RARalpha activity on differentiation. We propose that a crucial mechanism underlying PML/RARalpha oncogenic activity is the deregulation of a transcription factor, RARalpha, through its fusion with the dimerization interface of another nuclear protein, PML.

摘要

终末分化阻滞是急性早幼粒细胞白血病（APL）的一个显著特征，而维甲酸使其解除阻滞与疾病缓解相关。APL特异性的PML/RARα融合蛋白在造血前体细胞系中的表达会阻滞终末分化，这表明PML/RARα在APL原始细胞中可能具有相同的活性。我们在U937和TF-1细胞中表达了不同的PML/RARα突变体，并证明PML蛋白二聚化和RARα DNA结合结构域的完整性对于PML/RARα诱导的分化阻滞至关重要，且这些结构域仅在融合蛋白的背景下发挥其功能。对PML/RARα突变体的体内二聚化和细胞定位特性的分析表明，PML/RARα-PML和PML/RARα-RXR异二聚体对于PML/RARα在分化上的活性并非必需。我们提出，PML/RARα致癌活性的一个关键机制是转录因子RARα通过与另一种核蛋白PML的二聚化界面融合而发生失调。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60d8/452232/205c372e3330/emboj00018-0174-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60d8/452232/7cec197bed36/emboj00018-0170-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60d8/452232/19b299709a03/emboj00018-0171-a.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60d8/452232/6de7ca80aaf8/emboj00018-0172-b.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60d8/452232/205c372e3330/emboj00018-0174-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60d8/452232/7cec197bed36/emboj00018-0170-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60d8/452232/19b299709a03/emboj00018-0171-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60d8/452232/be669e274eee/emboj00018-0172-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60d8/452232/6de7ca80aaf8/emboj00018-0172-b.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60d8/452232/205c372e3330/emboj00018-0174-a.jpg

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本文引用的文献

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Acute promyelocytic leukemia.急性早幼粒细胞白血病
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ATO 通过增强钙蛋白酶介导的癌症生存蛋白 TG2 的降解来增加细胞 ROS 产生和凋亡。
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Benefits of Combined All-Trans Retinoic Acid and Arsenic Trioxide Treatment of Acute Promyelocytic Leukemia Cells and Further Enhancement by Inhibition of Atypically Expressed Transglutaminase 2.全反式维甲酸与三氧化二砷联合治疗急性早幼粒细胞白血病细胞的益处及通过抑制异常表达的转谷氨酰胺酶2进一步增强疗效
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Retinoic acid and arsenic trioxide induce lasting differentiation and demethylation of target genes in APL cells.维甲酸和三氧化二砷诱导 APL 细胞中靶基因的持久分化和去甲基化。
Sci Rep. 2019 Jul 1;9(1):9414. doi: 10.1038/s41598-019-45982-7.
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Establishment of a humanized APL model via the transplantation of PML-RARA-transduced human common myeloid progenitors into immunodeficient mice.通过将PML-RARA转导的人类普通髓系祖细胞移植到免疫缺陷小鼠中建立人源化急性早幼粒细胞白血病（APL）模型。
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The DNA binding property of PML/RARA but not the integrity of PML nuclear bodies is indispensable for leukemic transformation.PML/RARA的DNA结合特性而非PML核体的完整性对于白血病转化是必不可少的。
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Targeting the acute promyelocytic leukemia-associated fusion proteins PML/RARα and PLZF/RARα with interfering peptides.用干扰肽靶向急性早幼粒细胞白血病相关融合蛋白 PML/RARα 和 PLZF/RARα。
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PMLRAR homodimers: distinct DNA binding properties and heteromeric interactions with RXR.PML-RAR同源二聚体：独特的DNA结合特性以及与RXR的异源相互作用。
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Fusion between transcription factor CBF beta/PEBP2 beta and a myosin heavy chain in acute myeloid leukemia.急性髓系白血病中转录因子CBFβ/PEBP2β与肌球蛋白重链之间的融合
Science. 1993 Aug 20;261(5124):1041-4. doi: 10.1126/science.8351518.
6
Retinoic acid regulates aberrant nuclear localization of PML-RAR alpha in acute promyelocytic leukemia cells.维甲酸调节急性早幼粒细胞白血病细胞中PML-RARα的异常核定位。
Cell. 1994 Jan 28;76(2):345-56. doi: 10.1016/0092-8674(94)90341-7.
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A novel macromolecular structure is a target of the promyelocyte-retinoic acid receptor oncoprotein.一种新型大分子结构是早幼粒细胞-视黄酸受体癌蛋白的作用靶点。
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Blood. 1994 Jan 1;83(1):10-25.
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Cloning of the ALL-1 fusion partner, the AF-6 gene, involved in acute myeloid leukemias with the t(6;11) chromosome translocation.参与伴有t(6;11)染色体易位的急性髓性白血病的ALL-1融合伴侣AF-6基因的克隆。
Cancer Res. 1993 Dec 1;53(23):5624-8.
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A novel gene, AF-1p, fused to HRX in t(1;11)(p32;q23), is not related to AF-4, AF-9 nor ENL.一个与HRX在t(1;11)(p32;q23)中融合的新基因AF-1p，与AF-4、AF-9和ENL均无关联。
Oncogene. 1994 Apr;9(4):1039-45.