Sitterlin D, Tiollais P, Transy C
Unité de Recombinaison et Expression Génétique (INSERM U163), Institut Pasteur, Paris, France.
Oncogene. 1997 Mar 6;14(9):1067-74. doi: 10.1038/sj.onc.1200916.
In most cases, Acute Promyelocytic Leukemia (APL) is associated with t(15;17) translocation which juxtaposes sequences from PML and retinoic acid receptor alpha (RAR alpha) genes. The generated PML-RAR alpha fusion interferes with wild type RAR alpha-mediated transcription and disrupts subnuclear compartments, known as PML bodies. Both defects are corrected by all trans retinoic acid (ATRA) therapy which induces differentiation of leukemic cells and clinical remission. In a rare APL syndrome associated with t(11;17), fusion of the RAR alpha gene with the PLZF gene, encoding a Zinc-finger protein produces two reciprocal RAR alpha chimeras. Although PLZF-RAR alpha and PML-RAR alpha are similar in their apparent dominant negative effects, t(11;17)-associated APL is refractory to ATRA therapy. In a yeast two-hybrid genetic screening, we isolated clones encoding the GAL4 transactivation domain fused to various parts of PLZF. Using these autonomously transactivating hybrids, similar in structure to the RAR alpha-PLZF fusion, we mapped the DNA-binding domain of PLZF to the last five Zinc-fingers, a region retained in RAR alpha-PLZF chimera and characterized a specific PLZF target sequence. Our data support the hypothesis that RAR alpha-PLZF chimera is not an inert product of reciprocal translocation and may thus contribute to ATRA unresponsiveness of t(11;17)-associated APL.
在大多数情况下，急性早幼粒细胞白血病（APL）与t(15;17)易位相关，该易位使早幼粒细胞白血病（PML）基因和维甲酸受体α（RARα）基因的序列并列。产生的PML-RARα融合蛋白干扰野生型RARα介导的转录，并破坏被称为PML小体的核内亚结构域。全反式维甲酸（ATRA）疗法可纠正这两个缺陷，该疗法可诱导白血病细胞分化并实现临床缓解。在一种与t(11;17)相关的罕见APL综合征中，RARα基因与编码锌指蛋白的PLZF基因融合，产生了两种相互的RARα嵌合体。尽管PLZF-RARα和PML-RARα在其明显的显性负效应方面相似，但与t(11;17)相关的APL对ATRA疗法无效。在一项酵母双杂交基因筛选中，我们分离出了编码与PLZF不同部分融合的GAL4反式激活结构域的克隆。使用这些自主反式激活的杂种，其结构与RARα-PLZF融合蛋白相似，我们将PLZF的DNA结合结构域定位到最后五个锌指，该区域保留在RARα-PLZF嵌合体中，并鉴定了一个特定的PLZF靶序列。我们的数据支持这样的假设，即RARα-PLZF嵌合体不是相互易位的惰性产物，因此可能导致与t(11;17)相关的APL对ATRA无反应。
