Rapid diagnosis of acute promyelocytic leukemia by immunohistochemical localization of PML/RAR-alpha protein.
Rapid diagnosis of acute promyelocytic leukemia by immunohistochemical localization of PML/RAR-alpha protein.
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DOI：
10.1182/blood.v86.3.862.bloodjournal863862
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发表时间：
1995-08
期刊：
影响因子：
20.3
通讯作者：
J. Dyck;R. Warrell;R. Evans;W. Miller
中科院分区：
文献类型：
--
作者：
J. Dyck;R. Warrell;R. Evans;W. Miller
急性早幼粒细胞白血病（APL）的特征在于一致的染色体畸变，其将视黄酸受体α（RAR α）基因与新基因PML融合，导致PML/RAR-α融合蛋白的表达。APL细胞的免疫组织化学检查显示抗PML和抗RAR α抗体标记的独特异常分布。在正常细胞中观察到的PML标记模式由5至10个离散的球形核小体组成，称为POD（"PML致癌结构域"），而APL的标记模式由更小且数量更多的斑点图案组成。我们通过免疫组织化学（IH）检测了多种造血系统癌症患者的恶性细胞，发现这种异常的PML模式在t（15; 17）相关白血病患者的细胞中表达，但在其他肿瘤性疾病患者中不表达。32例急性髓细胞性白血病患者中，31例的IH结果与PML/RAR-α的逆转录聚合酶链反应一致，其中5例患者的APL初步临床诊断未得到细胞遗传学、分子检测或对全反式维甲酸（RA）反应的支持。在维甲酸治疗过程中以及完全缓解和复发时检查APL患者的细胞。在接受RA的患者的细胞中观察到PML标记重组为具有正常外观的POD。IH在临床缓解期间主要表现为正常的PML染色，尽管在复发时取自患者的细胞中再次观察到APL特异性标记模式。因此，IH为APL分子重排的存在和表达提供了独立的测定。检测APL特异性PML标记模式的相对容易和速度应使IH成为指导APL特异性治疗的有用诊断工具，并建立单个患者细胞中PML/RAR-α蛋白表达和定位的直接测定。
Acute promyelocytic leukemia (APL) is characterized by a consistent chromosomal aberration that fuses the retinoic acid receptor alpha (RAR alpha) gene with the novel gene PML, resulting in the expression of a PML/RAR-alpha fusion protein. Immunohistochemical examination of APL cells shows a unique abnormal distribution of anti-PML and anti-RAR alpha antibody labeling. The PML labeling pattern observed in normal cells consists of 5 to 10 discrete spherical nuclear bodies called PODs (for "PML oncogenic domains"), whereas that of APL consists of a smaller and far more numerous speckled pattern. We examined malignant cells from patients with a variety of hematopoietic cancers by immunohistochemistry (IH) and found this abnormal PML pattern expressed in cells from patients with t(15;17)-associated leukemia but not in patients with other neoplastic disorders. IH results agreed with reverse transcription polymerase chain reaction for PML/RAR-alpha in 31 of 32 patients with acute myelogenous leukemia, including 5 of 5 patients in whom the initial clinical diagnosis of APL was not supported by cytogenetics, molecular tests, or response to all-trans retinoic acid (RA). Cells from patients with APL were examined during the course of retinoid therapy and at the time of complete remission and relapse. Reorganization of the PML labeling into PODs with normal appearance was observed in cells from patients who received RA. IH showed primarily normal PML staining during clinical remission, although the APL-specific labeling pattern was again seen in cells taken from patients at the time of relapse. Thus, IH provides an independent assay for the presence and expression of the molecular rearrangement of APL. The relative ease and speed of detecting the APL-specific PML labeling pattern should make IH a useful diagnostic tool to guide specific therapy of APL, and establish a direct assay for PML/RAR-alpha protein expression and localization in individual patient cells.