Dyck J A, Warrell R P, Evans R M, Miller W H
Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, CA, USA.
Blood. 1995 Aug 1;86(3):862-7.
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.
急性早幼粒细胞白血病（APL）的特征是存在一种一致的染色体畸变，即维甲酸受体α（RARα）基因与新基因PML融合，导致PML/RAR-α融合蛋白的表达。对APL细胞进行免疫组织化学检查显示，抗PML和抗RARα抗体标记呈现独特的异常分布。在正常细胞中观察到的PML标记模式由5至10个离散的球形核体组成，称为PODs（“PML致癌结构域”），而APL的标记模式则由较小且数量多得多的斑点状模式组成。我们通过免疫组织化学（IH）检查了患有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的细胞中未表达。在32例急性髓性白血病患者中，31例的IH结果与PML/RAR-α的逆转录聚合酶链反应结果一致，其中包括5例最初临床诊断为APL但细胞遗传学、分子检测或对全反式维甲酸（RA）的反应不支持该诊断的患者。在维甲酸治疗过程中以及完全缓解和复发时，对APL患者的细胞进行了检查。在接受RA治疗的患者的细胞中观察到PML标记重新组织成外观正常的PODs。IH显示在临床缓解期间主要为正常的PML染色，尽管在复发时从患者身上获取的细胞中再次出现了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一种独立的检测方法。检测APL特异性PML标记模式相对容易且快速，这应使IH成为指导APL特异性治疗的有用诊断工具，并为个体患者细胞中的PML/RAR-α蛋白表达和定位建立直接检测方法。
