Department of Hematology, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu, China.
Int J Lab Hematol. 2010 Jun;32(3):344-50. doi: 10.1111/j.1751-553X.2009.01190.x. Epub 2009 Oct 26.
Several additional promyelocytic/retinoic acid receptor-alpha (PML/RARalpha) transcripts besides bcr1, bcr2, and bcr3 have been identified in patients with acute promyelocytic leukemia (APL). However, the expression levels of these specific isoforms and their clinical relevance have not been studied to date. The real-time quantitative polymerase chain reaction was established to detect each specific isoform of PML/RARalpha transcripts (bcr1/2, P46R3, P4R3, bcr3, and P2R3) in 46 APL patients. Whereas P46R3 and P4R3 isoforms were concurrently expressed in both bcr1- and bcr2-positive patients, P2R3 isoform was expressed only in bcr3-positive patients. A total of 13 patients had lower expression of bcr1/2 (median 11.60%, 0.86-108.51%) than that of P46R3 (median 14.26%, 6.03-222.91%; P = 0.001). The expression level of P4R3 (median 19.10%, 0.71-266.19%) was lower than the sum of bcr1/2 and P46R3 (median 37.94%, 9.62-403.51%) in all cases (P < 0.001). All 16 cases with bcr3 had concurrent low expression of P2R3 (P < 0.001). Structural analysis revealed that both P4R3 and P2R3 splicing resulting in the generation of a premature termination codon, which was recognized by nonsense-mediated decay (NMD). We suggest that alternative splicing of PML/RARalpha transcripts might be involved in NMD and each isoform should be quantified to further understand the pathogenesis of APL, stratify the risk of relapse, and monitor minimal residual disease.
除了 bcr1、bcr2 和 bcr3 之外，在急性早幼粒细胞白血病（APL）患者中还发现了几种其他的早幼粒细胞/维甲酸受体-α（PML/RARα）转录本。然而，迄今为止，这些特定亚型的表达水平及其临床相关性尚未得到研究。本研究建立了实时定量聚合酶链反应，以检测 46 例 APL 患者中 PML/RARα 转录本的每种特定亚型（bcr1/2、P46R3、P4R3、bcr3 和 P2R3）。虽然 P46R3 和 P4R3 亚型同时在 bcr1-和 bcr2-阳性患者中表达，但 P2R3 亚型仅在 bcr3-阳性患者中表达。共有 13 例患者 bcr1/2 的表达水平较低（中位数 11.60%，0.86-108.51%），低于 P46R3（中位数 14.26%，6.03-222.91%；P=0.001）。所有病例中 P4R3 的表达水平（中位数 19.10%，0.71-266.19%）均低于 bcr1/2 和 P46R3 的总和（中位数 37.94%，9.62-403.51%）（P<0.001）。所有 16 例 bcr3 患者均同时存在 P2R3 低表达（P<0.001）。结构分析表明，PML/RARα 转录本的剪接会导致提前终止密码子的产生，从而被无意义介导的衰变（NMD）所识别。我们认为 PML/RARα 转录本的选择性剪接可能参与 NMD，应定量检测每种亚型，以进一步了解 APL 的发病机制、分层复发风险，并监测微小残留病。
