Raspadori Donatella, Damiani Daniela, Michieli Mariagrazia, Stocchi Raffaella, Gentili Sara, Gozzetti Alessandro, Masolini Paola, Michelutti Angela, Geromin Antonella, Fanin Renato, Lauria Francesco
Department of Hematology, University of Siena, Italy.
Haematologica. 2002 Nov;87(11):1135-40.
Overexpression of P-glycoprotein (PGP), a multidrug-related (MDR) protein, is one of the most important factors responsible for reduced drug sensitivity in acute myeloid leukemia (AML). Recently, we demonstrated that the presence of CD56 antigen, an isoform of the neural adhesion molecule, in AML cells is a negative independent prognostic factor for the achievement of complete remission (CR) and correlates with shorter survival. Since in our previous report we observed a more frequent PGP expression in CD56+ patients, we hypothesized that the reduced response to chemotherapy in this group of patients was due to increased PGP-mediated drug efflux. To confirm this hypothesis in this study PGP and CD56 expression on AML cells was correlated with other clinical and biological features and treatment response.
Immunophenotypic analysis, including evaluation of CD56 and PGP expression, was performed using multiparameter flow cytometry on fresh and/or cryopreserved blast cells, obtained after informed consent, from bone marrow and/or peripheral blood of 143 consecutive newly diagnosed AML cases at the time of diagnosis. Samples expressing CD56 in at least 15% or more cells were considered as positive (CD56+). PGP expression was expressed as a mean fluorescence index (MFI) i.e. as the ratio of sample mean fluorescence channel and the isotypic control mean fluorescence channel.
Overall results showed that 67/143 cases were PGP-/CD56-, 23/143 were PGP+ /CD56+, 40/143 were PGP+/CD56- and the remaining 13/143 were PGP-/CD56+. CD56+ and PGP+ on AML cells significantly reduced the CR rate (83% in the PGP-/CD56- group vs 60% in the PGP-/CD56+ group, 46% in the PGP+/CD56- group and 58% in the PGP+/CD56+ group, p = 0.002). In addition we observed a significantly higher proportion of total failures in patients expressing PGP or CD56 compared to in the group not expressing either (73% vs 27%, respectively; p = 0.0001). CD56 and PGP overexpression influenced the overall survival: in fact, the median survival of CD56+ and PGP+ patients ranged from 10 to 23 months, while the actuarial survival of CD56-/PGP- patients at 5 years is 52% (p = 0.023).
Our data underline the independent negative prognostic role of PGP and CD56 expression in acute myeloid leukemia. Since the mechanism by which CD56 reduces drug sensitivity is still unknown, further investigations are required.
P-糖蛋白（PGP）是一种多药耐药（MDR）蛋白，其过表达是急性髓系白血病（AML）药物敏感性降低的最重要因素之一。最近，我们证明AML细胞中神经粘附分子的一种同种型CD56抗原的存在是实现完全缓解（CR）的独立阴性预后因素，并且与较短的生存期相关。由于在我们之前的报告中，我们观察到CD56阳性患者中PGP表达更频繁，我们推测这组患者对化疗反应降低是由于PGP介导的药物外排增加。为了在本研究中证实这一假设，对AML细胞上的PGP和CD56表达与其他临床和生物学特征及治疗反应进行了相关性分析。
对143例连续新诊断的AML患者在诊断时经知情同意后从骨髓和/或外周血获取的新鲜和/或冻存的原始细胞，使用多参数流式细胞术进行免疫表型分析，包括评估CD56和PGP表达。至少15%或更多细胞表达CD56的样本被视为阳性（CD56+）。PGP表达以平均荧光指数（MFI）表示，即样本平均荧光通道与同型对照平均荧光通道的比值。
总体结果显示，67/143例为PGP-/CD56-，23/143例为PGP+/CD56+，40/143例为PGP+/CD56-，其余13/143例为PGP-/CD56+。AML细胞上的CD56+和PGP+显著降低了CR率（PGP-/CD56-组为83%，PGP-/CD56+组为60%，PGP+/CD56-组为46%，PGP+/CD56+组为58%，p = 0.002）。此外，我们观察到与不表达PGP或CD56的组相比，表达PGP或CD56患者的总失败比例显著更高（分别为73%和27%；p = 0.0001）。CD56和PGP过表达影响总生存期：事实上，CD56+和PGP+患者的中位生存期为10至23个月，而CD56-/PGP-患者5年的精算生存率为52%（p = 0.023）。
我们的数据强调了PGP和CD56表达在急性髓系白血病中的独立阴性预后作用。由于CD56降低药物敏感性的机制仍不清楚，需要进一步研究。
