List A F, Spier C S, Grogan T M, Johnson C, Roe D J, Greer J P, Wolff S N, Broxterman H J, Scheffer G L, Scheper R J, Dalton W S
Section of Haematology/Oncology, Arizona Cancer Center, University of Arizona, Tucson, AZ 85724 USA.
Blood. 1996 Mar 15;87(6):2464-9.
The monoclonal antibody LRP56 recognizes a 110-kD major vault protein (lung-resistance protein [LRP]) overexpressed in several P-glycoprotein-negative (Pgp-), multidrug resistant tumor cell lines. To determine the frequency of LRP overexpression, its prognostic significance, and its relation to Pgp, we analyzed bone marrow specimens from 87 consecutive patients with acute leukemia. Diagnoses included de novo acute myeloid leukemia (AML; 21 patients), leukemia arising from an antecedent hematologic disorder or prior cytotoxic therapy (secondary AML; 27 patients), AML in relapse (29 patients), and blast phase of chronic myeloid leukemia (CML-BP; 10 patients). A granular cytoplasmic staining pattern was detected by immunocytochemistry in 32 (37%) cases, including 7 (33%) de novo AML, 13 (48%) secondary AML, 11 (38%) relapsed AML, and 1 of 10 CML-BP. Among 66 evaluable patients with AML, LRP overexpression was associated with an inferior response to induction chemotherapy (P = .0017). Remissions were achieved in 35% of LRP+ patients as compared with 68% of LRP- patients. Although Pgp adversely affected response in univariate analysis (P = .0414), only LRP had independent prognostic significance when compared in a logistic regression model (P = .0046). Differences in remission duration (P = .075) and overall survival (P = .058) approached significance only for LRP. Sequential specimens from remitting patients receiving treatment with the Pgp modulator cyclosporin-A showed emergence of the LRP phenotype despite a decrease or loss of Pgp at the time of treatment failure (P =.0304). Significant associations were observed between LRP and age greater than 55 years (P = .017), Pgp (P = .040), and prior treatment with mitoxantrone (P = .020) but not with CD34. These findings indicate that overexpression of the novel transporter protein LRP is an important predictor of treatment outcome in AML.
单克隆抗体LRP56可识别一种110-kD的主要穹窿蛋白（肺耐药蛋白[LRP]），该蛋白在几种P-糖蛋白阴性（Pgp-）、多药耐药肿瘤细胞系中过表达。为了确定LRP过表达的频率、其预后意义以及它与Pgp的关系，我们分析了87例连续急性白血病患者的骨髓标本。诊断包括初发急性髓系白血病（AML；21例患者）、由先前血液系统疾病或先前细胞毒性治疗引起的白血病（继发性AML；27例患者）、复发的AML（29例患者）以及慢性髓系白血病急变期（CML-BP；10例患者）。通过免疫细胞化学在32例（37%）病例中检测到颗粒状胞质染色模式，包括7例（33%）初发AML、13例（48%）继发性AML、11例（38%）复发AML以及10例CML-BP中的1例。在66例可评估的AML患者中，LRP过表达与诱导化疗反应较差相关（P = 0.0017）。LRP阳性患者的缓解率为35%，而LRP阴性患者为68%。虽然在单因素分析中Pgp对反应有不利影响（P = 0.0414），但在逻辑回归模型中比较时，只有LRP具有独立的预后意义（P = 0.0046）。仅LRP在缓解持续时间（P = 0.075）和总生存期（P = 0.058）方面的差异接近显著。接受Pgp调节剂环孢素A治疗的缓解患者的序贯标本显示，尽管在治疗失败时Pgp减少或消失，但LRP表型仍出现（P = 0.0304）。观察到LRP与年龄大于55岁（P = 0.017）、Pgp（P = 0.040）以及先前用米托蒽醌治疗（P = 0.020）之间存在显著关联，但与CD34无关。这些发现表明，新型转运蛋白LRP的过表达是AML治疗结果的重要预测指标。
