Bartholomae Stephan, Gruhn Bernd, Debatin Klaus-Michael, Zimmermann Martin, Creutzig Ursula, Reinhardt Dirk, Steinbach Daniel
University of Ulm, Children's Hospital, Ulm, Germany.
Jena University Hospital, Department of Pediatrics, Jena, Germany.
Pediatr Blood Cancer. 2016 Feb;63(2):242-7. doi: 10.1002/pbc.25785. Epub 2015 Oct 29.
To analyze whether expression of ABC-transporters is associated with remission rate and long-term outcome in a prospective clinical trial of childhood acute myeloid leukemia (AML).
The expression of four ABC-transporter genes (ABCA3 encoding drug transporter ABCA3, ABCB1 encoding multidrug resistance protein 1, ABCC3 encoding multidrug resistance-associated protein 3, and ABCG2 encoding breast cancer resistance protein) was measured by TaqMan real time polymerase chain reaction in pretreatment samples from 112 children with AML. Patients were treated according to multicenter study AML-Berlin, Frankfurt, Munich (BFM) 2004.
ABCC3 (P = 0.009) and ABCG2 (P = 0.03) were associated with a lower chance to achieve remission after the first course of chemotherapy. ABCC3 was associated with lower relapse free survival (RFS) (P = 0.02). ABCG2 was expressed at higher levels in subtypes of AML with favorable outcome but within standard- and high-risk patients, it was associated with poor outcome (P = 0.02). A strong association was observed between the number of overexpressed ABC-transporters and the chance to achieve remission (P = 0.01) or the chance of RFS (P < 0.001).
The intensive treatment regimen of AML-BFM 2004 did not readily overcome drug resistance caused by ABC-transporters. Inhibition of ABC-transporters might be particularly useful in patients who express multiple of these genes.
在一项儿童急性髓系白血病（AML）的前瞻性临床试验中，分析ABC转运蛋白的表达与缓解率及长期预后是否相关。
采用TaqMan实时聚合酶链反应检测了112例AML患儿预处理样本中四个ABC转运蛋白基因（编码药物转运蛋白ABCA3的ABCA3、编码多药耐药蛋白1的ABCB1、编码多药耐药相关蛋白3的ABCC3以及编码乳腺癌耐药蛋白的ABCG2）的表达。患者按照多中心研究AML-柏林、法兰克福、慕尼黑（BFM）2004方案进行治疗。
ABCC3（P = 0.009）和ABCG2（P = 0.03）与首个化疗疗程后达到缓解的机会较低相关。ABCC与较低的无复发生存率（RFS）相关（P = 0.02）。ABCG2在预后良好的AML亚型中表达水平较高，但在标准风险和高风险患者中，它与不良预后相关（P = 0.02）。观察到过表达的ABC转运蛋白数量与达到缓解的机会（P = 0.01）或RFS机会（P < 0.001）之间存在强烈关联。
AML-BFM 2004的强化治疗方案未能轻易克服由ABC转运蛋白引起的耐药性。抑制ABC转运蛋白可能对表达多个此类基因的患者特别有用。
