Yang J, Bogni A, Cheng C, Bleibel W K, Cai X, Fan Y, Yang W, Rocha J C C, Pei D, Liu W, Dolan M E, Pui C-H, Relling M V
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Clin Pharmacol Ther. 2008 Dec;84(6):691-7. doi: 10.1038/clpt.2008.86. Epub 2008 May 28.
Therapy-related acute myeloid leukemia (t-AML) caused by MLL rearrangements (rMLL) can arise from topoisomerase II agents. However, whether rMLL-related leukemogenesis is inextricably linked to drug cytotoxicity remains controversial. We therefore compared (i) rMLL in children with acute lymphoblastic leukemia (ALL) who developed t-AML and those who did not, (ii) epipodophyllotoxin toxicity in patients with t-AML and in controls, and (iii) rMLL in cells sensitive to etoposide and in those resistant to etoposide. In children with ALL, rMLL appeared to be more frequent in children who developed t-AML than in those who did not (seven pairs, P = 0.04), although independent of the cumulative etoposide dose (P = 0.5). Similarly, the frequency of epipodophyllotoxin-related toxicities did not differ between patients with t-AML and controls (26 pairs, P > 0.17). Moreover, in 25 cell lines, etoposide-induced MLL fusions did not differ in sensitive vs. resistant lines at equitoxic concentrations (P = 0.65). Together, these results indicate that epipodophyllotoxin-mediated leukemogenesis is not directly linked to drug cytotoxicity.
由MLL重排（rMLL）引起的治疗相关急性髓系白血病（t-AML）可由拓扑异构酶II抑制剂诱发。然而，rMLL相关的白血病发生是否与药物细胞毒性有着千丝万缕的联系仍存在争议。因此，我们比较了以下几组情况：（i）发生t-AML的急性淋巴细胞白血病（ALL）患儿与未发生t-AML的ALL患儿中的rMLL；（ii）t-AML患者与对照组患者中表鬼臼毒素的毒性；（iii）对依托泊苷敏感的细胞与对依托泊苷耐药的细胞中的rMLL。在ALL患儿中，发生t-AML的患儿rMLL似乎比未发生t-AML的患儿更常见（7对，P = 0.04），尽管与依托泊苷的累积剂量无关（P = 0.5）。同样，t-AML患者与对照组患者中表鬼臼毒素相关毒性的发生率没有差异（26对，P > 0.17）。此外，在25个细胞系中，在等毒性浓度下，依托泊苷诱导的MLL融合在敏感细胞系和耐药细胞系中没有差异（P = 0.65）。总之，这些结果表明表鬼臼毒素介导的白血病发生与药物细胞毒性没有直接联系。
