Etoposide sensitivity does not predict MLL rearrangements or risk of therapy-related acute myeloid leukemia

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.