Molecular emergence of acute myeloid leukemia during treatment for acute lymphoblastic leukemia

Therapy-related acute myeloid leukemias (t-AML) with translocations of the MLL gene are associated with the use of topoisomerase II inhibitors. We est ablished the emergence of the malignant clone in a child who developed t-AM L with a t(11;19) (q23;p13.3) during treatment for acute lymphoblastic leuk emia (ALL). The MLL-ENL and the reciprocal ENL-MLL genomic fusions and thei r chimeric transcripts were characterized from samples collected at the tim e of t-AML diagnosis. We used PCR with patient-specific genomic primers to establish the emergence of the MLL-ENL fusion in serially obtained DNA samp les. The MLL-ENL fusion was not detectable in bone marrow at the time of AL L diagnosis or after 2 months of chemotherapy (frequency <8.3 x 10(-7) cell s(-1)). The genomic fusion was first detected in bone marrow after 6 months of treatment at a frequency of one in 4,000 mononuclear bone marrow cells; the frequency was one in 70 cells after 20 months of therapy. At the first detection of MLL-ENL, the only topoisomerase II inhibitors the patient had received were one dose of daunorubicin and two doses of etoposide. The MLL -ENL fusion was not detectable in blood at the time of ALL diagnosis or aft er 0.7, 2, 8, 10, and 12 months of therapy but was detectable in blood at 1 6 months (one in 2.3 x 10(4) cells). Recombinogenic Alu sequences bracketed the breakpoints in both fusions. These data indicate that the malignant cl one was not present before therapy, arose early during chemotherapy, and wa s able to proliferate even during exposure to antileukemic therapy.