Comparative genomic analysis of PML and RARA breakpoints in paired diagnosis/relapse samples of patients with acute promyelocytic leukemia treated with a//-trans retinoic acid and chemotherapy

摘要

Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia characterized by a balanced reciprocal translocation between chromosomes 15 and 17, which results in the PML/RARA fusion gene. Currently, the use of a//-trans retinoic acid (ATRA) combined to anthracycline-based chemotherapy induces long-term remissions in at least 80% of APL cases, and a low probability of relapse around 10% [1,2]. Besides characterizing a proportion of de novo acute leukemias, nonrandom chromosomal translocations may be associated with therapy-related leukemias arising after cytotoxic treatment of malignant or nonmalignant disorders. In particular, it has been reported that the t(15;17) translocation occurring in therapy-related APL (t-APL) may result from exposure to cytotoxic drugs targeting the topoisomerase II (topo-ll) enzyme [3]. Mitoxantrone (MTZ), a topo-ll inhibitor, has been shown to induce DNA breakage in a 'hotspot' region of 8-bp within PML intron 6 in t-APLs developing after breast cancer [4]. The presence of this hotspot in the PML gene has been further confirmed in t-APL occurring in patients who received MTZ for the treatment of multiple sclerosis [5]. Finally, a biased distribution of breakpoints in RARA gene has been also described in de novo APL as compared to t-APL [6].