Molecular Pathogenesis of Secondary Acute Promyelocytic Leukemia

Abstract

Balanced chromosomal translocations that generate chimeric oncoproteins are considered to be initiating lesions in the pathogenesis of acute myeloid leukemia. The most frequent is the t(15;17)(q22;q21), which fuses the PML and RARA genes, giving rise to acute promyelocytic leukemia (APL). An increasing proportion of APL cases are therapy-related (t-APL), which develop following exposure to radiotherapy and/or chemotherapeutic agents that target DNA topoisomerase II (topoII), particularly mitoxantrone and epirubicin. To gain insights into molecular mechanisms underlying the formation of the t(15;17) we mapped the translocation breakpoints in a series of t-APLs, which revealed significant clustering according to the nature of the drug exposure. Remarkably, in approximately half of t-APL cases arising following mitoxantrone treatment for breast cancer or multiple sclerosis, the chromosome 15 breakpoint fell within an 8-bp “hotspot” region in PML intron 6, which was confirmed to be a preferential site of topoII-mediated DNA cleavage induced by mitoxantrone. Chromosome 15 breakpoints falling outside the “hotspot”, and the corresponding RARA breakpoints were also shown to be functional topoII cleavage sites. The observation that particular regions of the PML and RARA loci are susceptible to topoII-mediated DNA damage induced by epirubicin and mitoxantrone may underlie the propensity of these agents to cause APL.

Genomic analysis of therapy‐related acute promyelocytic leukemias arising after malignant and non‐malignant disorders

“…Seven of 12 patients received topoisomerase II targeting agents for the treatment of primary disease. By comparing RARA intron 2 breakpoint data of the present series with the previously reported cases of t-APL [7], we observed five RARA intron 2 breakpoints within 1-3 bp of one another (pts 2, 4, 5, 7, and 10). Patient 7 was diagnosed with Lewis-Sumner syndrome, a multifocal demyelinating neuropathy, did not receive topoisomerase II inhibitors before APL development.…”

Global characteristics of childhood acute promyelocytic leukemia

“…Under the WHO classification of AML (ICD-10 C92.0), t-AMLs following chemotherapy are considered to be distinct diagnostic entities [38], and the system recognizes two types of t-AML based on causative therapy: alkylating agent/radiation–related and a topoisomerase II inhibitor–related types [27]. Similar to therapy-related leukemias with MLL translocations, t-APL following treatment with topoisomerase II inhibitors has distinct breakpoints at chromosomal translocations involving the RAR α gene, which appear to be caused by the drug-topoisomerase ‘ cleavable complexes ’ [39, 40]. Such breakpoint features are a direct link between a causal exposure and leukemia, which hopefully could be extended to de novo or idiopathic APL in the future.…”

Investigation into experimental toxicological properties of plant protection products having a potential link to Parkinson's disease and childhood leukaemia†

“…Acute leukaemia is an adverse effect recorded in etoposide-treated patients, showing MLL rearrangements that are in many ways analogous to those in infant leukaemia Joannides et al, 2010Joannides et al, , 2011. Therefore the proposed AOP is supported by a number of convincing inferential evidences by means of using etoposide as a tool compound to empirically support the linkage between the proposed molecular initiating event (MIE) and the adverse outcome (AO).…”