Molecular biology of therapy-related leukaemias.
Therapy-related leukaemias are becoming an increasing healthcare problem as more patients survive their primary cancers. The nature of the causative agent has an important bearing upon the characteristics, biology, time to onset and prognosis of the resultant leukaemia. Agents targeting topoisomerase II induce acute leukaemias with balanced translocations that generally arise within 3 years, often involving the MLL, RUNX1 and RARA loci at 11q23, 21q22 and 17q21 respectively. Chromosomal breakpoints have been found to be preferential sites of topoisomerase II cleavage, which are believed to be repaired by the nonhomologous end-joining DNA repair pathway to generate chimaeric oncoproteins that underlie the resultant leukaemias. Therapy-related acute myeloid leukaemias occurring after exposure to antimetabolites and/or alkylating agents are biologically distinct with a longer latency period, being characterised by more complex karyotypes and loss of p53. Although treatment of therapy-related leukaemias represents a considerable challenge due to prior therapy and comorbidities, curative therapy is possible, particularly in those with favourable karyotypic features.
Joannides
Melanie
M
Department of Medical & Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London, UK.
Grimwade
David
D
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects; D019457:Chromosome Breakage / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics; D004250:DNA Topoisomerases, Type II / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000139:chemically induced / Q000235:genetics*; D008954:Models, Biological; D008967:Molecular Biology; D016609:Neoplasms, Second Primary / Q000139:chemically induced / Q000235:genetics*
D018906:Antineoplastic Agents, Alkylating; D004250:DNA Topoisomerases, Type II