Clinical and Translational Oncology

, Volume 12, Issue 1, pp 8–14 | Cite as

Molecular biology of therapy-related leukaemias

Educational Series


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 non-homologous 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.


Topoisomerase Therapy-related AML Alkylating agents 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Kollmannsberger C, Hartman JT, Kanz L, Bokemeyer C (1998) Risk of secondary myeloid leukaemia and myelodysplastic syndrome following standard-dose chemotherapy or high-dose chemotherapy with stem cell support in patients with potentially curable malignancies. J Cancer Res Clin Oncol 124:207–214CrossRefPubMedGoogle Scholar
  2. 2.
    Rowley JD, Golomb HM, Vardiman JW (1977) Nonrandom chromosomal abnormalities in acute nonlymphocytic leukemia in patients treated for Hodgkin’s disease and non-Hodgkin’s lymphoma. Blood 50:759–770Google Scholar
  3. 3.
    Leone G, Luca M, Alessandro P et al (1999) The incidence of secondary leukaemias. Haematologica 84:937–945PubMedGoogle Scholar
  4. 4.
    Pedersen-Bjergaard J, Andersen MK, Christiansen DH, Nerlov C (2002) Genetic pathways in therapy-related myelodysplasia and acute myeloid leukemia Blood 99:1909–1912CrossRefPubMedGoogle Scholar
  5. 5.
    Harris NL Jaffe ES, Diebold J et al (1999) World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting. Airlie House, Virginia, November 1997. J Clin Oncol 17:3835–3849PubMedGoogle Scholar
  6. 6.
    Rowley JD, Olney H (2002) International workshop on the relationship of prior therapy to balanced chromosome aberrations in therapy related myelodysplastic syndromes and acute leukemia: overview report. Genes Chromosomes Cancer 33: 331–345CrossRefPubMedGoogle Scholar
  7. 7.
    Ahuja HG, Felix CA, Aplan PD (2000) Potential role of DNA topoisomerase II poisons in the generation of t(11;20)(p15;q11) translocations. Genes Chromosomes Cancer 29:96–105CrossRefPubMedGoogle Scholar
  8. 8.
    Pedersen-Bjergaard J, Andersen MK, Andersen MT, Christiansen DH (2008) Genetics of therapy related myelodysplasia and acute myeloid leukemia. Leukemia 22:240–248CrossRefPubMedGoogle Scholar
  9. 9.
    Swerdlow SH, Campo E, Harris NL et al (eds) (2008) WHO classification of tumours of haematopoietic and lymphoid tissues. IARC, LyonGoogle Scholar
  10. 10.
    Carli PM, Sgro C, Parchin-Geneste N et al (2000) Increase therapy-related leukemia secondary to breast cancer. Leukemia 14:1014–1017CrossRefPubMedGoogle Scholar
  11. 11.
    Beaumont M, Sanz M, Carli PM et al (2003) Therapy-related acute promyelocytic leukemia. J Clin Oncol 21:2123–2137CrossRefPubMedGoogle Scholar
  12. 12.
    Sanz MA, Grimwade D, Tallman MS et al (2009) Management of acute promyelocytic leukemia: Recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 113:1875–1891CrossRefPubMedGoogle Scholar
  13. 13.
    Grimwade D, Hills RK (2009) Independent prognostic factors for AML outcome. Hematology Am Soc Hematol Educ Program 385–395Google Scholar
  14. 14.
    Hartwell LH, Hood L, Goldberg ML et al (2006) Genetics: from genes to genomes, 3rd edn. McGraw-Hill Science, New YorkGoogle Scholar
  15. 15.
    Osheroff N, Zechiedrich LE, Gale KC (1991) Catalytic function of DNA topoisomerase II. BioEssays 13:269–273CrossRefPubMedGoogle Scholar
  16. 16.
    McClendin K, Osheroff N (2007) DNA topoisomerase II, genotoxicity, and cancer. Mutat Res 623:83–97Google Scholar
  17. 17.
    Burden A, Osheroff N (1998) Mechanism of action of eukaryotic topoisomerase II and drugs targeted to the enzyme. Biochim Biophys Acta 1400:139–154PubMedGoogle Scholar
  18. 18.
    Zechiedrich EL, Osheroff N (1990) Eukaryotic topoisomerases recognize nucleic acid topology by preferentially interacting with DNA crossovers. EMBO J 9:4555–4562PubMedGoogle Scholar
  19. 19.
    Hagerman PJ (1988) Flexibility of DNA. Annu Rev Biophys Chem 17:265–286CrossRefGoogle Scholar
  20. 20.
    Spitzner JR, Muller MT (1988) A consensus sequence for cleavage by vertebrate DNA topoisomerase II. Nucleic Acids Res 16:5533–5556CrossRefPubMedGoogle Scholar
  21. 21.
    Deweese JE, Osheroff N (2008) The DNA cleavage reaction of topoisomerase II: wolf in sheep’s clothing. Nucleic Acids Res 37:738–748CrossRefPubMedGoogle Scholar
  22. 22.
    Deweese JE, Osheroff MA, Osheroff N (2009) DNA topology and topoisomerases: teaching a knotty subject. Biochem Mol Biol Educ 37:2–10CrossRefGoogle Scholar
  23. 23.
    Baguley BC, Ferguson LR (1998) Mutagenetic properties of topoisomerase-targeted drugs. Biochim Biophys Acta 1400:213–222PubMedGoogle Scholar
  24. 24.
    Sander M, Hsieh T (1982) Double strand DNA cleavage by type ll DNA topoisomerase from Drosophila melanogaster. J Biol Chem 285:8421–8428Google Scholar
  25. 25.
    Muller BU, Spitzner JR, DiDonato JA et al (1988) Single-strand DNA cleaves by eukaryotic topoisomerase ll. Biochemistry 27:8369–8379CrossRefPubMedGoogle Scholar
  26. 26.
    Liu LF, Rowe TC, Yang L et al (1983) Cleavage of DNA by mammalian DNA topoisomerase ll. J Biol Chem 258:15365–15370PubMedGoogle Scholar
  27. 27.
    Felix CA (2001) Leukemias related to treatment with DNA topoisomerase II inhibitors. Med Pediatr Oncol 36:525–535CrossRefPubMedGoogle Scholar
  28. 28.
    Allan JM, Travis LB (2005) Mechanisms of therapy related carcinogenesis. Nat Rev 5:943–955Google Scholar
  29. 29.
    Mori H, Colman SM, Xiao Z et al (2002) Chromosome translocations and covert leukemic clones are generated during normal fetal development. Proc Natl Acad Sci U S A 99:8242–8247CrossRefPubMedGoogle Scholar
  30. 30.
    Basecke J, Cepek L, Mannhalter C et al (2002) Transcription of AML1/ETO in bone marrow and cord blood of individuals without acute myelogenous leukemia. Blood 100:2267–2268CrossRefPubMedGoogle Scholar
  31. 31.
    Stanulla M, Wang J, Chervinsky DS et al (1997) DNA cleavage within the MLL breakpoint cluster region is a specific event which occurs as part of higher-order chromatin fragmentation during the initial stages of apoptosis. Mol Cell Biol 17:4070–4079PubMedGoogle Scholar
  32. 32.
    Betti CJ, Villalobos MJ, Diaz MO, Vaughan AT (2001) Apoptotic triggers initiate translocations within the MLL gene involving non-homologous end joining repair system. Cancer Res 61:4550–4555PubMedGoogle Scholar
  33. 33.
    Sim SP, Liu LF (2001) Nucleolytic cleavage of the mixed lineage leukemia breakpoint cluster region during apoptosis. J Biol Chem 276:31590–31595CrossRefPubMedGoogle Scholar
  34. 34.
    Betti CJ, Villalobos MJ, Diaz MO, Vaughan AT (2003) Apoptotic stimuli initiate MLL-AF9 translocations that are transcribed in cells capable of division. Cancer Res 63:1377–1381PubMedGoogle Scholar
  35. 35.
    Felix CA, Kolaris CP, Osheroff N (2006) Topoisomerase II and the etiology of chromosomal translocations. DNA Repair (Amst) 5:1093–1108CrossRefGoogle Scholar
  36. 36.
    Lovett BD, Strumberg D, Blair IA et al (2001) Etoposide metabolites enhance DNA topoisomerase II cleavage near leukemia-associated MLL translocation breakpoints. Biochemistry 40:1159–1170CrossRefPubMedGoogle Scholar
  37. 37.
    Lovett BD, Lo Nigro L, Rappaport EF et al (2001) Near-precise interchromosomal recombination and functional DNA topoisomerase II cleavage sites at MLL and AF-4 genomic breakpoints in treatment-related acute lymphoblastic leukemia with t(4;11) translocation. Proc Natl Acad Sci U S A 98:9802–9807CrossRefPubMedGoogle Scholar
  38. 38.
    Whitmarsh RJ, Saginario C, Zhuo Y et al (2003) Reciprocal DNA topoisomerase II cleavage events at 5′-TATTA-3′ sequences in MLL and AF-9 create homologous single-stranded overhangs that anneal to form der(11) and der(9) genomic breakpoint junctions in treatment-related AML without further processing. Oncogene 22:8448–8459CrossRefPubMedGoogle Scholar
  39. 39.
    Mistry AR, Felix CA, Whitmarsh RJ et al (2005) DNA topoisomerase II in therapy related acute promyelocytic leukemia. N Engl J Med 352:1529–1538CrossRefPubMedGoogle Scholar
  40. 40.
    Fortune JM, Osheroff N (2000) Topoisomerase II as a target for anticancer drugs: when enzymes stop being nice. Prog Nucleic Acid Res Mol Biol 64:221–253CrossRefPubMedGoogle Scholar
  41. 41.
    Hasan SK, Mays AN, Ottone T et al (2008) Molecular analysis of t(15;17) genomic breakpoints in secondary acute promyelocytic leukemia arising after treatment of multiple sclerosis. Blood 112:3383–3390CrossRefPubMedGoogle Scholar
  42. 42.
    Mays AN, Osheroff N, Xiao Y et al (2009) Evidence for direct involvement of epirubicin in the formation of chromosomal translocations in t(15;17) therapy-related acute promyelocytic leukemia. Blood [Epub ahead of print]Google Scholar
  43. 43.
    Ghalie RG, Mauch E, Edan G et al (2002) A study of therapy-related acute leukaemia after mitoxantrone therapy for multiple sclerosis. Mult Scler 8:441–445CrossRefPubMedGoogle Scholar
  44. 44.
    Pedersen-Bjergaard J, Specht L, Larsen SO et al (1987) Risk of therapy-related leukaemia and preleukaemia after Hodgkins disease. Relation to age, cumulative dose of alkylating agents and time from chemotherapy. Lancet 2:83–88CrossRefPubMedGoogle Scholar
  45. 45.
    Saffhill R, Margison GP, O’Connor PJ (1985) Mechanisms of carcinogenesis induced by alkylating agents. Biochim Biophys Acta 823:111–145PubMedGoogle Scholar
  46. 46.
    Davis SM (2001) Therapy-related leukemia associated with alkylating agents. Med Paediatr Oncol 36:536–540CrossRefGoogle Scholar
  47. 47.
    Worrillow LJ, Allan JM (2006) Deregulation of homologous recombination DNA repair in alkylating agent-treated stem cell clones: a possible role in the aetiology of chemotherapy-induced leukaemia. Oncogene 25:1709–1720CrossRefPubMedGoogle Scholar
  48. 48.
    Brooks P, Lawley PD (1961) The reaction of mono- and di-functional alkylating agents with nucleic acids. Biochem J 80:496–503Google Scholar
  49. 49.
    Chaney SG, Sancar A (1996) DNA repair: enzymatic mechanism and relevance to drug response. J Natl Cancer Inst 88:1346–1360CrossRefPubMedGoogle Scholar
  50. 50.
    Drablos F, Feyzi E, Aas PA et al (2004) Alkylation damage in DNA and RNA—repair mechanism and medical significance. DNA Repair (Amst) 3:1389–1407CrossRefGoogle Scholar
  51. 51.
    Dann EJ, Rowe RM (2001) Biology and therapy of secondary leukaemias. Best Pract Res Clin Haematol 14:119–137CrossRefPubMedGoogle Scholar
  52. 52.
    Kyle RA, Pierre RV, Bayrd ED (1975) Multiple myeloma and acute leukaemia associated with alkylating agents. Arch Intern Med 135:185–192CrossRefPubMedGoogle Scholar
  53. 53.
    Karran P, Offman J, Bignami M (2003) Human mismatch repair, drug-induced DNA damage, and secondary cancer. Biochemie 85:1149–1160CrossRefGoogle Scholar
  54. 54.
    Smith MA, McCaffrey RP, Karp JE (1996) The secondary leukaemias: challenges and research directions. J Natl Cancer Inst 88:407–413CrossRefPubMedGoogle Scholar
  55. 55.
    Ebert BL (2009) Deletion 5q in myelodysplastic syndrome: a paradigm for the study of hemizygous deletions in cancer. Leukemia 23:1252–1256CrossRefPubMedGoogle Scholar
  56. 56.
    Liu TX, Becker MW, Jelinek J et al (2007) Chromosome 5q deletion and epigenetic suppression of the gene encoding alpha-catenin (CTNNA1) in myeloid cell transformation. Nat Med 13:78–83CrossRefPubMedGoogle Scholar
  57. 57.
    Ebert BL, Pretz J, Bosco J et al (2008) Identification of RPS14 as a 5q-syndrome gene by RNA interference screen. Nature 451:335–339CrossRefPubMedGoogle Scholar
  58. 58.
    Starczynowski DT, Kuchenbauer F, Argiropoulos B et al (2009) Identification of miR-145 and miR-146a as mediators of the 5q-syndrome phenotype. Nat Med [Epub ahead of print]Google Scholar
  59. 59.
    Christiansen DH, Andersen MK, Pedersen-Bjergaard J (2001) Mutations with loss of heterozygosity of p53 are common in therapy-related myelodysplasia and acute myeloid leukaemia after exposure to alkylating agents and significantly associated with deletion or loss of 5q, a complex karyotype and poor prognosis. J Clin Oncol 19: 1405–1413PubMedGoogle Scholar
  60. 60.
    Pui CH, Riberio C, Hancock ML et al (1991) Acute myeloid leukemia in children treated with epipodophyllotoxins for acute lymphoblastic leukemia. N Engl J Med 325:1682–1687PubMedCrossRefGoogle Scholar
  61. 61.
    Praga C, Bergh J, Bliss J et al (2005) Risk of acute myeloid leukemia and myelodysplastic syndrome in trials of adjuvant epirubicin for early breast cancer: Correlation with doses of epirubicin and cyclophosphamide. J Clin Oncol 23:4179–4191CrossRefPubMedGoogle Scholar
  62. 62.
    Seedhouse C, Russell N (2007) Advances in the understanding of susceptibility to treatment-related acute myeloid leukaemia. Br J Haematol 137: 513–529CrossRefPubMedGoogle Scholar

Copyright information

© Feseo 2010

Authors and Affiliations

  1. 1.Department of Medical & Molecular GeneticsKing’s College London School of MedicineLondonUK

Personalised recommendations