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Therapy Related Myeliod Leukemia

Genome-wide approach to identify risk factors for therapy-related myeloid leukemia

Leukemia volume 20, pages 239–246 (2006)Cite this article

Abstract

Using a target gene approach, only a few host genetic risk factors for treatment-related myeloid leukemia (t-ML) have been defined. Gene expression microarrays allow for a more genome-wide approach to assess possible genetic risk factors for t-ML. We assessed gene expression profiles (n=12 625 probe sets) in diagnostic acute lymphoblastic leukemic cells from 228 children treated on protocols that included leukemogenic agents such as etoposide, 13 of whom developed t-ML. Expression of 68 probes, corresponding to 63 genes, was significantly related to risk of t-ML. Hierarchical clustering of these probe sets clustered patients into three groups with 94, 122 and 12 patients, respectively; 12 of the 13 patients who went on to develop t-ML were overrepresented in the latter group (P<0.0001). A permutation test indicated a low likelihood that these probe sets and clusters were obtained by chance (P<0.001). Distinguishing genes included transcription-related oncogenes (v-Myb, Pax-5), cyclins (CCNG1, CCNG2 and CCND1) and histone HIST1H4C. Common transcription factor recognition elements among similarly up- or downregulated genes included several involved in hematopoietic differentiation or leukemogenesis (Maz, PU.1, ARNT). This approach has identified several genes whose expression distinguishes patients at risk of t-ML, and suggests targets for assessing germline predisposition to leukemogenesis.

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References

  1. Neglia JP, Friedman DL, Yasui Y, Mertens AC, Hammond S, Stovall M et al. Second malignant neoplasms in five-year survivors of childhood cancer: childhood cancer survivor study. J Natl Cancer Inst 2001; 93: 618–629.

    Article  CAS  PubMed  Google Scholar 

  2. Smith MA, McCaffrey RP, Karp JE . The secondary leukemias: challenges and research directions. J Natl Cancer Inst 1996; 88: 407–418.

    Article  CAS  PubMed  Google Scholar 

  3. Andersen MK, Christiansen DH, Jensen BA, Ernst P, Hauge G, Pedersen-Bjergaard J . Therapy-related acute lymphoblastic leukaemia with MLL rearrangements following DNA topoisomerase II inhibitors, an increasing problem: report on two new cases and review of the literature since 1992. Br J Haematol 2001; 114: 539–543.

    Article  CAS  PubMed  Google Scholar 

  4. Pedersen-Bjergaard J, Rowley JD . The balanced and the unbalanced chromosome aberrations of acute myeloid leukemia may develop in different ways and may contribute differently to malignant transformation. Blood 1994; 83: 2780–2786.

    CAS  PubMed  Google Scholar 

  5. Pui C-H, Behm FG, Raimondi SC, Dodge RK, George SL, Rivera GK et al. Secondary acute myeloid leukemia in children treated for acute lymphoid leukemia. N Engl J Med 1989; 321: 136–142.

    Article  CAS  PubMed  Google Scholar 

  6. Pui C-H, Relling MV . Topoisomerase II inhibitor-related acute myeloid leukemia. Br J Haematol 2000; 109: 13–23.

    Article  CAS  PubMed  Google Scholar 

  7. Pui CH, Relling MV, Rivera GK, Hancock ML, Raimondi SC, Heslop HE et al. Epipodophyllotoxin-related acute myeloid leukemia – a study of 35 cases. Leukemia 1995; 9: 1680–1684.

    CAS  PubMed  Google Scholar 

  8. Smith MA, Rubinstein L, Anderson JR, Arthur D, Catalano PJ, Freidlin B et al. Secondary leukemia or myelodysplastic syndrome after treatment with epipodophyllotoxins. J Clin Oncol 1999; 17: 569–577.

    Article  CAS  PubMed  Google Scholar 

  9. Pedersen-Bjergaard J, Andersen MK, Christiansen DH, Nerlov C . Genetic pathways in therapy-related myelodysplasia and acute myeloid leukemia. Blood 2002; 99: 1909–1912.

    Article  CAS  PubMed  Google Scholar 

  10. Domer PH, Head DR, Renganathan N, Raimondi SC, Yang E, Atlas M . Molecular analysis of 13 cases of MLL/11q23 secondary acute leukemia and identification of topoisomerase II consensus-binding sequences near the chromosomal breakpoint of a secondary leukemia with the t(4;11). Leukemia 1995; 9: 1305–1312.

    CAS  PubMed  Google Scholar 

  11. Strissel PL, Strick R, Rowley JD, Zeleznik-Le NJ . An in vivo topoisomerase II cleavage site and a DNase I hypersensitive site colocalize near exon 9 in the MLL breakpoint cluster region. Blood 1998; 92: 3793–3803.

    CAS  PubMed  Google Scholar 

  12. Super HG, Strissel PL, Sobulo OM, Burian D, Reshmi SC, Roe B et al. Identification of complex genomic breakpoint junctions in the t(9;11) MLL-AF9 fusion gene in acute leukemia. Genes Chromosomes Cancer 1997; 20: 185–195.

    Article  CAS  PubMed  Google Scholar 

  13. Yeoh EJ, Ross ME, Shurtleff SA, Williams WK, Patel D, Mahfouz R et al. Classification, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene expression profiling. Cancer Cell 2002; 1: 133–143.

    Article  CAS  PubMed  Google Scholar 

  14. Ross ME, Zhou X, Song G, Shurtleff SA, Girtman K, Williams WK et al. Classification of pediatric acute lymphoblastic leukemia by gene expression profiling. Blood 2003; 102: 2951–2959.

    Article  CAS  PubMed  Google Scholar 

  15. Ohmine K, Ota J, Ueda M, Ueno S, Yoshida K, Yamashita Y et al. Characterization of stage progression in chronic myeloid leukemia by DNA microarray with purified hematopoietic stem cells. Oncogene 2001; 20: 8249–8257.

    Article  CAS  PubMed  Google Scholar 

  16. Pui CH, Campana D, Evans WE . Childhood acute lymphoblastic leukaemia – current status and future perspectives. Lancet Oncol 2001; 2: 597–607.

    Article  CAS  PubMed  Google Scholar 

  17. Schrappe M, Reiter A, Ludwig WD, Harbott J, Zimmermann M, Hiddemann W et al. Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: results of trial ALL-BFM 90. German-Austrian-Swiss ALL-BFM Study Group. Blood 2000; 95: 3310–3322.

    CAS  PubMed  Google Scholar 

  18. Silverman LB, Declerck L, Gelber RD, Dalton VK, Asselin BL, Barr RD et al. Results of Dana–Farber Cancer Institute Consortium protocols for children with newly diagnosed acute lymphoblastic leukemia (1981–1995). Leukemia 2000; 14: 2247–2256.

    Article  CAS  PubMed  Google Scholar 

  19. Golub TR, Slonim DK, Tamayo P, Huard C, Gaasenbeek M, Mesirov JP et al. Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. Science 1999; 286: 531–537.

    Article  CAS  PubMed  Google Scholar 

  20. Holleman A, Cheok MH, den Boer ML, Yang W, Veerman AJ, Kazemier KM et al. Gene-expression patterns in drug-resistant acute lymphoblastic leukemia cells and response to treatment. N Engl J Med 2004; 351: 533–542.

    Article  CAS  PubMed  Google Scholar 

  21. Cheung VG, Conlin LK, Weber TM, Arcaro M, Jen KY, Morley M et al. Natural variation in human gene expression assessed in lymphoblastoid cells. Nat Genet 2003; 33: 422–425.

    Article  CAS  PubMed  Google Scholar 

  22. French D, Wilkinson MR, Yang W, de Chaisemartin L, Cook EH, Das S et al. Global gene expression as a function of germline genetic variation. Hum Mol Genet 2005; 14: 1621–1629.

    Article  CAS  PubMed  Google Scholar 

  23. Edick MJ, Cheng C, Yang W, Cheok M, Wilkinson MR, Pei D et al. Lymphoid gene expression as a predictor of risk of secondary brain tumors. Genes Chromosomes Cancer 2005; 42: 107–116.

    Article  CAS  PubMed  Google Scholar 

  24. Relling MV, Boyett JM, Blanco JG, Raimondi S, Behm FG, Sandlund JT et al. Granulocyte-colony stimulating factor and the risk of secondary myeloid malignancy after etoposide treatment. Blood 2003; 101: 3862–3867.

    Article  CAS  PubMed  Google Scholar 

  25. Pui CH, Sandlund JT, Pei D, Campana D, Rivera GK, Ribeiro RC et al. Improved outcome for children with acute lymphoblastic leukemia: results of Total Therapy Study XIIIB at St Jude Children's Research Hospital. Blood 2004; 104: 2690–2696.

    Article  CAS  PubMed  Google Scholar 

  26. Fine JP, Gray RJ . A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 1999; 94: 496–509.

    Article  Google Scholar 

  27. Cox DR . Regression Models and Life Tables. J R Stat Soc 1972; B34: 187–220.

    Google Scholar 

  28. Cox DR . Partial likelihood. Biometrika 1975; 62: 269–276.

    Article  Google Scholar 

  29. Gray RJ . A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 1988; 16: 1141–1154.

    Article  Google Scholar 

  30. Rocha JC, Cheng C, Liu W, Kishi S, Das S, Cook EH et al. Pharmacogenetics of outcome in children with acute lymphoblastic leukemia. Blood 2005; 105: 4752–4758.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Collins FS, Brooks LD, Chakravarti A . A DNA polymorphism discovery resource for research on human genetic variation. Genome Res 1998; 8: 1229–1231.

    Article  CAS  PubMed  Google Scholar 

  32. Aach J, Bulyk ML, Church GM, Comander J, Derti A, Shendure J . Computational comparison of two draft sequences of the human genome. Nature 2001; 409: 856–859.

    Article  CAS  PubMed  Google Scholar 

  33. Frith MC, Fu Y, Yu L, Chen JF, Hansen U, Weng Z . Detection of functional DNA motifs via statistical over-representation. Nucl Acids Res 2004; 32: 1372–1381.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Felix CA, Walker AH, Lange BJ, Williams TM, Winick NJ, Cheung NK et al. Association of CYP3A4 genotype with treatment-related leukemia. Proc Natl Acad Sci USA 1998; 95: 13176–13181.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Relling MV, Yanishevski Y, Nemec J, Evans WE, Boyett JM, Behm FG et al. Etoposide and antimetabolite pharmacology in patients who develop secondary acute myeloid leukemia. Leukemia 1998; 12: 346–352.

    Article  CAS  PubMed  Google Scholar 

  36. Blanco JG, Edick MJ, Relling MV . Etoposide induces chimeric Mll gene fusions. FASEB J 2004; 18: 173–175.

    Article  CAS  PubMed  Google Scholar 

  37. Rowley JD, Olney HJ . 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 2002; 33: 331–345.

    Article  PubMed  Google Scholar 

  38. Luscher B, Eisenman RN . New light on Myc and Myb. Part II. Myb. Genes Dev 1990; 4: 2235–2241.

    Article  CAS  PubMed  Google Scholar 

  39. Adams B, Dorfler P, Aguzzi A, Kozmik Z, Urbanek P, Maurer-Fogy I et al. Pax-5 encodes the transcription factor BSAP and is expressed in B lymphocytes, the developing CNS, and adult testis. Genes Dev 1992; 6: 1589–1607.

    Article  CAS  PubMed  Google Scholar 

  40. Kishi H, Jin ZX, Wei XC, Nagata T, Matsuda T, Saito S et al. Cooperative binding of c-Myb and Pax-5 activates the RAG-2 promoter in immature B cells. Blood 2002; 99: 576–583.

    Article  CAS  PubMed  Google Scholar 

  41. McBlane JF, van Gent DC, Ramsden DA, Romeo C, Cuomo CA, Gellert M et al. Cleavage at a V(D)J recombination signal requires only RAG1 and RAG2 proteins and occurs in two steps. Cell 1995; 83: 387–395.

    Article  CAS  PubMed  Google Scholar 

  42. Oettinger MA, Schatz DG, Gorka C, Baltimore D . RAG-1 and RAG-2, adjacent genes that synergistically activate V(D)J recombination. Science 1990; 248: 1517–1523.

    Article  CAS  PubMed  Google Scholar 

  43. Schatz DG, Oettinger MA, Baltimore D . The V(D)J recombinase activating gene (RAG-1). Cell 1989; 59: 1035–1048.

    Article  CAS  PubMed  Google Scholar 

  44. van Gent DC, Ramsden DA, Gellert M . The RAG1 and RAG2 proteins establish the 12/23 rule in V(D)J recombination. Cell 1996; 85: 107–113.

    Article  CAS  PubMed  Google Scholar 

  45. Chen C-L, Fuscoe JC, Liu Q, Relling MV . Etoposide causes illegitimate V(D)J recombination in human lymphoid leukemic cells. Blood 1996; 88: 2210–2218.

    CAS  PubMed  Google Scholar 

  46. Chen C-L, Fuscoe JC, Liu Q, Pui C-H, Mahmoud HH, Relling MV . Relationship between cytotoxicity and site-specific DNA recombination after in vitro exposure of leukemia cells to etoposide. J Natl Cancer Inst 1996; 88: 1840–1847.

    Article  CAS  PubMed  Google Scholar 

  47. Okamoto K, Beach D . Cyclin G is a transcriptional target of the p53 tumor suppressor protein. EMBO J 1994; 13: 4816–4822.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Zauberman A, Lupo A, Oren M . Identification of p53 target genes through immune selection of genomic DNA: the cyclin G gene contains two distinct p53 binding sites. Oncogene 1995; 10: 2361–2366.

    CAS  PubMed  Google Scholar 

  49. Yancopoulos GD, Alt FW . Developmentally controlled and tissue-specific expression of unrearranged VH gene segments. Cell 1985; 40: 271–281.

    Article  CAS  PubMed  Google Scholar 

  50. Johnson K, Angelin-Duclos C, Park S, Calame KL . Changes in histone acetylation are associated with differences in accessibility of V(H) gene segments to V-DJ recombination during B-cell ontogeny and development. Mol Cell Biol 2003; 23: 2438–2450.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Strahl BD, Allis CD . The language of covalent histone modifications. Nature 2000; 403: 41–45.

    Article  CAS  PubMed  Google Scholar 

  52. DeKoter RP, Walsh JC, Singh H . PU.1 regulates both cytokine-dependent proliferation and differentiation of granulocyte/macrophage progenitors. EMBO J 1998; 17: 4456–4468.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Rosenbauer F, Wagner K, Kutok JL, Iwasaki H, Le Beau MM, Okuno Y et al. Acute myeloid leukemia induced by graded reduction of a lineage-specific transcription factor, PU.1. Nat Genet 2004; 36: 624–630.

    Article  CAS  PubMed  Google Scholar 

  54. Scott EW, Fisher RC, Olson MC, Kehrli EW, Simon MC, Singh H . PU.1 functions in a cell-autonomous manner to control the differentiation of multipotential lymphoid-myeloid progenitors. Immunity 1997; 6: 437–447.

    Article  CAS  PubMed  Google Scholar 

  55. Salomon-Nguyen F, la-Valle V, Mauchauffe M, Busson-Le CM, Ghysdael J, Berger R et al. The t(1;12)(q21;p13) translocation of human acute myeloblastic leukemia results in a TEL-ARNT fusion. Proc Natl Acad Sci USA 2000; 97: 6757–6762.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Armstrong SA, Staunton JE, Silverman LB, Pieters R, den Boer ML, Minden MD et al. MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia. Nat Genet 2002; 30: 41–47.

    Article  CAS  PubMed  Google Scholar 

  57. Ross ME, Mahfouz R, Onciu M, Liu HC, Zhou X, Song G et al. Gene expression profiling of pediatric acute myelogenous leukemia. Blood 2004; 104: 3679–3687.

    Article  CAS  PubMed  Google Scholar 

  58. Edick MJ, Cheng C, Yang W, Cheok M, Wilkinson M, Pei D et al. Lymphoid gene expression as a predictor of risk of secondary brain tumors. Genes Chromosomes Cancer 2005; 42: 107–116.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank our protocol co-investigators, clinical and research staff, and the patients and their parents for their participation. This work was supported by NCI CA 51001, CA 78224, CA 36401, CA 21765 and the NIH/NIGMS Pharmacogenetics Research Network and Database (U01 GM61393, U01GM61374, http://pharmgkb.org/) from the National Institutes of Health; by a Center of Excellence grant from the State of Tennessee; and by American Lebanese Syrian Associated Charities (ALSAC). C-H Pui is the American Cancer Society FM Kirby Clinical Research Professor.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, The University of Tennessee, Memphis, TN, USA

    A Bogni, W Yang, J Pfeffer, D French & M V Relling

  2. Department of Biostatistics, The University of Tennessee, Memphis, TN, USA

    C Cheng & W Liu

  3. Hartwell Center, The University of Tennessee, Memphis, TN, USA

    S Mukatira

  4. Department of Pathology, The University of Tennessee, Memphis, TN, USA

    J R Downing & C-H Pui

  5. Department of Hematology/Oncology St Jude Children's Research Hospital, The University of Tennessee, Memphis, TN, USA

    C-H Pui

  6. Colleges of Medicine and Pharmacy, The University of Tennessee, Memphis, TN, USA

    C-H Pui & M V Relling

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  1. A Bogni
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Correspondence to M V Relling.

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Supplementary Information accompanies the article on the Leukemia website (http://www.nature.com/leu/).

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Bogni, A., Cheng, C., Liu, W. et al. Genome-wide approach to identify risk factors for therapy-related myeloid leukemia. Leukemia 20, 239–246 (2006). https://doi.org/10.1038/sj.leu.2404059

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