Abstract
The genetic risk factors for etoposide-induced leukemia with MLL translocations remain largely unknown. To identify genetic risk factors for and novel characteristics of secondary leukemia, we profiled 116 204 single nucleotide polymorphisms (SNPs) in germline and paired leukemic cell DNA from 13 secondary leukemia/myelodysplasia cases and germline DNA from 13 matched and 156 unmatched controls, all with acute lymphoblastic leukemia treated with etoposide. We analyzed global gene expression from a partially overlapping cohort. No single locus was altered in most cases. We discovered 81 regions of loss of heterozygosity (LOH) in leukemic blasts and 309 SNPs whose allele frequencies differed in cases vs controls. Candidate genes were prioritized on the basis of genes whose SNPs or expression differentiated cases from controls or showed LOH or copy number change in germline vs paired blast DNA from the13 cases. Three biological pathways were altered: adhesion, Wnt signaling and regulation of actin. Validation experiments using a genome scan for etoposide-induced leukemogenic MLL chimeric fusions in 15 HapMap cell lines also implicated genes involved in adhesion, a process linked to de novo leukemogenesis. Independent clinical epidemiologic and in vitro genome-wide approaches converged to identify novel pathways that may contribute to therapy-induced leukemia.
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References
Bhatia S, Sklar C . Second cancers in survivors of childhood cancer. Nat Rev Cancer 2001; 2: 124–132.
Pui C-H, Ribeiro R, Hancock ML, Rivera GK, Evans WE, Raimondi S et al. Acute myeloid leukemia in children treated with epipodophyllotoxins for acute lymphocytic leukemia. N Engl J Med 1991; 325: 1682–1687.
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.
Pedersen-Bjergaard J . Insights into leukemogenesis from therapy-related leukemia. N Engl J Med 2005; 352: 1591–1594.
Mistry AR, Felix CA, Whitmarsh RJ, Mason A, Reiter A, Cassinat B et al. DNA topoisomerase II in therapy-related acute promyelocytic leukemia. N Engl J Med 2005; 352: 1529–1538.
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.
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.
Pui C-H, Relling MV, Behm FG, Hancock ML, Boyett JM, Raimondi SC et al. L-asparaginase may potentiate the leukemogenic effect of the epipodophyllotoxins. Leukemia 1995; 9: 1680–1684.
Thomsen J, Schroder H, Kristinsson J, Madsen B, Szumlanski C, Weinshilboum R et al. Possible carcinogenic effect of 6-mercaptopurine on bone marrow stem cells. Cancer 1999; 86: 1080–1086.
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.
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.
Allan JM, Wild CP, Rollinson S, Willett EV, Moorman AV, Dovey GJ et al. Polymorphism in glutathione S-transferase P1 is associated with susceptibility to chemotherapy-induced leukemia. Proc Natl Acad Sci USA 2001; 98: 11592–11597.
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.
Stegmaier K, Ross KN, Colavito SA, O'Malley S, Stockwell BR, Golub TR . Gene expression-based high-throughput screening (GE-HTS) and application to leukemia differentiation. Nat Genet 2004; 36: 257–263.
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.
Bogni A, Cheng C, Liu W, Yang W, Pfeffer J, Mukatira S et al. Genome-wide approach to identify risk factors for therapy-related myeloid leukemia. Leukemia 2006; 20: 239–246.
Super HJ, McCabe NR, Thirman MJ, Larson RA, Le Beau MM, Pedersen-Bjergaard J et al. Rearrangements of the MLL gene in therapy-related acute myeloid leukemia in patients previously treated with agents targeting DNA-topoisomerase II. Blood 1993; 82: 3705–3711.
Forster A, Pannell R, Drynan LF, McCormack M, Collins EC, Daser A et al. Engineering de novo reciprocal chromosomal translocations associated with Mll to replicate primary events of human cancer. Cancer Cell 2003; 3: 449–458.
Lavau C, Luo RT, Du C, Thirman MJ . Retrovirus-mediated gene transfer of MLL-ELL transforms primary myeloid progenitors and causes acute myeloid leukemias in mice. Proc Natl Acad Sci USA 2000; 97: 10984–10989.
So CW, Karsunky H, Passegue E, Cozzio A, Weissman IL, Cleary ML . MLL-GAS7 transforms multipotent hematopoietic progenitors and induces mixed lineage leukemias in mice. Cancer Cell 2003; 3: 161–171.
Blanco JG, Edick MJ, Relling MV . Etoposide induces chimeric Mll gene fusions. FASEB J 2004; 18: 173–175.
Betti CJ, Villalobos MJ, Diaz MO, Vaughan AT . Apoptotic stimuli initiate MLL-AF9 translocations that are transcribed in cells capable of division. Cancer Res 2003; 63: 1377–1381.
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.
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.
Cheung VG, Spielman RS, Ewens KG, Weber TM, Morley M, Burdick JT . Mapping determinants of human gene expression by regional and genome-wide association. Nature 2005; 437: 1365–1369.
Lehmann EL . Nonparametrics: Statistical Methods Based on Ranks. Calif. Holden-Day: San Francisco, 1975.
Lin M, Wei LJ, Sellers WR, Lieberfarb M, Wong WH, Li C . dChipSNP: significance curve and clustering of SNP-array-based loss-of-heterozygosity data. Bioinformatics 2004; 20: 1233–1240.
Pounds S, Cheng C . Robust estimation of the false discovery rate. Bioinformatics 2006; 22: 1979–1987.
Dolan ME, Newbold KG, Nagasubramanian R, Wu X, Ratain MJ, Cook Jr EH et al. Heritability and linkage analysis of sensitivity to cisplatin-induced cytotoxicity. Cancer Res 2004; 64: 4353–4356.
Huang RS, Duan S, Bleibel WK, Kistner EO, Zhang W, Clark TA et al. A genome-wide approach to identify genetic variants that contribute to etoposide-induced cytotoxicity. Proc Natl Acad Sci USA 2007; 104: 9758–9763.
Kanehisa M, Goto S, Hattori M, Aoki-Kinoshita KF, Itoh M, Kawashima S et al. From genomics to chemical genomics: new developments in KEGG. Nucleic Acids Res 2006; 34: D354–D357.
Hattori M, Minato N . Rap1 GTPase: functions, regulation, and malignancy. J Biochem (Tokyo) 2003; 134: 479–484.
Ishida D, Kometani K, Yang H, Kakugawa K, Masuda K, Iwai K et al. Myeloproliferative stem cell disorders by deregulated Rap1 activation in SPA-1-deficient mice. Cancer Cell 2003; 4: 55–65.
Tashiro E, Tsuchiya A, Imoto M . Functions of cyclin D1 as an oncogene and regulation of cyclin D1 expression. Cancer Sci 2007; 98: 629–635.
Stossel TP, Condeelis J, Cooley L, Hartwig JH, Noegel A, Schleicher M et al. Filamins as integrators of cell mechanics and signalling. Nat Rev Mol Cell Biol 2001; 2: 138–145.
Feng Q, Baird D, Peng X, Wang J, Ly T, Guan JL et al. Cool-1 functions as an essential regulatory node for EGF receptor- and Src-mediated cell growth. Nat Cell Biol 2006; 8: 945–956.
Engers R, Zwaka TP, Gohr L, Weber A, Gerharz CD, Gabbert HE . Tiam1 mutations in human renal-cell carcinomas. Int J Cancer 2000; 88: 369–376.
Ives JH, gna-Bricarelli F, Basso G, Antonarakis SE, Jee R, Cotter F et al. Increased levels of a chromosome 21-encoded tumour invasion and metastasis factor (TIAM1) mRNA in bone marrow of Down syndrome children during the acute phase of AML(M7). Genes Chromosomes Cancer 1998; 23: 61–66.
Horsley V, Pavlath GK . NFAT: ubiquitous regulator of cell differentiation and adaptation. J Cell Biol 2002; 156: 771–774.
Chowdhury D, Keogh MC, Ishii H, Peterson CL, Buratowski S, Lieberman J . Gamma-H2AX dephosphorylation by protein phosphatase 2A facilitates DNA double-strand break repair. Mol Cell 2005; 20: 801–809.
Legate KR, Montanez E, Kudlacek O, Fassler R . ILK, PINCH and parvin: the tIPP of integrin signalling. Nat Rev Mol Cell Biol 2006; 7: 20–31.
Long MW . Blood cell cytoadhesion molecules. Exp Hematol 1992; 20: 288–301.
Geijtenbeek TB, van KY, van Vliet SJ, Renes MH, Raymakers RA, Figdor CG . High frequency of adhesion defects in B-lineage acute lymphoblastic leukemia. Blood 1999; 94: 754–764.
Clark EA, Brugge JS . Integrins and signal transduction pathways: the road taken. Science 1995; 268: 233–239.
Zhao J, Bian ZC, Yee K, Chen BP, Chien S, Guan JL . Identification of transcription factor KLF8 as a downstream target of focal adhesion kinase in its regulation of cyclin D1 and cell cycle progression. Mol Cell 2003; 11: 1503–1515.
Gordon MY, Dowding CR, Riley GP, Goldman JM, Greaves MF . Altered adhesive interactions with marrow stroma of haematopoietic progenitor cells in chronic myeloid leukaemia. Nature 1987; 328: 342–344.
Verfaillie CM, McCarthy JB, McGlave PB . Mechanisms underlying abnormal trafficking of malignant progenitors in chronic myelogenous leukemia. Decreased adhesion to stroma and fibronectin but increased adhesion to the basement membrane components laminin and collagen type IV. J Clin Invest 1992; 90: 1232–1241.
Bazzoni G, Carlesso N, Griffin JD, Hemler ME . Bcr/Abl expression stimulates integrin function in hematopoietic cell lines. J Clin Invest 1996; 98: 521–528.
Kramer A, Horner S, Willer A, Fruehauf S, Hochhaus A, Hallek M et al. Adhesion to fibronectin stimulates proliferation of wild-type and bcr/abl-transfected murine hematopoietic cells. Proc Natl Acad Sci USA 1999; 96: 2087–2092.
Sonoda Y, Matsumoto Y, Funakoshi M, Yamamoto D, Hanks SK, Kasahara T . Anti-apoptotic role of focal adhesion kinase (FAK). Induction of inhibitor-of-apoptosis proteins and apoptosis suppression by the overexpression of FAK in a human leukemic cell line, HL-60. J Biol Chem 2000; 275: 16309–16315.
Blanco JG, Edick MJ, Hancock ML, Winick NJ, Dervieux T, Amylon MD et al. Genetic polymorphisms in CYP3A5, CYP3A4 and NQO1 in children who developed therapy-related myeloid malignancies. Pharmacogenetics 2002; 12: 605–611.
Mullighan CG, Goorha S, Radtke I, Miller CB, Coustan-Smith E, Dalton JD et al. Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature 2007; 446: 758–764.
Acknowledgements
We thank the clinical staff, patients and their parents for their participation; Jean Cai, Pam McGill and Natalie Ellington for their laboratory assistance; and Nancy Kornegay, Deqing Pei, Xiaoping Su, Suraj Mukatira and Jeana Cromer for data analysis. This work was supported by NCI T32-CA070089, CA 51001, CA 78224, CA 36401, CA21765 and the NIH/NIGMS PGRN (U01 GM61393, U01GM61374 http://pharmgkb.org/ PS 207016) 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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Hartford, C., Yang, W., Cheng, C. et al. Genome scan implicates adhesion biological pathways in secondary leukemia. Leukemia 21, 2128–2136 (2007). https://doi.org/10.1038/sj.leu.2404885
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DOI: https://doi.org/10.1038/sj.leu.2404885
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