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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

Abstract

Few t(9;11) translocations in DNA topoisomerase II inhibitor-related leukemias have been studied in detail and the DNA damage mechanism remains controversial. We characterized the der(11) and der(9) genomic breakpoint junctions in a case of AML following etoposide and doxorubicin. Etoposide-, etoposide metabolite- and doxorubicin-induced DNA topoisomerase II cleavage was examined in normal homologues of the MLL and AF-9 breakpoint sequences using an in vitro assay. Induction of DNA topoisomerase II cleavage complexes in CEM and K562 cell lines was investigated using an in vivo complex of enzyme assay. The translocation occurred between identical 5′-TATTA-3′ sequences in MLL intron 8 and AF-9 intron 5 without the gain or loss of bases. The 5′-TATTA-3′ sequences were reciprocally cleaved by DNA topoisomerase II in the presence of etoposide, etoposide catechol or etoposide quinone, creating homologous 4-base 5′ overhangs that would anneal to form both breakpoint junctions without any processing. der(11) and der(4) translocation breakpoints in a treatment-related ALL at the same site in MLL are consistent with a damage hotspot. Etoposide and both etoposide metabolites induced DNA topoisomerase II cleavage complexes in the hematopoietic cell lines. These results favor the model in which the chromosomal breakage leading to MLL translocations in DNA topoisomerase II inhibitor-related leukemias is a consequence of DNA topoisomerase II cleavage.

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References

  • Andersen AH, Christiansen K, Zechiedrich EL, Jensen PS, Osheroff N and Westergaard O . (1989). Biochemistry, 28, 6237–6244.

  • Aplan PD, Chervinsky DS, Stanulla M and Burhans WC . (1996). Blood, 87, 2649–2658.

  • Atlas M, Head D, Behm F, Schmidt E, Zeleznik-Le NJ, Roe BA, Burian D and Domer PH . (1998). Leukemia, 12, 1895–1902.

  • Bae Y-S, Kawasaki I, Ikeda H and Liu LF . (1988). Proc. Natl. Acad. Sci. USA, 85, 2076–2080.

  • Ben-Yehuda D, Krichevsky S, Shafran S, Cohen SB, Goldschmidt N, Kedmi M, Neriah SB and Rund D . (2002). Blood, 100 (Suppl 1), 324a.

  • Betti CJ, Villalobos MJ, Diaz MO and Vaughan AT . (2003). Cancer Res., 63, 1377–1381.

  • Betti CJ, Villalobos MJ, Diaz MO and Vaughan ATM . (2001). Cancer Res., 61, 4550–4555.

  • Blanco JG, Dervieux T, Edick MJ, Mehta PK, Rubnitz JE, Shurtleff SA, Raimondi SC, Behm FG, Pui C-H and Relling MV . (2001). Proc. Natl. Acad. Sci. USA, 98, 10338–10343.

  • Bloomfield CD, Archer KJ, Mrozek K, Lillington DM, Kaneko Y, Head DR, Dal Cin P and Raimondi SC . (2002). Genes Chromosomes Cancer, 33, 362–378.

  • Broeker PL, Super HG, Thirman MJ, Pomykala H, Yonebayashi Y, Tanabe S, Zeleznik-Le N and Rowley JD . (1996). Blood, 87, 1912–1922.

  • Bromberg KD, Burgin AB and Osheroff N . (2003). J. Biol. Chem., 278, 7406–7412.

  • Bromberg KD and Osheroff N . (2001). Biochemistry, 40, 8410–8418.

  • Burden DA and Osheroff N . (1998). Biochim. Biophys. Acta, 1400, 139–154.

  • Byl JA, Cline SD, Utsugi T, Kobunai T, Yamada Y and Osheroff N . (2001). Biochemistry, 40, 712–718.

  • Capranico G, Jaxel C, Raberge M, Kohn KW and Pommier Y . (1990a). Nucleic Acids Res., 18, 4553–4559.

  • Capranico G, Kohn KW and Pommier Y . (1990b). Nucleic Acids Res., 18, 6611–6619.

  • Charron M and Hancock R . (1991). Chromosoma, 100, 97–102.

  • Daheron L, Veinstein A, Brizard F, Drabkin H, Lacotte L, Guilhot F, Larsen CJ, Brizard A and Roche J . (2001). Genes Chromosomes Cancer, 31, 382–389.

  • Domer PH, Head DR, Renganathan N, Raimondi SC, Yang E and Atlas M . (1995). Leukemia, 9, 1305–1312.

  • Felix CA . (2001). Med. Pediatr. Oncol., 36, 525–535.

  • Felix CA, Hosler MR, Slater DJ, Megonigal MD, Lovett BD, Williams TM, Nowell PC, Spinner NB, Owens NL, Hoxie J, Croce CM, Lange BJ and Rappaport EF . (1999). Mol. Diagn., 4, 269–283.

  • Felix CA, Kim CS, Megonigal MD, Slater DJ, Jones DH, Spinner NB, Stump T, Hosler MR, Nowell PC, Lange BJ and Rappaport EF . (1997). Blood, 90, 4679–4686.

  • Felix CA, Lange BJ, Hosler MR, Fertala J and Bjornsti M-A . (1995). Cancer Res., 55, 4287–4292.

  • Felix CA, Walker AH, Lange BJ, Williams TM, Winick NJ, Cheung NK, Lovett BD, Nowell PC, Blair IA and Rebbeck TR . (1998). Proc. Natl. Acad. Sci. USA, 95, 13176–13181.

  • Fortune JM and Osheroff N . (2000). Prog. Nucleic Acids Res. Mol. Biol., 64, 221–253.

  • Gillert E, Leis T, Repp R, Reichel M, Hosch A, Breitenlohner I, Angermuller S, Borkhardt A, Harbott J, Lampert F, Griesinger F, Greil J, Fey GH and Marschalek R . (1999). Oncogene, 18, 4663–4671.

  • Gu Y, Nakamura T, Alder H, Prasad R, Canaani O, Cimino G, Croce CM and Canaani E . (1992). Cell, 71, 701–708.

  • Isaacs RJ, Davies SL, Sandri MI, Redwood C, Wells NJ and Hickson ID . (1998). Biochim. Biophys. Acta, 1400, 121–137.

  • Jackson SP . (2002). Carcinogenesis, 23, 687–696.

  • Kaufmann SH . (1998). Biochim. Biophys. Acta, 1400, 196–211.

  • Langer T, Metzler M, Reinhardt D, Viehmann S, Borkhardt A, Reichel M, Stanulla M, Schrappe M, Creutzig U, Ritter J, Leis T, Jacobs U, Harbott J, Beck JD, Rascher W and Repp R . (2003). Genes Chromosomes Cancer, 36, 393–401.

  • Lee MP and Hsieh T . (1992). Nucleic Acids Res., 20, 5027–5033.

  • Liang F, Han M, Romanienko PJ and Jasin M . (1998). Proc. Natl. Acad. Sci. USA, 95, 5172–5177.

  • Lovett BD, Lo Nigro L, Rappaport EF, Blair IA, Osheroff N, Zheng N, Megonigal MD, Williams WR, Nowell PC and Felix CA . (2001a). Proc. Natl. Acad. Sci. USA, 98, 9802–9807.

  • Lovett BD, Strumberg D, Blair IA, Pang S, Burden DA, Megonigal MD, Rappaport EF, Osheroff N, Pommier Y and Felix CA . (2001b). Biochemistry, 40, 1159–1170.

  • Lozzio B and Lozzio C . (1979). Leuk. Res., 3, 363–370.

  • Megonigal MD, Cheung NK, Rappaport EF, Nowell PC, Wilson RB, Jones DH, Addya K, Leonard DG, Kushner BH, Williams TM, Lange BJ and Felix CA . (2000). Proc. Natl. Acad. Sci. USA, 97, 2814–2819.

  • Megonigal MD, Rappaport EF, Jones DH, Kim CS, Nowell PC, Lange BJ and Felix CA . (1997). Proc. Natl. Acad. Sci. USA, 94, 11583–11588.

  • Megonigal MD, Rappaport EF, Jones DH, Williams TM, Lovett BD, Kelly KM, Lerou PH, Moulton T, Budarf ML and Felix CA . (1998). Proc. Natl. Acad. Sci. USA, 95, 6413–6418.

  • Muller MT, Spitzner JR, DiDonato JA, Mehta VB and Tsutsui K . (1988). Biochemistry, 27, 8369–8379.

  • Negrini M, Felix CA, Martin C, Lange BJ, Nakamura T, Canaani E and Croce CM . (1993). Cancer Res., 53, 4489–4492.

  • Osheroff N . (1989). Biochemistry, 28, 6157–6160.

  • Pommier Y and Bertrand R . (1993). The Causes and Consequences of Chromosomal Aberrations, Kirsch IR (ed). CRC Press: Boca Raton, FL, pp. 277–309.

    Google Scholar 

  • Pourquier P, Takebayashi Y, Urasaki Y, Gioffre C, Kohlhagen G and Pommier Y . (2000). Proc. Natl. Acad. Sci. USA, 97, 1885–1890.

  • Raffini LJ, Cheung N-KV, Rappaport EF and Felix CA . (2002a). Proceedings of the ANR Meeting 2002, Abstract PC-55.

  • Raffini LJ, Slater DJ, Rappaport EF, LO Nigro L, Cheung N-KV, Biegel JA, Nowell PC, Lange BJ and Felix CA . (2002b). Proc. Natl. Acad. Sci. USA, 99, 4568–4573.

  • Ratain MJ, Kaminer LS, Bitran JD, Larson RA, Le Beau MM, Skosey C, Purl S, Hoffman PC, Wade J, Vardiman JW, Daly K, Rowley JD and Golomb HM . (1987). Blood, 70, 1412–1417.

  • Reichel M, Gillert E, Angermuller S, Hensel JP, Heidel F, Lode M, Leis T, Biondi A, Haas OA, Strehl S, Panzer-Grumayer ER, Griesinger F, Beck JD, Greil J, Fey GH, Uckun FM and Marschalek R . (2001). Oncogene, 20, 2900–2907.

  • Ross JA . (2003). Am. Soc. Clin. Oncol., 3, 243–249.

  • Ross JA, Potter JD, Reaman GH, Pendergrass TW and Robison LL . (1996). Cancer Causes Control, 7, 581–590.

  • Rowley JD and Olney HJ . (2002). Genes Chromosomes Cancer, 33, 331–345.

  • Sandoval C, Pui C-H, Bowman LC, Heaton D, Hurwitz CA, Raimondi SC, Behm FG and Head DR . (1993). J. Clin. Oncol., 11, 1039–1045.

  • Secker-Walker LM, Stewart EL and Todd A . (1985). Med. Pediatr. Oncol., 13, 48–50.

  • Sim S-P and Liu LF . (2001). J. Biol. Chem., 276, 31590–31595.

  • Slater DJ, Hilgenfeld E, Rappaport EF, Shah N, Meek RG, Williams WR, Lovett BD, Osheroff N, Autar RS, Ried T and Felix CA . (2002). Oncogene, 21, 4706–4714.

  • Sobulo OM, Borrow J, Tomek R, Reshmi S, Harden A, Schlegelberger B, Housman D, Doggett NA, Rowley JD and Zeleznik-Le NJ . (1997). Proc. Natl. Acad. Sci. USA, 94, 8732–8737.

  • Stanulla M, Wang J, Chervinsky DS, Thandla S and Aplan PD . (1997). Mol. Cell. Biol., 17, 4070–4079.

  • Strick R, Strissel PL, Borgens S, Smith SL and Rowley JD . (2000). Proc. Natl. Acad. Sci. USA, 97, 4790–4795.

  • Strissel PL, Strick R, Rowley JD and Zeleznik-Le NJ . (1998). Blood, 92, 3793–3803.

  • Subramanian D, Furbee CS and Muller MT . (2001). DNA Topoisomerase Protocols, Part II: Enzymology and Drugs, Osheroff N and Bjornsti M-A. (eds). Humana Press, Inc.: Totowa, NJ.

    Google Scholar 

  • Subramanian D, Kraut E, Staubus A, Young DC and Muller MT . (1995). Cancer Res., 55, 2097–2103.

  • Super HG, Strissel PL, Sobulo OM, Burian D, Reshmi SC, Roe B, Zeleznik-Le NJ, Diaz MO and Rowley JD . (1997). Genes Chromosomes Cancer, 20, 185–195.

  • Uzman BG, Foley GE, Farber S and Lazarus H . (1966). Cancer, 19, 1725–1742.

  • Wang JC . (1996). Annu. Rev. Biochem., 65, 635–692.

  • Wang JC, Caron PR and Kim RA . (1990). Cell, 62, 403–406.

  • Weh HJ, Kabisch H, Landbeck G and Hossfeld DK . (1986). J. Clin. Oncol., 4, 1518–1520.

  • Zechiedrich EL, Christiansen K, Andersen AH, Westergaard O and Osheroff N . (1989). Biochemistry, 28, 6229–6236.

  • Zhou R-H, Wang P, Zou Y, Jackson-Cook C and Povirk L . (1997). Cancer Res., 57, 4699–4702.

  • Zinkevich V and Beech I . (2000). Mol. Biol. Today, 1, 29–33.

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Acknowledgements

We thank Lee Helman for patient materials and clinical history and Joanne Byl for valuable discussions. CA Felix was supported by NIH Grants CA77683, CA85469, CA80175, Leukemia and Lymphoma Society Translational Research Award, Leukemia and Lymphoma Society SCOR Grant, Joshua Kahan Foundation and Friends of Joseph Claffey Fund. N Osheroff was supported by NIH Grant GM33944, while E Hilgenfeld by Deutsche Krebshilfe Postdoctoral Fellowship.

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Correspondence to Carolyn A Felix.

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Whitmarsh, R., Saginario, C., Zhuo, Y. et al. 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, 8448–8459 (2003). https://doi.org/10.1038/sj.onc.1207052

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