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Cytogenetic and molecular heterogeneity of 7q36/12p13 rearrangements in childhood AML

Leukemia volume 16, pages 2408–2416 (2002)Cite this article

Abstract

The t(7;12)(q36;p13) is a recurrent abnormality in acute myeloid leukemia (AML) of childhood. The involved gene on chromosome 12 is TEL; the 7q36 partner gene has not been identified. We describe morphologic, molecular and cytogenetic characterization of two cases of 7q36/12p13-associated AML that provide important insights regarding the consequences of this rearrangement. First, the molecular organization of the breakpoint regions differ significantly: one case is a reciprocal 7;12 translocation (RTR); the other has an insertion of 7q into 12p (INS). While 12p13 breakpoints in both patients interrupt TEL intron 1, the centromere to telomere orientation of the 7q36 sequences relative to the TEL sequences are inverted in INS compared to RTR. This difference makes it difficult to postulate a mechanism whereby both patients could produce a common fusion transcript. Further, no evidence was obtained for any TEL-containing fusion transcripts. Finally, we report the first cloning of a 7;12 genomic breakpoint (from RTR) and find that it maps to a site 30 kbp proximal to the HLXB9 gene in 7q36. Together, these data suggest that, unlike most leukemia-associated chromosomal rearrangements, the important consequence of the t(7;12) is likely not the generation of a novel fusion transcript, but instead the inactivation of TEL and/or a gene at 7q36.

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References

  1. Slater RM, von Drunen E, Kroes WG, Weghuis DO, van den Berg E, Smit EM, van der Does-van den Berg A, van Wering E, Hahlen K, Carroll AJ, Raimondi SC, Beverloo HB . t(7;12)(q36;p13) and t(7;12)(q32;p13) – translocations involving ETV6 in children 18 months of age or younger with myeloid disorders Leukemia 2001 15: 915–920

    Article  CAS  Google Scholar 

  2. Tosi S, Harbott J, Teigler-Schlegel A, Haas OA, Pirc-Danoewinata H, Harrison CJ, Biondi A, Cazzaniga G, Kempski H, Scherer SW, Kearney L . t(7;12)(q36;p13), a new recurrent translocation involving ETV6 in infant leukemia Genes Chromos Cancer 2000 29: 325–332

    Article  CAS  Google Scholar 

  3. Wlodarska I, La Starza R, Baens M, Dierlamm J, Uyttebroeck A, Selleslag D, Francine A, Mecucci C, Hagemeijer A, Van den Berghe H, Marynen P . Fluorescence in situ hybridization characterization of new translocations involving TEL (ETV6) in a wide spectrum of hematologic malignancies Blood 1998 91: 1399–1406

    CAS  PubMed  Google Scholar 

  4. Satake N, Maseki N, Nishiyama M, Kobayashi H, Sakurai M, Inaba H, Katano N, Horikoshi Y, Eguchi H, Miyake M, Seto M, Kaneko Y . Chromosome abnormalities and MLL rearrangements in acute myeloid leukemia of infants Leukemia 1999 13: 1013–1017

    Article  CAS  Google Scholar 

  5. Beverloo HB, Panagopoulos I, Isaksson M, van Wering E, van Drunen E, de Klein A, Johansson B, Slater R . Fusion of the homeobox gene HLXB9 and the ETV6 gene in infant acute myeloid leukemias with the t(7;12)(q36;p13) Cancer Res 2001 61: 5374–5377

    CAS  PubMed  Google Scholar 

  6. Chakrabarti SR, Nucifora G . The leukemia-associated gene TEL encodes a transcription repressor which associates with SMRT and mSin3A Biochem Biophys Res Commun 1999 264: 871–877

    Article  CAS  Google Scholar 

  7. Lopez RG, Carron C, Oury C, Gardellin P, Bernard O, Ghysdael J . TEL is a sequence-specific transcriptional repressor J Biol Chem 1999 274: 30132–30138

    Article  CAS  Google Scholar 

  8. Fenrick R, Wang L, Nip J, Amann JM, Rooney RJ, Walker-Daniels J, Crawford HC, Hulboy DL, Kinch MS, Matrisian LM, Hiebert SW . TEL, a putative tumor suppressor, modulates cell growth and cell morphology of ras-transformed cells while repressing the transcription of stromelysin-1 Mol Cell Biol 2000 20: 5828–5839

    Article  CAS  Google Scholar 

  9. Wang LC, Kuo F, Fujiwara Y, Gilliland DG, Golub TR, Orkin SH . Yolk sac angiogenic defect and intra-embryonic apoptosis in mice lacking the Ets-related factor TEL Embo J 1997 16: 4374–4383

    Article  CAS  Google Scholar 

  10. Wang LC, Swat W, Fujiwara Y, Davidson L, Visvader J, Kuo F, Alt FW, Gilliland DG, Golub TR, Orkin SH . The TEL/ETV6 gene is required specifically for hematopoiesis in the bone marrow Genes Dev 1998 12: 2392–2402

    Article  CAS  Google Scholar 

  11. Golub TR, Barker GF, Lovett M, Gilliland DG . Fusion of PDGF receptor beta to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation Cell 1994 77: 307–316

    Article  CAS  Google Scholar 

  12. Odero MD, Carlson K, Calasanz MJ, Lahortiga I, Chinwalla V, Rowley JD . Identification of new translocations involving ETV6 in hematologic malignancies by fluorescence in situ hybridization and spectral karyotyping Genes Chromos Cancer 2001 31: 134–142

    Article  CAS  Google Scholar 

  13. Rowley JD . The role of chromosome translocations in leukemogenesis Semin Hematol 1999 36 (Suppl. 7): 59–72

    Google Scholar 

  14. Golub TR, Barker GF, Stegmaier K, Gilliland DG . Involvement of the TEL gene in hematologic malignancy by diverse molecular genetic mechanisms Curr Top Microbiol Immunol 1996 211: 279–288

    CAS  PubMed  Google Scholar 

  15. Golub TR, Barker GF, Stegmaier K, Gilliland DG . The TEL gene contributes to the pathogenesis of myeloid and lymphoid leukemias by diverse molecular genetic mechanisms Curr Top Microbiol Immunol 1997 220: 67–79

    CAS  PubMed  Google Scholar 

  16. Kuno Y, Abe A, Emi N, Iida M, Yokozawa T, Towatari M, Tanimoto M, Saito H . Constitutive kinase activation of the TEL-Syk fusion gene in myelodysplastic syndrome with t(9;12)(q22;p12) Blood 2001 97: 1050–1055

    Article  CAS  Google Scholar 

  17. Lacronique V, Boureux A, Valle VD, Poirel H, Quang CT, Mauchauffe M, Berthou C, Lessard M, Berger R, Ghysdael J, Bernard OA . A TEL-JAK2 fusion protein with constitutive kinase activity in human leukemia Science 1997 278: 1309–1312

    Article  CAS  Google Scholar 

  18. Papadopoulos P, Ridge SA, Boucher CA, Stocking C, Wiedemann LM . The novel activation of ABL by fusion to an ets-related gene, TEL Cancer Res 1995 55: 34–38

    CAS  PubMed  Google Scholar 

  19. Peeters P, Raynaud SD, Cools J, Wlodarska I, Grosgeorge J, Philip P, Monpoux F, Van Rompaey L, Baens M, Van den Berghe H, Marynen P . Fusion of TEL, the ETS-variant gene 6 (ETV6), to the receptor-associated kinase JAK2 as a result of t(9;12) in a lymphoid and t(9;15;12) in a myeloid leukemia Blood 1997 90: 2535–2540

    CAS  PubMed  Google Scholar 

  20. Schwaller J, Frantsve J, Aster J, Williams IR, Tomasson MH, Ross TS, Peeters P, Van Rompaey L, Van Etten RA, Ilaria R Jr, Marynen P, Gilliland DG . Transformation of hematopoietic cell lines to growth-factor independence and induction of a fatal myelo- and lymphoproliferative disease in mice by retrovirally transduced TEL/JAK2 fusion genes EMBO J 1998 17: 5321–5333

    Article  CAS  Google Scholar 

  21. Yagasaki F, Wakao D, Yokoyama Y, Uchida Y, Murohashi I, Kayano H, Taniwaki M, Matsuda A, Bessho M . Fusion of ETV6 to fibroblast growth factor receptor 3 in peripheral T-cell lymphoma with a t(4;12)(p16;p13) chromosomal translocation Cancer Res 2001 61: 8371–8374

    CAS  PubMed  Google Scholar 

  22. Suto Y, Sato Y, Smith SD, Rowley JD, Bohlander SK . A t(6;12)(q23;p13) results in the fusion of ETV6 to a novel gene, STL, in a B-cell ALL cell line Genes Chromos Cancer 1997 18: 254–268

    Article  CAS  Google Scholar 

  23. Yagasaki F, Jinnai I, Yoshida S, Yokoyama Y, Matsuda A, Kusumoto S, Kobayashi H, Terasaki H, Ohyashiki K, Asou N, Murohashi I, Bessho M, Hirashima K . Fusion of TEL/ETV6 to a novel ACS2 in myelodysplastic syndrome and acute myelogenous leukemia with t(5;12)(q31;p13) Genes Chromos Cancer 1999 26: 192–202

    Article  CAS  Google Scholar 

  24. Cools J, Mentens N, Odero MD, Peeters P, Wlodarska I, Delforge M, Hagemeijer A, Marynen P . Evidence for position effects as a variant ETV6-mediated leukemogenic mechanism in myeloid leukemias with a t(4;12)(q11-q12;p13) or t(5;12)(q31;p13) Blood 2002 99: 1776–1784

    Article  CAS  Google Scholar 

  25. ISCN. An International System for Human Cytogenetic Nomenclature S Karger: Basel: 1995

  26. Fink JM, Dobyns WB, Guerrini R, Hirsch BA . Identification of a duplication of Xq28 associated with bilateral periventricular nodular heterotopia Am J Hum Genet 1997 61: 379–387

    Article  CAS  Google Scholar 

  27. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues IARC Press: Lyon 2001

  28. Nucifora G . The EVI1 gene in myeloid leukemia Leukemia 1997 11: 2022–2031

    Article  CAS  Google Scholar 

  29. Peeters P, Wlodarska I, Baens M, Criel A, Selleslag D, Hagemeijer A, Van den Berghe H, Marynen P . Fusion of ETV6 to MDS1/EVI1 as a result of t(3;12)(q26;p13) in myeloproliferative disorders Cancer Res 1997 57: 564–569

    CAS  PubMed  Google Scholar 

  30. Pekarsky Y, Rynditch A, Wieser R, Fonatsch C, Gardiner K . Activation of a novel gene in 3q21 and identification of intergenic fusion transcripts with ecotropic viral insertion site I in leukemia Cancer Res 1997 57: 3914–3919

    CAS  PubMed  Google Scholar 

  31. Jacks T, Shih TS, Schmitt EM, Bronson RT, Bernards A, Weinberg RA . Tumour predisposition in mice heterozygous for a targeted mutation in Nf1 Nat Genet 1994 7: 353–361

    Article  CAS  Google Scholar 

  32. Fero ML, Randel E, Gurley KE, Roberts JM, Kemp CJ . The murine gene p27Kip1 is haploinsufficient for tumour suppression Nature 1998 396: 177–180

    Article  CAS  Google Scholar 

  33. Venkatachalam S, Shi YP, Jones SN, Vogel H, Bradley A, Pinkel D, Donehower LA . Retention of wild-type p53 in tumors from p53 heterozygous mice: reduction of p53 dosage can promote cancer formation EMBO J 1998 17: 4657–4667

    Article  CAS  Google Scholar 

  34. Shannon KM, Le Beau MM, Largaespada DA, Killeen N . Modeling myeloid leukemia tumor suppressor gene inactivation in the mouse Semin Cancer Biol 2001 11: 191–200

    Article  CAS  Google Scholar 

  35. Chomczynski P, Sacchi N . Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction Anal Biochem 1987 162: 156–159

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors would like to acknowledge the contribution of Dr Scott Benson to the early stages of this work and the Department of Pediatrics, Divisions of Hematology/Oncology and Blood and Marrow Transplantation at the University of Minnesota for providing clinical information. This work was supported by a grant from the Leukemia Research Fund (to BH and KFC).

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Authors and Affiliations

  1. Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA

    HM Simmons

  2. Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA

    L Oseth, P Nguyen & B Hirsch

  3. Children's Hospitals and Clinics-Minneapolis, University of Minnesota, Minneapolis, MN, USA

    M O'Leary

  4. Institute of Human Genetics, University of Minnesota, Minneapolis, MN, USA

    KF Conklin & B Hirsch

  5. Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN, USA

    KF Conklin & B Hirsch

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  1. HM Simmons
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Simmons, H., Oseth, L., Nguyen, P. et al. Cytogenetic and molecular heterogeneity of 7q36/12p13 rearrangements in childhood AML. Leukemia 16, 2408–2416 (2002). https://doi.org/10.1038/sj.leu.2402773

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