Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Progress
  • Published:

Translocations, cancer and the puzzle of specificity

Nature Genetics volume 19, pages 121–124 (1998)Cite this article

Abstract

The finding of acquired chromosomal translocations that are consistently associated with specific tumour types supports the premise of lineage-specific mechanisms of tumorigenesis. We review the evidence indicating that the specificity of these translocations and the corresponding gene fusions is related to biological constraints at the level of recombination, expression, and protein function. A dynamic relationship between the gene fusion and the cellular environment is proposed in which the environment influences the selection of oncogenic fusions and the oncogenic fusion in turn influences the cellular environment.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Model of the requisite events for an acquired chromosomal translocation to participate in tumorigenesis.

Similar content being viewed by others

References

  1. Daley, G.Q. & Ben-Neriah, Y. Implicating the bcr/abl gene in the pathogenesis of Philadelphia Chromosome-positive human leukemia. Adv. Cancer Res. 57, 151–184 (1991)

    Article  CAS  Google Scholar 

  2. Knezevich, S.R., McFadden, D.E., Tao, W., Lim, J.F. & Sorensen, P.H.B. A novel ETV6-NRTK3 gene fusion in congenital fibrosarcoma . Nature Genet. 18, 184–187 (1998)

    Article  CAS  Google Scholar 

  3. Rabbits, T.H. Chromosomal translocations in human cancer. Nature 372, 143–149 (1994)

    Article  Google Scholar 

  4. Lowy, D.R. & Willumsen, B.M. Function and regulation of ras . Annu. Rev. Biochem. 62, 851–891 (1993)

    Article  CAS  Google Scholar 

  5. Levine, A.J. p53, the cellular gatekeeper for growth and division. Cell 88, 323–331 (1997)

    Article  CAS  Google Scholar 

  6. Nucifora, G. AML1 and the 8;21 and 3;21 translocations in acute and chronic myeloid leukemia. Blood 86, 1–14 ( 1995)

    Article  CAS  Google Scholar 

  7. Barr, F.G. Molecular genetics and pathogenesis of rhabdomyosarcoma. J. Ped. Hemat. Oncol. 19, 483–491 (1997)

    Article  CAS  Google Scholar 

  8. Okuda, T., van Deursen, J., Hiebert, S.W., Grosveld, G. & Downing, J.R. AML1, the target of multiple chromosomal translocations in human leukemia, is essential for normal fetal liver hematopoiesis. Cell 84, 321–330 ( 1996)

    Article  CAS  Google Scholar 

  9. Dei Tos, A.P. & Dal Cin, P. The role of cytogenetics in the classification of soft tissue tumors. Virchows Arch. 431, 83–94 (1997)

    Article  CAS  Google Scholar 

  10. May, W.A. et al.The Ewing's sarcoma EWS/FLI-1 fusion gene encodes a more potent transcriptional activator and is a more powerful transforming gene than FLI-1. Mol. Cell. Biol. 13, 7393–7398 (1993)

    Article  CAS  Google Scholar 

  11. Zinszner, H., Albalat, R. & Ron, D. A novel effector domain from the RNA-binding protein TLS or EWS is required for oncogenic transformation by CHOP. Genes Dev. 8, 2513–2526 (1994)

    Article  CAS  Google Scholar 

  12. Daley, G.Q., McLaughlin, J., Witte, O.N. & Baltimore, D. The CML-specific P210 bcr/abl protein, unlike v-abl, does not transform NIH/3T3 fibroblasts. Science 237, 532–535 (1987)

    Article  CAS  Google Scholar 

  13. Shore, S.K., La Cava, M., Yendapalli, S. & Reddy, E.P. Structural alterations in the carboxyl-terminal domain of the BCRABL gene product activate its fibroblastic transforming potential. J. Biol. Chem. 269, 5413–5419 (1994)

    CAS  PubMed  Google Scholar 

  14. Renshaw, M.W., McWhirter, J.R. & Wang, J.Y.J. The human leukemia oncogene bcr-abl abrogates the anchorage requirement but not the growth factor requirement for proliferation . Mol. Cell. Biol. 15, 1286–1293 (1995)

    Article  CAS  Google Scholar 

  15. Sanchez-Garcia, I. & Grutz, G. Tumorigenic activity of the BCR-ABL oncogenes is mediated by BCL2. Proc. Natl. Acad. Sci. USA 92, 5287–5291 ( 1995)

    Article  CAS  Google Scholar 

  16. Grignani, F. et al. The acute promyelocytic leukemia-specific PML-RARα fusion protein inhibits differentiation and promotes survival of myeloid precursor cells. Cell 74, 423–431 ( 1993)

    Article  CAS  Google Scholar 

  17. Kuroda, M. et al. Oncogenic transformation and inhibition of adipocytic conversion of preadipocytes by TLS/FUS-CHOP type II chimeric protein. Am. J. Pathol. 151, 735–744 (1997)

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Fu, X. & Kamps, M.P. E2a-Pbx1 induces aberrant expression of tissue-specific and developmentally regulated genes when expressed in NIH 3T3 fibroblasts. Mol. Cell. Biol. 17, 1503 –1512 (1997)

    Article  CAS  Google Scholar 

  19. Ferrucci, P.R. et al. Cell death induction by the acute promyelocytic leukemia-specific PML/RARα fusion protein. Proc. Natl. Acad. Sci. USA 94, 10901–10906 (1997)

    Article  CAS  Google Scholar 

  20. Serrano, M., Lin, A.W., McCurrach, M.E., Beach, D. & Lowe, S.W. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88,593–602 ( 1997)

    Article  CAS  Google Scholar 

  21. Evan, G.I. et al. Induction of apoptosis in fibroblasts by c-myc protein. Cell 69, 119–128 (1992)

    Article  CAS  Google Scholar 

  22. Heisterkamp, N., Jenster, G., Kioussis, D., Pattengale, P.K. & Groffen, J. Human bcr-abl gene has a lethal effect on embryogenesis. Transgenic Res. 1, 45–53 (1991)

    Article  CAS  Google Scholar 

  23. Voncken, J.W. et al. BCR/ABL P210 and P190 cause distinct leukemia in transgenic mice. Blood 86, 4603–4611 ( 1995)

    Article  CAS  Google Scholar 

  24. David, G., Terris, B., Marchio, A., Lavau, C. & Dejean, A. The acute promyelocytic leukemia PML-RARα protein induces hepatic preneoplastic and neoplastic lesions in transgenic mice. Oncogene 14, 1547–1554 ( 1997)

    Article  CAS  Google Scholar 

  25. Grisolano, J.L., Wesselschmidt, R.L., Pelicci, P.G. & Ley, T.J. Altered myeloid development and acute leukemia in transgenic mice expressing PML-RARα under control of cathepsin G regulatory sequences. Blood 89, 376–387 ( 1997)

    Article  CAS  Google Scholar 

  26. Brown, D. et al. A PMLRARα transgene initiates murine acute promyelocytic leukemia . Proc. Natl. Acad. Sci. USA 94, 2551–2556 (1997)

    Article  CAS  Google Scholar 

  27. Early, E. et al. Transgenic expression of PML/RARα impairs myelopoiesis. Proc. Natl. Acad. Sci. USA 93, 7900–7904 (1996)

    Article  CAS  Google Scholar 

  28. Castellanos, A. et al. A BCR-ABLp190 fusion gene made by homologous recombination causes B-cell acute lymphoblastic leukemias in chimeric mice with independence of the endogenous bcr product. Blood 90, 2168–2174 (1997)

    Article  CAS  Google Scholar 

  29. Corral, J. et al. An Mll-AF9 fusion gene made by homologous recombination causes acute leukemia in chimeric mice: a method to create fusion oncogenes. Cell 85, 853–861 (1996)

    Article  CAS  Google Scholar 

  30. Yergeau, D.A. et al. Embryonic lethality and impairment of haematopoiesis in mice heterozygous for an AML1-ETO fusion gene. Nature Genet. 15, 303–306 (1997)

    Article  CAS  Google Scholar 

  31. Castilla, L.H. et al. Failure of embryonic hematopoiesis and lethal hemorrhages in mouse embryos heterozygous for a knocked-in leukemia gene CBFB-MYH11. Cell 87, 687–696 (1996)

    Article  CAS  Google Scholar 

  32. Haluska, F.G., Finger, L.R., Kagan, J. & Croce, C.M. Molecular genetics of chromosomal translocations in B- and T-lymphoid malignancies. in Molecular Genetics in Cancer Diagnosis (ed. Cossman, J.) 143–162 (Elsevier, New York, 1990)

    Google Scholar 

  33. Chissoe, S.L. et al. Sequence and analysis of the human ABL gene, the BCR gene, and regions involved in the Philadelphia chromosomal translocation. Genomics 27, 67–82 ( 1995)

    Article  CAS  Google Scholar 

  34. Wang, P., Zhou, R.-H., Zou, Y., Jackson-Cook, C.K. & Povirk, L.F. Highly conservative reciprocal translocations formed by apparent joining of exchanged DNA double-strand break ends. Proc. Natl. Acad. Sci. USA 94, 12018–12023 (1997)

    Article  CAS  Google Scholar 

  35. Roth, D.B. & Wilson, J.H. Nonhomologous recombination in mammalian cells: role for short sequence homologies in the joining reaction. Mol. Cell. Biol. 6, 4295–4304 (1986)

    Article  CAS  Google Scholar 

  36. Aplan, P.D., Chervinsky, D.S., Stanulla, M. & Burhans, W.C. Site-specific DNA cleavage within the MLL breakpoint cluster region induced by topoisomerase II inhibitors. Blood 87, 2649–58 (1996)

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, 19104-6082, Pennsylvania , USA

    Frederic G. Barr

Authors
  1. Frederic G. Barr
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Frederic G. Barr.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Barr, F. Translocations, cancer and the puzzle of specificity. Nat Genet 19, 121–124 (1998). https://doi.org/10.1038/475

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/475

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing