Human chronic lymphocytic leukemia modeled in mouse by targeted TCL1 expression.
Journal: 2002/June - Proceedings of the National Academy of Sciences of the United States of America
ISSN: 0027-8424
Abstract:
The TCL1 gene at 14q32.1 is involved in chromosomal translocations and inversions in mature T cell leukemias. These leukemias are classified either as T prolymphocytic leukemias, which occur very late in life, or as T chronic lymphocytic leukemias, which often arise in patients with ataxia telangiectasia (AT) at a young age. In transgenic animals, the deregulated expression of TCL1 leads to mature T cell leukemia, demonstrating the role of TCL1 in the initiation of malignant transformation in T cell neoplasia. Expression of high levels of Tcl1 have also been found in a variety of human tumor-derived B cell lines ranging from pre-B cell to mature B cell. Here we describe the phenotype of transgenic mice, E mu-TCL1, established with TCL1 under the control of a V(H) promoter-Ig(H)-E mu enhancer to target TCL1 expression to immature and mature B cells. Flow cytometric analysis reveals a markedly expanded CD5(+) population in the peritoneal cavity of E mu-TCL1 mice starting at 2 mo of age that becomes evident in the spleen by 3-5 mo and in the bone marrow by 5-8 mo. Analysis of Ig gene rearrangements indicates monoclonality or oligoclonality in these populations, suggesting a preneoplastic expansion of CD5(+) B cell clones, with the elder mice eventually developing a chronic lymphocytic leukemia (CLL)-like disorder resembling human B-CLL. Our findings provide an animal model for CLL, the most common human leukemia, and demonstrate that deregulation of the Tcl1 pathway plays a crucial role in CLL pathogenesis.
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Proc Natl Acad Sci U S A 99(10): 6955-6960

Human chronic lymphocytic leukemia modeled in mouse by targeted <em>TCL1</em> expression

Kimmel Cancer Center, Jefferson Medical College, 233 South 10th Street, Philadelphia, PA 19107; Institute for Cancer Research, Fox Chase Cancer Center, 7701 Burholme Avenue, Philadelphia, PA 19111; and Laboratory of Molecular Oncogenesis, Istituto Dermopatico dell'Immacolata, Via dei Monti di Creta 104, 00167 Rome, Italy
To whom reprint requests should be addressed. E-mail: ude.ujt.icj.cal@ecorc_c.
Contributed by Carlo M. Croce
Contributed by Carlo M. Croce
Accepted 2002 Mar 27.

Abstract

The TCL1 gene at 14q32.1 is involved in chromosomal translocations and inversions in mature T cell leukemias. These leukemias are classified either as T prolymphocytic leukemias, which occur very late in life, or as T chronic lymphocytic leukemias, which often arise in patients with ataxia telangiectasia (AT) at a young age. In transgenic animals, the deregulated expression of TCL1 leads to mature T cell leukemia, demonstrating the role of TCL1 in the initiation of malignant transformation in T cell neoplasia. Expression of high levels of Tcl1 have also been found in a variety of human tumor-derived B cell lines ranging from pre-B cell to mature B cell. Here we describe the phenotype of transgenic mice, Eμ-TCL1, established with TCL1 under the control of a VH promoter-IgH-Eμ enhancer to target TCL1 expression to immature and mature B cells. Flow cytometric analysis reveals a markedly expanded CD5 population in the peritoneal cavity of Eμ-TCL1 mice starting at 2 mo of age that becomes evident in the spleen by 3–5 mo and in the bone marrow by 5–8 mo. Analysis of Ig gene rearrangements indicates monoclonality or oligoclonality in these populations, suggesting a preneoplastic expansion of CD5 B cell clones, with the elder mice eventually developing a chronic lymphocytic leukemia (CLL)-like disorder resembling human B-CLL. Our findings provide an animal model for CLL, the most common human leukemia, and demonstrate that deregulation of the Tcl1 pathway plays a crucial role in CLL pathogenesis.

Abstract

B cell chronic lymphocytic leukemia (B-CLL) is the most common leukemia in the Western world, with as many as 10,000 new cases reported each year in the United States (1, 2). Characteristically, B-CLL is a disease of elderly people resulting from the progressive accumulation of a leukemic clone that may be derived from a normal CD5 B lymphocyte (3). B-CLL has a consistent association with CD5 expression (3), and, although there is still a debate on the role and significance of CD5 expression on B cells, it remains reasonable to consider CD5 B cells as the normal counterpart of B-CLL (4, 5).

Human hematopoietic malignancies are often caused by chromosome translocations involving either T cell receptor (TCR) or immunoglobulin loci (6). These chromosome breakpoints juxtapose enhancer elements of TCR and Ig loci to protooncogenes, leading to tumor initiation through oncogene deregulation (7, 8). We have previously identified the T cell leukemia-1 (TCL1) gene at chromosome 14q32.1 (9) that is commonly activated by inversions or translocations that juxtapose it to a T cell receptor locus at 14q11 or 7q35. TCL1 has been found to be overexpressed in sporadic and ataxia telangiectasia-associated T prolymphocytic leukemia (T-PLL; refs. 10 and 11). We also provided evidence that TCL1 is a bona fide oncogene, developing a transgenic mouse model where ectopic expression driven by the lck promoter in the T cell compartment results in the development of mature T cell leukemias after a long latency period, in a pattern closely resembling human mature T cell leukemia (12). In normal T cells, TCL1 is expressed only at the very early CD4/CD8 double negative stage, whereas more mature T cells lack TCL1 expression (9). In the B cell lineage, the product of the TCL1 gene, Tcl1, has been found in pre-B cells, surface IgM-expressing virgin B cells, mantle cells and germinal center B cells, whereas it is down-regulated at later stages of B cell differentiation, i.e., plasma cells (9). Interestingly, high levels of Tcl1 have been found in a broad variety of human tumor-derived B cell lines and in many cases of B cell neoplasias (13, 14). To elucidate the role of TCL1 in B cell development and in B cell neoplasia, we generated transgenic mice under the control of a promoter and enhancer whose activity specifically targets expression of the transgene to the B cell compartment (15). Here, we show that Eμ-TCL1 transgenic mice develop a disease resembling human CLL. The mice develop at first a preleukemic state evident in blood, spleen, bone marrow, peritoneal cavity, and peripheral lymphoid tissue, developing later a frank leukemia with all characteristics of CLL. These findings strongly indicate that TCL1 and/or other gene(s) in the TCL1 pathway are responsible for the initiation of human CLL.

Variations from the germ-line sequence are underlined. N regions are in lowercase.

Acknowledgments

We thank A. Shaw for the gift of the expression vector, T. Manser and J. Rothestein for valuable suggestions, D. Remotti for reviewing some spleen sections, J. Letofsky and S. Rattan for expert technical assistance, J. Faust and A. Acosta for the preliminary flow cytometric analysis, and the transgenic mouse facility and the laboratory animal services at the Kimmel Cancer Center. This study was supported by National Institutes of Health grants to R.R.H., by Associazione Italiana Ricerca sul Cancro grants to G.R., and by National Cancer Institute grants to C.M.C.

Acknowledgments

Abbreviations

TCL-1T cell leukemia 1
B-CLLB chronic lymphocytic leukemia
PIpropidium iodide
LDI-PCRlong distance inverse PCR
MZmarginal zone
Abbreviations

References

  • 1. Rai K, Patel D C In: Hematology: Basic Principles and Practice. Hoffman R, Banz E J Jr, Shattil S J, editors. New York: Churchill Livingstone; 1995. pp. 1308–1321. [PubMed][Google Scholar]
  • 2. Landis S H, Murray T, Bolden S, Wingo P A. CA Cancer J Clin. 1998;48:6–29.[PubMed]
  • 3. Caligaris-Cappio F, Gobbi M, Bofill M, Janossy G. J Exp Med. 1982;155:623–628.
  • 4. Boumsell L, Bernard A, Lepage V, Degos L, Lemerle J, Dausset J, L. Eur J Immunol. 1978;8:900–904.[PubMed]
  • 5. Kantor A B. Immunol Today. 1991;12:389–391.[PubMed]
  • 6. Croce C M. Cell. 1987;49:155–156.[PubMed]
  • 7. Dalla-Favera R, Bregni M, Erikson J, Patterson D, Gallo R C, Croce C M. Proc Natl Acad Sci USA. 1982;79:7824–7827.
  • 8. ar-Rushdi A, Nishikura K, Erikson R W, Rovera G, Croce C M. Science. 1983;222:390–393.[PubMed]
  • 9. Virgilio L, Narducci M G, Isobe M, Billips L G, Cooper M D, Croce C M, Russo G. Proc Natl Acad Sci USA. 1994;91:12530–12534.
  • 10. Narducci M G, Stoppacciaro A, Imada K, Uchiyama T, Virgilio L, Lazzeri C, Croce C M, Russo G. Cancer Res. 1997;57:5452–5456.[PubMed]
  • 11. Thick J, Metacalfe J A, Mak Y-F, Beatty D, Minegishi, Dyer M J S, Lucas G, Taylor A M R. Oncogene. 1996;12:379–386.[PubMed]
  • 12. Virgilio L, Lazzeri C, Bichi R, Nibu K, Narducci M G, Russo G, Rothstein J L, Croce C M. Proc Natl Acad Sci USA. 1998;95:3885–3889.
  • 13. Takizawa J, Suzuki R, Kuroda H, Utsunomiya A, Kagami Y, Joh T, Aizawa Y, Ueda R, Seto M. Jpn J Cancer Res. 1998;89:712–718.
  • 14. Narducci M G, Pescarmona E, Lazzeri C, Signoretti S, Lavinia A M, Remotti D, Scala E, Baroni C D, Stoppacciaro A, Croce C M, et al Cancer Res. 2000;60:2095–2100.[PubMed][Google Scholar]
  • 15. Shaw A C, Swat W, Ferrini R, Davidson L, Alt F W. J Exp Med. 1999;189:123–129.
  • 16. Hardy R R, Carmack C E, Shinton S A, Kemp J D, Hayakawa K. J Exp Med. 1991;173:1213–1225.
  • 17. Hardy R R In: The Handbook of Experimental Immunology. 4th Ed. Weir D M, Herzenberg L A, Blackwell C C, Herzenberg L A, editors. Edinburgh: Blackwell Scientific; 1986. pp. 31.1–31.12. [PubMed][Google Scholar]
  • 18. Li Y S, Wasserman R, Hayakawa K, Hardy R R. Immunity. 1996;5:527–535.[PubMed]
  • 19. Hardy R R, Carmack C E, Li Y S, Hayakawa K. Immunol Rev. 1994;137:91–118.[PubMed]
  • 20. Willis T G, Jadayel D M, Coignet L J A, Abdul-Rauf M, Treleaven J G, Catovsky D, Dyer M J S. Blood. 1997;90:2456–2464.[PubMed]
  • 21. Kantor A B, Herzenberg L A. Annu Rev Immunol. 1993;11:501–538.[PubMed]
  • 22. Hayakawa K, Hardy R R. Annu Rev Immunol. 1988;6:197–218.[PubMed]
  • 23. Lanier L L, Warner N L, Ledbetter J A, Herzenberg L A. J Exp Med. 1981;153:998–1003.
  • 24. Phillips J A, Mehta K, Fernandez C, Raveché E S. Cancer Res. 1992;52:437–443.[PubMed]
  • 25. Chen X, Martin F, Forbush K A, Perlmutter R M, Kearney J F. Int Immunol. 1997;9:27–41.[PubMed]
  • 26. Pennell C A, Arnold L W, Haughton G, Clarke S H. J Immunol. 1988;141:2788–2796.[PubMed]
  • 27. Li Y S, Hayakawa K, Hardy R R. J Exp Med. 1993;178:951–960.
  • 28. Andreeff M, Darzynkiewicz Z, Sharpless T K, Clarkson B D, Melamed M R. Blood. 1980;55:282–293.[PubMed]
  • 29. Nilsson K In: Chronic Lymphocytic Leukemia: Scientific Advances &amp; Clinical Development. Cheson B D, editor. New York: Dekker; 1992. pp. 33–45. [PubMed][Google Scholar]
  • 30. Kantor A B, Merrill C E, Herzenberg L A, Hillson J L. J Immunol. 1997;158:1175–1186.[PubMed]
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