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.

  • Letter
  • Published:

Deficiency of the adaptor SLP-65 in pre-B-cell acute lymphoblastic leukaemia

Abstract

Acute lymphoblastic leukaemia (ALL) is the commonest form of childhood malignancy, and most cases arise from B-cell clones arrested at the pre-B-cell stage of differentiation1,2. The molecular events that arrest pre-B-cell differentiation in the leukaemic pre-B cells have not been well characterized. Here we show that the differentiation regulator SLP-65 (an adaptor protein also called BLNK or BASH3,4,5,6) inhibits pre-B-cell leukaemia in mice. Reconstitution of SLP-65 expression in a SLP-65-/- pre-B-cell line led to enhanced differentiation in vitro and prevented the development of pre-B-cell leukaemia in immune-deficient mice. Tyrosine 96 of SLP-65 was required for this activity. The murine SLP-65-/- pre-B-cell leukaemia resembles human childhood pre-B ALL. Indeed, 16 of the 34 childhood pre-B ALL samples that were tested showed a complete loss or drastic reduction of SLP-65 expression. This loss is probably due to the incorporation of alternative exons into SLP-65 transcripts, leading to premature stop codons. Thus, the somatic loss of SLP-65 and the accompanying block in pre-B-cell differentiation might be one of the primary causes of childhood pre-B ALL.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: The Btk binding site is essential for the tumour suppressor activity of SLP-65.
Figure 2: Absence of SLP-65 expression in samples derived from pre-B ALL patients.
Figure 3: SLP-65 expression in CD19-purified lymphoblasts from patients with pre-B ALL.

Similar content being viewed by others

References

  1. Jennings, C. D. & Foon, K. A. Recent advances in flow cytometry: application to the diagnosis of hematologic malignancy. Blood 90, 2863–2892 (1997)

    CAS  PubMed  Google Scholar 

  2. Ma, S. K., Wan, T. S. K. & Chan, L. C. Cytogenetics and molecular genetics of childhood leukemia. Hematol. Oncol. 17, 91–105 (1999)

    Article  CAS  PubMed  Google Scholar 

  3. Wienands, J. et al. SLP-65: a new signaling component in B lymphocytes which requires expression of the antigen receptor for phosphorylation. J. Exp. Med. 188, 791–795 (1998)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Fu, C., Turck, C. W., Kurosaki, T. & Chan, A. C. Blnk—a central linker protein in B cell activation. Immunity 9, 93–103 (1998)

    Article  CAS  PubMed  Google Scholar 

  5. Goitsuka, R. et al. BASH, a novel signaling molecule preferentially expressed in B cells of the bursa of Fabricius. J. Immunol. 161, 5804–5808 (1998)

    CAS  PubMed  Google Scholar 

  6. Minegishi, Y. et al. An essential role for BLNK in human B cell development. Science 286, 1954–1957 (1999)

    Article  CAS  PubMed  Google Scholar 

  7. Jumaa, H. et al. Abnormal development and function of B lymphocytes in mice deficient for the signaling adaptor protein SLP-65. Immunity 11, 547–554 (1999)

    Article  CAS  PubMed  Google Scholar 

  8. Pappu, R. et al. Requirement for B cell linker protein (BLNK) in B cell development. Science 286, 1949–1954 (1999)

    Article  CAS  PubMed  Google Scholar 

  9. Hayashi, K. et al. The B cell-restricted adaptor BASH is required for normal development and antigen receptor-mediated activation of B cells. Proc. Natl Acad. Sci. USA 97, 2755–2760 (2000)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  10. Xu, S. L. et al. B cell development and activation defects resulting in xid-like immunodeficiency in BLNK/SLP-65-deficient mice. Int. Immunol. 12, 397–404 (2000)

    Article  CAS  PubMed  Google Scholar 

  11. Flemming, A., Brummer, T., Reth, M. & Jumaa, H. The adaptor protein SLP-65 acts as a tumour suppressor that limits pre-B cell expansion. Nature Immunol. 4, 38–43 (2003)

    Article  CAS  Google Scholar 

  12. Chiu, C. W., Dalton, M., Ishiai, M., Kurosaki, T. & Chan, A. C. BLNK: molecular scaffolding through ‘cis’-mediated organization of signaling prroteins. EMBO J. 21, 6461–6472 (2002)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Disanto, J. P., Muller, W., Guygrand, D., Fischer, A. & Rajewsky, K. Lymphoid development in mice with a targeted deletion of the interleukin 2 receptor gamma chain. Proc. Natl Acad. Sci. USA 92, 377–381 (1995)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  14. Goodman, P. A., Wood, C. M., Vassilev, A., Mao, C. & Uckun, F. M. Spleen tyrosine kinase (Syk) deficiency in childhood pro-B acute lymphoblastic leukemia. Oncogene 20, 3969–3978 (2001)

    Article  CAS  PubMed  Google Scholar 

  15. Hilleren, P. & Parker, R. Mechanisms of mRNA surveillance in eukaryotes. Annu. Rev. Genet. 33, 229–260 (1999)

    Article  CAS  PubMed  Google Scholar 

  16. Advani, A. S. & Pendergast, A. M. Bcr–Abl variants: biological and clinical aspects. Leuk. Res. 26, 713–720 (2002)

    Article  CAS  PubMed  Google Scholar 

  17. Umiel, T., Pattengale, P. & Weinberg, K. Recombination activating gene-1 (RAG-1) expression in all differentiation stages of B-lineage precursor acute lymphoblastic leukemia. Leukemia 7, 435–440 (1993)

    CAS  PubMed  Google Scholar 

  18. Nishii, K. et al. Expression of B cell-associated transcription factors in B-cell precursor acute lymphoblastic leukemia cells: association with PU.1 expression, phenotype, and immunogenotype. Int. J. Hematol. 71, 372–378 (2000)

    CAS  PubMed  Google Scholar 

  19. Beishuizen, A. et al. Multiple rearranged immunoglobulin genes in childhood acute lymphoblastic leukemia of precursor B-cell origin. Leukemia 5, 657–667 (1991)

    CAS  PubMed  Google Scholar 

  20. Gu, Y. et al. The t(4;11) chromosome translocation of human acute leukemias fuses the ALL-1 gene, related to Drosophila trithorax, to the AF-4 gene. Cell 71, 701–708 (1992)

    Article  CAS  PubMed  Google Scholar 

  21. Tkachuk, D. C., Kohler, S. & Cleary, M. L. Involvement of a homolog of Drosophila trithorax by 11q23 chromosomal translocations in acute leukemias. Cell 71, 691–700 (1992)

    Article  CAS  PubMed  Google Scholar 

  22. Domer, P. H. et al. Acute mixed-lineage leukemia t(4;11)(q21;q23) generates an MLL–AF4 fusion product. Proc. Natl Acad. Sci. USA 90, 7884–7888 (1993)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  23. Armstrong, S. A. et al. MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia. Nature Genet. 30, 41–47 (2002)

    Article  CAS  PubMed  Google Scholar 

  24. Nordqvist, K., Ohman, K. & Akusjarvi, G. Human adenovirus encodes two proteins which have opposite effects on accumulation of alternatively spliced mRNAs. Mol. Cell. Biol. 14, 437–445 (1994)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Rajewsky, K. Clonal selection and learning in the antibody system. Nature 381, 751–758 (1996)

    Article  ADS  CAS  PubMed  Google Scholar 

  26. Zhu, C. M. et al. Unrepaired DNA breaks in p53-deficient cells lead to oncogenic gene amplification subsequent to translocations. Cell 109, 811–821 (2002)

    Article  CAS  PubMed  Google Scholar 

  27. Schrappe, M. et al. Long-term results of four consecutive trials in childhood ALL performed by the ALL-BFM study group from 1981 to 1995. Leukemia 14, 2205–2222 (2000)

    Article  CAS  PubMed  Google Scholar 

  28. Edery, I. et al. Involvement of eukaryotic initiation factor 4A in the cap recognition process. J. Biol. Chem. 258, 11398–11403 (1983)

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank E. Bergsträsser (Zürich), U. zur Stadt (Hamburg), J. Harbott (Giessen) and O. G. Ottmann (Frankfurt) for pre-B ALL samples; W.-D. Ludwig (Berlin) and J. Harbott (Giessen) for immunophenotyping and molecular genetic studies of the patients from Freiburg and Hanover; P. Nielsen for reading the manuscript and H. Mossmann for help in the mouse experiments; and C. Eschbach and U. Stauffer for technical support. Financial support for these experiments was provided by the Deutsche Forschungs Gemeinschaft and the Leibniz programme to M.R.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Hassan Jumaa or Michael Reth.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jumaa, H., Bossaller, L., Portugal, K. et al. Deficiency of the adaptor SLP-65 in pre-B-cell acute lymphoblastic leukaemia. Nature 423, 452–456 (2003). https://doi.org/10.1038/nature01608

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature01608

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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