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:

Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome

Nature Genetics volume 32, pages 148–152 (2002)Cite this article

Abstract

Children with Down syndrome have a 10–20-fold elevated risk of developing leukemia, particularly acute megakaryoblastic leukemia (AMKL)1. While a subset of pediatric AMKLs is associated with the 1;22 translocation and expression of a mutant fusion protein2,3, the genetic alterations that promote Down syndrome–related AMKL (DS-AMKL) have remained elusive. Here we show that leukemic cells from every individual with DS-AMKL that we examined contain mutations in GATA1, encoding the essential hematopoietic transcription factor GATA1 (GATA binding protein 1 or globin transcription factor 1). Each mutation results in the introduction of a premature stop codon in the gene sequence that encodes the amino-terminal activation domain. These mutations prevent synthesis of full-length GATA1, but not synthesis of a shorter variant that is initiated downstream. We show that the shorter GATA1 protein, which lacks the N-terminal activation domain, binds DNA and interacts with its essential cofactor Friend of GATA1 (FOG1; encoded by ZFPM1)4 to the same extent as does full-length GATA1, but has a reduced transactivation potential. Although some reports suggest that the activation domain is dispensable in cell-culture models of hematopoiesis5,6, one study has shown that it is required for normal development in vivo7. Together, these findings indicate that loss of wildtype GATA1 constitutes one step in the pathogenesis of AMKL in Down syndrome.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Figure 1: GATA1 mutations in Down syndrome–related AMKL.
Figure 2: Proteins encoded by wildtype and mutated GATA1 alleles in transfected cells, hematopoietic cell lines and cells from individual DS-AMKL-1.
Figure 3: Functional analysis of the GATA1 protein of 40 kD.

Similar content being viewed by others

References

  1. Lange, B. The management of neoplastic disorders of haematopoiesis in children with Down's syndrome. Br. J. Haematol. 110, 512–524 (2000).

    Article  CAS  Google Scholar 

  2. Dickstein, J.I., Davis, E.M. & Roulston, D. Localization of the chromosome 22 breakpoints in two cases of acute megakaryoblastic leukemia with t(1;22)(p13;q13). Cancer Genet. Cytogenet. 129, 150–154 (2001).

    Article  CAS  Google Scholar 

  3. Ma, Z. et al. Fusion of two novel genes, RBM15 and MKL1, in the t(1;22)(p13;q13) of acute megakaryoblastic leukemia. Nature Genet. 28, 220–221 (2001).

    Article  CAS  Google Scholar 

  4. Tsang, A.P. et al. FOG, a multitype zinc finger protein, acts as a cofactor for transcription factor GATA-1 in erythroid and megakaryocytic differentiation. Cell 90, 109–119 (1997).

    Article  CAS  Google Scholar 

  5. Visvader, J.E., Crossley, M., Hill, J., Orkin, S.H. & Adams, J.M. The C-terminal zinc finger of GATA-1 or GATA-2 is sufficient to induce megakaryocytic differentiation of an early myeloid cell line. Mol. Cell. Biol. 15, 634–641 (1995).

    Article  CAS  Google Scholar 

  6. Weiss, M.J., Yu, C. & Orkin, S.H. Erythroid-cell-specific properties of transcription factor GATA-1 revealed by phenotypic rescue of a gene-targeted cell line. Mol. Cell. Biol. 17, 1642–1651 (1997).

    Article  CAS  Google Scholar 

  7. Shimizu, R., Takahashi, S., Ohneda, K., Engel, J.D. & Yamamoto, M. In vivo requirements for GATA-1 functional domains during primitive and definitive erythropoiesis. EMBO J. 20, 5250–5260 (2001).

    Article  CAS  Google Scholar 

  8. Nichols, K.E. et al. Familial dyserythropoietic anaemia and thrombocytopenia due to an inherited mutation in GATA1. Nature Genet. 24, 266–270 (2000).

    Article  CAS  Google Scholar 

  9. Freson, K. et al. Platelet characteristics in patients with X-linked macrothrombocytopenia because of a novel GATA1 mutation. Blood 98, 85–92 (2001).

    Article  CAS  Google Scholar 

  10. Mehaffey, M.G., Newton, A.L., Gandhi, M.J., Crossley, M. & Drachman, J.G. X-linked thrombocytopenia caused by a novel mutation of GATA-1. Blood 98, 2681–2688 (2001).

    Article  CAS  Google Scholar 

  11. Orkin, S.H. Diversification of haematopoietic stem cells to specific lineages. Nature Rev. Genet. 1, 57–64 (2000).

    Article  CAS  Google Scholar 

  12. Shivdasani, R.A., Fujiwara, Y., McDevitt, M.A. & Orkin, S.H. A lineage-selective knockout establishes the critical role of transcription factor GATA-1 in megakaryocyte growth and platelet development. EMBO J. 16, 3965–3973 (1997).

    Article  CAS  Google Scholar 

  13. Vyas, P., Ault, K., Jackson, C.W., Orkin, S.H. & Shivdasani, R.A. Consequences of GATA-1 deficiency in megakaryocytes and platelets. Blood 93, 2867–2875 (1999).

    CAS  PubMed  Google Scholar 

  14. Song, W.J. et al. Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia. Nature Genet. 23, 166–175 (1999).

    Article  CAS  Google Scholar 

  15. Michaud, J. et al. In vitro analyses of known and novel RUNX1/AML1 mutations in dominant familial platelet disorder with predisposition to acute myelogenous leukemia: implications for mechanisms of pathogenesis. Blood 99, 1364–1372 (2002).

    Article  CAS  Google Scholar 

  16. Osato, M. et al. Biallelic and heterozygous point mutations in the runt domain of the AML1 gene associated with myeloblastic leukemias. Blood 93, 1817–1824 (1999).

    CAS  PubMed  Google Scholar 

  17. Preudhomme, C. et al. High incidence of biallelic point mutations in the Runt domain of the AML1/PEBP2αB gene in Mo acute myeloid leukemia and in myeloid malignancies with acquired trisomy 21. Blood 96, 2862–2869 (2000).

    CAS  PubMed  Google Scholar 

  18. Crispino, J.D., Lodish, M.B., MacKay, J.P. & Orkin, S.H. Use of altered specificity mutants to probe a specific protein–protein interaction in differentiation: the GATA-1:FOG complex. Mol. Cell 3, 219–228 (1999).

    Article  CAS  Google Scholar 

  19. Calligaris, R., Bottardi, S., Cogoi, S., Apezteguia, I. & Santoro, C. Alternative translation initiation site usage results in two functionally distinct forms of the GATA-1 transcription factor. Proc. Natl Acad. Sci. USA 92, 11598–11602 (1995).

    Article  CAS  Google Scholar 

  20. Komatsu, N. et al. Growth and differentiation of a human megakaryoblastic cell line, CMK. Blood 74, 42–48 (1989).

    CAS  PubMed  Google Scholar 

  21. Sato, T. et al. Establishment of a human leukaemic cell line (CMK) with megakaryocytic characteristics from a Down's syndrome patient with acute megakaryoblastic leukaemia. Br. J. Haematol. 72, 184–190 (1989).

    Article  CAS  Google Scholar 

  22. Martin, D.I. & Orkin, S.H. Transcriptional activation and DNA binding by the erythroid factor GF-1/NF-E1/Eryf 1. Genes Dev. 4, 1886–1898 (1990).

    Article  CAS  Google Scholar 

  23. Fujiwara, Y., Browne, C.P., Cunniff, K., Goff, S.C. & Orkin, S.H. Arrested development of embryonic red cell precursors in mouse embryos lacking transcription factor GATA-1. Proc. Natl Acad. Sci. USA 93, 12355–12358 (1996).

    Article  CAS  Google Scholar 

  24. McDevitt, M.A., Shivdasani, R.A., Fujiwara, Y., Yang, H. & Orkin, S.H. A 'knockdown' mutation created by cis-element gene targeting reveals the dependence of erythroid cell maturation on the level of transcription factor GATA-1. Proc. Natl Acad. Sci. USA 94, 6781–6785 (1997).

    Article  CAS  Google Scholar 

  25. Takahashi, S. et al. Role of GATA-1 in proliferation and differentiation of definitive erythroid and megakaryocytic cells in vivo. Blood 92, 434–442 (1998).

    CAS  PubMed  Google Scholar 

  26. Kelly, L., Clark, J. & Gilliland, D.G. Comprehensive genotypic analysis of leukemia: clinical and therapeutic implications. Curr. Opin. Oncol. 14, 10–18 (2002).

    Article  CAS  Google Scholar 

  27. Busson-Le Coniat, M., Nguyen Khac, F., Daniel, M.T., Bernard, O.A. & Berger, R. Chromosome 21 abnormalities with AML1 amplification in acute lymphoblastic leukemia. Genes Chromosom. Cancer 32, 244–249 (2001).

    Article  CAS  Google Scholar 

  28. Dal Cin, P. et al. Amplification of AML1 in childhood acute lymphoblastic leukemias. Genes Chromosom. Cancer 30, 407–409 (2001).

    Article  CAS  Google Scholar 

  29. Wang, P. et al. dic(5;17): a recurring abnormality in malignant myeloid disorders associated with mutations of TP53. Genes Chromosom. Cancer 20, 282–291 (1997).

    Article  CAS  Google Scholar 

  30. Trainor, C.D. et al. A palindromic regulatory site within vertebrate GATA-1 promoters requires both zinc-fingers of the GATA-1 DNA-binding domain for high- affinity interaction. Mol. Cell. Biol. 16, 2238–2247 (1996).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank K. Nichols, S. Orkin, K. Shannon and M. Weiss for insight and discussion; S. Droho and E. Smith for reviewing the manuscript; A. Fernald for assistance with the SSCP assay; and D. Tenen for advice on generating cell lysates. This work was supported, in part, by the Aplastic Anemia and MDS International Foundation (M.G.), the Cancer Research Foundation (J.D.C.) and the Picower Foundation (M.A.M.). J.D.C. is a recipient of a Burroughs Wellcome Fund Career Award in the Biomedical Sciences.

Author information

Authors and Affiliations

  1. Ben May Institute for Cancer Research, University of Chicago, Chicago, 60637, Illinois, USA

    Joshua Wechsler, Marianne Greene & John D. Crispino

  2. Division of Hematology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Michael A. McDevitt

  3. Department of Pathology, University of Chicago, Chicago, Illinois, USA

    John Anastasi

  4. Greenebaum Cancer Center, University of Maryland, Baltimore, Maryland, USA

    Judith E. Karp

  5. Department of Medicine, University of Chicago, Chicago, Illinois, USA

    Michelle M. Le Beau

Authors
  1. Joshua Wechsler
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marianne Greene
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael A. McDevitt
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. John Anastasi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Judith E. Karp
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michelle M. Le Beau
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. John D. Crispino
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to John D. Crispino.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wechsler, J., Greene, M., McDevitt, M. et al. Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome. Nat Genet 32, 148–152 (2002). https://doi.org/10.1038/ng955

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng955

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