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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.

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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.

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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.

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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

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Correspondence to John D. Crispino.

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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

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