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Developmental stage–selective effect of somatically mutated leukemogenic transcription factor GATA1

Nature Genetics volume 37, pages 613–619 (2005)Cite this article

Abstract

Acquired mutations in the hematopoietic transcription factor GATA binding protein-1 (GATA1) are found in megakaryoblasts from nearly all individuals with Down syndrome with transient myeloproliferative disorder (TMD, also called transient leukemia) and the related acute megakaryoblastic leukemia (DS-AMKL, also called DS-AML M7)1,2,3,4,5,6. These mutations lead to production of a variant GATA1 protein (GATA1s) that is truncated at its N terminus. To understand the biological properties of GATA1s and its relation to DS-AMKL and TMD, we used gene targeting to generate Gata1 alleles that express GATA1s in mice. We show that the dominant action of GATA1s leads to hyperproliferation of a unique, previously unrecognized yolk sac and fetal liver progenitor, which we propose accounts for the transient nature of TMD and the restriction of DS-AMKL to infants. Our observations raise the possibility that the target cells in other leukemias of infancy and early childhood are distinct from those in adult leukemias and underscore the interplay between specific oncoproteins and potential target cells.

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Figure 1: GATA1s supports normal adult megakaryopoiesis.
Figure 2: GATA1s perturbs fetal hematopoiesis and leads to hyperproliferation of a transient wave of yolk sac and fetal liver progenitors.
Figure 3: GATA1s largely uncouples cellular proliferation from differentiation.
Figure 4: GATA1s acts dominantly on sensitive progenitor cells.
Figure 5: Proposed model of target cells and pathways leading to DS-AMKL.

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Acknowledgements

We thank H. Hock, Y. Fujiwara and J.-P. Bourquin for suggestions and technical assistance; C. Browne and O. Ogai for technical assistance with ES cell targeting; A. Williams and N. Stokes for help with transgenic mice; M. Hamblen for general lab support; and R. Shivdasani and Z. Chen for discussion and help on megakaryocyte ex vivo culture. Z.L. is a Fellow of the Leukemia & Lymphoma Society. J.-H.K. is supported by the German National Academic Foundation and the AML-BFM Study Group. This work was supported by grants to S.H.O. from the US National Institutes of Health. S.H.O. is an Investigator of the Howard Hughes Medical Institute.

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Authors and Affiliations

  1. Division of Hematology/Oncology, Childrens Hospital, Boston, 02115, Massachusetts, USA

    Zhe Li, Frank J Godinho, Jan-Henning Klusmann, Mireia Garriga-Canut, Channing Yu & Stuart H Orkin

  2. Harvard Medical School, Boston, 02115, Massachusetts, USA

    Zhe Li, Channing Yu & Stuart H Orkin

  3. Howard Hughes Medical Institute, Boston, 02115, Massachusetts, USA

    Frank J Godinho & Stuart H Orkin

  4. Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, 02115, Massachusetts, USA

    Stuart H Orkin

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  1. Zhe Li
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Correspondence to Stuart H Orkin.

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Supplementary information

Supplementary Fig. 1

Targeting strategies. (PDF 48 kb)

Supplementary Fig. 2

GATA1e2fl conditional knockin. (PDF 168 kb)

Supplementary Fig. 3

AChE and antibody staining. (PDF 203 kb)

Supplementary Table 1

Summary of the microarray data. (PDF 164 kb)

Supplementary Table 2

Primer sequences. (PDF 20 kb)

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Li, Z., Godinho, F., Klusmann, JH. et al. Developmental stage–selective effect of somatically mutated leukemogenic transcription factor GATA1. Nat Genet 37, 613–619 (2005). https://doi.org/10.1038/ng1566

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