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Molecular and Cellular Biology, September 2009, p. 5168-5180, Vol. 29, No. 18
0270-7306/09/$08.00+0     doi:10.1128/MCB.00482-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

GATA-2 Reinforces Megakaryocyte Development in the Absence of GATA-1{triangledown} ,{dagger}

Zan Huang,1 Louis C. Dore,2 Zhe Li,3 Stuart H. Orkin,4 Gang Feng,5 Simon Lin,5 and John D. Crispino1*

Department of Medicine, Division of Hematology/Oncology,1 Integrated Graduate Program, Northwestern University, Chicago, Illinois 60611,2 Children's Hospital,3 Department of Pediatric Oncology, Dana Farber Cancer Institute, Harvard Stem Cell Institute and Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02115,4 Bioinformatics Program, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois 606115

Received 14 April 2009/ Returned for modification 26 May 2009/ Accepted 11 July 2009

GATA-2 is an essential transcription factor that regulates multiple aspects of hematopoiesis. Dysregulation of GATA-2 is a hallmark of acute megakaryoblastic leukemia in children with Down syndrome, a malignancy that is defined by the combination of trisomy 21 and a GATA1 mutation. Here, we show that GATA-2 is required for normal megakaryocyte development as well as aberrant megakaryopoiesis in Gata1 mutant cells. Furthermore, we demonstrate that GATA-2 indirectly controls cell cycle progression in GATA-1-deficient megakaryocytes. Genome-wide microarray analysis and chromatin immunoprecipitation studies revealed that GATA-2 regulates a wide set of genes, including cell cycle regulators and megakaryocyte-specific genes. Surprisingly, GATA-2 also negatively regulates the expression of crucial myeloid transcription factors, such as Sfpi1 and Cebpa. In the absence of GATA-1, GATA-2 prevents induction of a latent myeloid gene expression program. Thus, GATA-2 contributes to cell cycle progression and the maintenance of megakaryocyte identity of GATA-1-deficient cells, including GATA-1s-expressing fetal megakaryocyte progenitors. Moreover, our data reveal that overexpression of GATA-2 facilitates aberrant megakaryopoiesis.

* Corresponding author. Mailing address: Northwestern University, Division of Hematology & Oncology, 303 E Superior Street, Lurie Research Building 5-113, Chicago, IL 60611. Phone: (312) 503-1504. Fax: (312) 503-0189. E-mail: j-crispino{at}northwestern.edu

{triangledown} Published ahead of print on 20 July 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, September 2009, p. 5168-5180, Vol. 29, No. 18
0270-7306/09/$08.00+0     doi:10.1128/MCB.00482-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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