GATA-2 reinforces megakaryocyte development in the absence of GATA-1.
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.
Huang
Zan
Z
Division of Hematology & Oncology, Northwestern University, Lurie Research Building 5-113, Chicago, IL 60611, USA.
Dore
Louis C
LC
Li
Zhe
Z
Orkin
Stuart H
SH
Feng
Gang
G
Lin
Simon
S
Crispino
John D
JD
D000818:Animals; D017209:Apoptosis; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000378:metabolism; D002453:Cell Cycle; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D015536:Down-Regulation / Q000235:genetics; D050982:GATA1 Transcription Factor / Q000172:deficiency* / Q000378:metabolism; D050989:GATA2 Transcription Factor / Q000378:metabolism*; D055879:Gene Knock-In Techniques; D055785:Gene Knockdown Techniques; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008533:Megakaryocytes / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D022423:Myeloid Cells / Q000166:cytology / Q000378:metabolism; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D015203:Reproducibility of Results; D015534:Trans-Activators / Q000378:metabolism; D000099232:Proto-Oncogene Protein Spi-1
D022763:CCAAT-Enhancer-Binding Protein-alpha; D050982:GATA1 Transcription Factor; D050989:GATA2 Transcription Factor; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C494689:Gata1 protein, mouse; C494712:Gata2 protein, mouse