Transcription factor GATA-1 and Down syndrome leukemogenesis.
Mutations in transcription factors constitute one means by which normal hematopoietic progenitors are converted to leukemic stem cells. Recently, acquired mutations in the megakaryocytic regulator GATA1 have been found in essentially all cases of acute megakaryoblastic leukemia (AMkL) in children with Down syndrome and in the closely related malignancy transient myeloproliferative disorder. In all cases, mutations in GATA1 lead to the expression of a shorter isoform of GATA-1, named GATA-1s. Because GATA-1s retains both DNA binding zinc fingers, but is missing the N-terminal transactivation domain, it has been predicted that the inability of GATA-1s to regulate its normal class of megakaryocytic target genes is the mechanism by which mutations in GATA1 contribute to the disease. Indeed, several recent reports have confirmed that GATA-1s fails to properly regulate the growth of megakaryocytic precursors, likely through aberrant transcriptional regulation. Although the specific target genes of GATA-1 mis-regulated by GATA-1s that drive this abnormal growth remain undefined, multiple candidate genes have been identified via gene array studies. Finally, the inability of GATA-1s to promote expression of important metabolic genes, such as cytadine deaminase, likely contributes to the remarkable hypersensitivity of AMkL blasts to cytosine arabinoside. Future studies to define the entire class of genes dysregulated by mutations in GATA1 will provide important insights into the etiology of these malignancies.
Muntean
Andrew G
AG
Ben May Institute for Cancer Research, University of Chicago, IL 60637, USA.
Ge
Yubin
Y
Taub
Jeffrey W
JW
Crispino
John D
JD
D004247:DNA / Q000737:chemistry; D004314:Down Syndrome / Q000150:complications* / Q000235:genetics*; D050982:GATA1 Transcription Factor / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007947:Leukemia, Megakaryoblastic, Acute / Q000150:complications* / Q000235:genetics*; D008954:Models, Biological; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000235:genetics; D011485:Protein Binding; D012680:Sensitivity and Specificity; D013234:Stem Cells / Q000166:cytology; D016335:Zinc Fingers
D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; D004247:DNA