Molecular insights into Down syndrome-associated leukemia.
OBJECTIVE
Four years ago it was discovered that nearly all cases of transient myeloproliferative disorder and acute megakaryocytic leukemia in children with Down syndrome acquire mutations in the hematopoietic transcription factor gene GATA1. Studies within the past year, described within this review, have provided tremendous insights into the role of GATA1 mutations in these malignancies.


RESULTS
In the past year, our understanding of the molecular and cellular consequences of GATA1 mutations has been greatly enhanced. Most importantly, we have learned that these mutations, which result in the exclusive production of the short GATA1 isoform named GATA1s, have a distinct effect on fetal liver progenitors. In addition, multiple studies have shown that GATA1s can substitute for GATA1 in many aspects of megakaryocytic maturation. Finally, an important clinical study has revealed that GATA1 mutations alone are insufficient for leukemia.


CONCLUSIONS
Leukemia in children with Down syndrome requires at least three cooperating events--trisomy 21, a GATA1 mutation, and a third, as yet undefined, genetic alteration. Recent studies have provided tremendous insights into the GATA1 side of the story. Future experiments with human patient samples and mouse models will likely increase our awareness of the role of trisomy 21 in transient myeloproliferative disorder and acute megakaryocytic leukemia.
Vyas
Paresh
P
Department of Haematology, MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK.
Crispino
John D
JD
D000818:Animals; D002648:Child; D002891:Chromosomes, Human, Pair 21; D004314:Down Syndrome / Q000235:genetics*; D050982:GATA1 Transcription Factor / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D007947:Leukemia, Megakaryoblastic, Acute / Q000175:diagnosis / Q000209:etiology / Q000235:genetics*; D051379:Mice; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000175:diagnosis / Q000209:etiology / Q000235:genetics*; D010641:Phenotype
D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human