About 10% of patients with Down syndrome (DS) are born with a transient megakaryoblastic leukemia. We (

Rainis et al.
Blood
2003
;
102
:
981
) and others have demonstrated acquired intrauterine inactivating mutations in the X-linked gene GATA1 in these leukemias. The gene(s) on chromosome 21 that promote the proliferation of these abnormal megakaryoblasts are presently unknown. We hypothesize such a role to the ets transcription factor ERG that is located at the critical DS region on chromosome 21. This hypothesis is based on the close homology between ERG and FLI-1, a transcription factor that induces megakaryopoiesis through cooperation with GATA1. ERG occasionally replaces FLI-1 in the translocation with EWS in Ewing sarcoma and is also involved in the leukemogenic translocation FUS-ERG. However no role for ERG in hematopoiesis has been demonstrated so far. Here we show that (a) ERG is expressed in platelets and in megakaryoblastic cell lines, including those derived from Down Syndrome. (b) ERG is expressed in primary leukemic cells from DS patients. (c) Its expression is induced upon megakaryocytic differentiation (d) ERG collaborates with GATA1 in activation of megakaryocytic promoters in reporter assays; and (e) Forced ectopic expression of ERG in K562 cells induces megakaryocytic differentiation. Thus we provide the first evidence that the ERG gene participate in megakaryopoiesis. Promotion of megakaryopoiesis caused by its overexpression in DS coupled with the differentiation arrest induced by the acquired mutation in GATA1 may explain the high incidence of a congenital megakaryoblastic proliferation disorder in Down Syndrome.

Topics:
acute megakaryocytic leukemias, down syndrome, ewing's sarcoma, genes, intrauterine route of drug administration, leukemia, leukemic cells, megakaryocytopoiesis, transcription factor, translocation (genetics)

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2005, The American Society of Hematology
2004
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