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Down Syndrome Abstract
of the Month: Sept 2002

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Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome

Wechsler J, Greene M, McDevitt MA, Anastasi J, Karp JE, Le Beau MM, Crispino JD
Nat Genet 2002 Sep;32(1):148-152

Ben May Institute for Cancer Research, University of Chicago, Illinois, USA.

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Children with Down syndrome have a 10 to 20-fold elevated risk of developing leukemia, particularly acute megakaryoblastic leukemia (AMKL). While a subset of pediatric AMKLs is associated with the 1;22 translocation and expression of a mutant fusion protein, the genetic alterations that promote Down syndrome-related AMKL (DS-AMKL) have remained elusive. Here we show that leukemic cells from every individual with DS-AMKL that we examined contain mutations in GATA1, encoding the essential hematopoietic transcription factor GATA1 (GATA binding protein 1 or globin transcription factor 1). Each mutation results in the introduction of a premature stop codon in the gene sequence that encodes the amino-terminal activation domain. These mutations prevent synthesis of full-length GATA1, but not synthesis of a shorter variant that is initiated downstream. We show that the shorter GATA1 protein, which lacks the N-terminal activation domain, binds DNA and interacts with its essential cofactor Friend of GATA1 (FOG1; encoded by ZFPM1) to the same extent as does full-length GATA1, but has a reduced transactivation potential. Although some reports suggest that the activation domain is dispensable in cell-culture models of hematopoiesis, one study has shown that it is required for normal development in vivo. Together, these findings indicate that loss of wildtype GATA1 constitutes one step in the pathogenesis of AMKL in Down syndrome.

My comments:

This study fills in part of the process for how some children with DS develop leukemia. A defect in the GATA1 gene, which is located on the X chromosome, was shown to have the same defect in all 6 children with DS and acute megakaryoblastic leukemia, a rare form of acute myeloid leukemia (AML). Megakaryocytes are the cells in the bone marrow which become platelets. AMKL is much more common in children with DS than in the general population.

The GATA1 gene's basic function appears to be the production of a protein essential for the production of red blood cells and platelets. The mutation seen in these cases created a "premature stop codon," which means that the defective gene halted production of the protein too soon. In the absence of normal GATA1 proteins, megakaryocytes do not become platelets.

In AMKL, not only is there an absence of platelets, but there is also a rapid production of megakaryocytes. So the development of AMKL is children with DS results from a combination of two factors: the presence of the mutant GATA1, and some other factor that encourages the proliferation of megakaryocytes. This second factor is most likely connected to the 21st chromosome. The authors state that a candidate gene on the 21st chromosome is the RUNX1 gene, which has been associated with the development of AML previously.

The more we find out about leukemia in DS, the faster we can diagnose it and the better we can treat it.

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