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Blood, 1 December 2008, Vol. 112, No. 12, pp. 4503-4506.
Prepublished online as a Blood First Edition Paper on September 23, 2008; DOI 10.1182/blood-2008-05-157859.
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Submitted May 16, 2008
Accepted August 29, 2008
Trisomy 21 enhances human fetal erythro-megakaryocytic development
Stella T Chou, Joanna B Opalinska, Yu Yao, Myriam A Fernandes, Anna Kalota, John SJ Brooks, John K Choi, Alan M Gewirtz, Gwenn-ael Danet-Desnoyers, Richard L Nemiroff, and Mitchell J Weiss*
Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, PA, United States
Division of Hematology/Oncology, The University of Pennsylvania School of Medicine, Philadelphia, PA, United States
Department of Pathology, Pennsylvania Hospital, Philadelphia, PA, United States
Department of Pathology, The Children's Hospital of Philadelphia, Philadelphia, PA, United States
Department of Obstetrics and Gynecology, The University of Pennsylvania School of Medicine, Philadelphia, PA, United States
Department of Pediatrics, The University of Pennsylvania School of Medicine, Philadelphia, PA, United States
* Corresponding author; email: weissmi{at}email.chop.edu.
Children with Down syndrome exhibit two related hematopoietic diseases: transient myeloproliferative disorder (TMD) and acute megakaryoblastic leukemia (AMKL). Both exhibit clonal expansion of blasts with bi-phenotypic erythroid and megakaryocyte features and contain somatic GATA1 mutations. While altered GATA1 inhibits erythro-megakaryocytic development, less is known about how trisomy 21 impacts blood formation, particularly in the human fetus where TMD and AMKL originate. We used in vitro and mouse transplantation assays to study hematopoiesis in trisomy 21 fetal livers with normal GATA1 alleles. Remarkably, trisomy 21 progenitors exhibited enhanced production of erythroid and megakaryocytic cells that proliferated excessively. Our findings indicate that trisomy 21 itself is associated with cell-autonomous expansion of erythro-megakaryocytic progenitors. This may predispose to TMD and AMKL by increasing the pool of cells susceptible to malignant transformation through acquired mutations in GATA1 and other cooperating genes.
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