Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 109, Issue 43, Pages 17567-17572Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1215468109
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Funding
- National Institutes of Health as part of the Progenitor Cell Biology Consortium of the National Heart, Lung and Blood Institute [U01 HL 10001]
- Harvard Stem Cell Institute
- Howard Hughes Medical Institute
- Lady Tata Memorial Trust fellowship
- Leukemia and Lymphoma Research Fund fellowship
- Kay Kendal Leukemia Fund fellowship
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Trisomy 21 is associated with hematopoietic abnormalities in the fetal liver, a preleukemic condition termed transient myeloproliferative disorder, and increased incidence of acute megakaryoblastic leukemia. Human trisomy 21 pluripotent cells of various origins, human embryionic stem (hES), and induced pluripotent stem (iPS) cells, were differentiated in vitro as a model to recapitulate the effects of trisomy on hematopoiesis. To mitigate clonal variation, we isolated disomic and trisomic subclones from the same parental iPS line, thereby generating subclones isogenic except for chromosome 21. Under differentiation conditions favoring development of fetal liver-like, gamma-globin expressing, definitive hematopoiesis, we found that trisomic cells of hES, iPS, or isogenic origins exhibited a two-to fivefold increase in a population of CD43(+)(Leukosialin)/CD235(+)(Glycophorin A) hematopoietic cells, accompanied by increased multilineage colony-forming potential in colony-forming assays. These findings establish an intrinsic disturbance of multilineage myeloid hematopoiesis in trisomy 21 at the fetal liver stage.
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