期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 109, 期 43, 页码 17579-17584出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1211405109
关键词
transient myeloproliferative disorder; aneuploidy; human fetus
资金
- Leukemia and Lymphoma Research Specialist Programme Award [08030]
- Imperial College Biomedical Research Centre
- Oxford Partnership Biomedical Research Centre National Institute for Health Research Biomedical Research Centre scheme
- Leukemia and Lymphoma Research
- Medical Research Council
- Kay Kendall Leukaemia Fund
- MRC [G0501838, G1002092, G0801073, MC_UU_12009/5] Funding Source: UKRI
- Medical Research Council [G0801073, G1002092, G1000801c, MC_UU_12009/5, G0501838] Funding Source: researchfish
- National Institute for Health Research [CL-2010-21-011] Funding Source: researchfish
The 40-fold increase in childhood megakaryocyte-erythroid and B-cell leukemia in Down syndrome implicates trisomy 21 (T21) in perturbing fetal hematopoiesis. Here, we show that compared with primary disomic controls, primary T21 fetal liver (FL) hematopoietic stem cells (HSC) and megakaryocyte-erythroid progenitors are markedly increased, whereas granulocyte-macrophage progenitors are reduced. Commensurately, HSC and megakaryocyte-erythroid progenitors show higher clonogenicity, with increased megakaryocyte, megakaryocyte-erythroid, and replatable blast colonies. Biased megakaryocyte-erythroid-primed gene expression was detected as early as the HSC compartment. In lymphopoiesis, T21 FL lymphoid-primed multipotential progenitors and early lymphoid progenitor numbers are maintained, but there was a 10-fold reduction in committed PreproB-lymphoid progenitors and the functional B-cell potential of HSC and early lymphoid progenitor is severely impaired, in tandem with reduced early lymphoid gene expression. The same pattern was seen in all T21 FL samples and no samples had GATA1 mutations. Therefore, T21 itself causes multiple distinct defects in FL myelo- and lymphopoiesis.
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