Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 2012 Oct 23;109(43):17567-72. doi: 10.1073/pnas.1215468109. Epub 2012 Oct 8.
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 embryonic 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, γ-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.
21 三体与胎儿肝脏中的造血异常有关，这是一种称为短暂性髓系增生异常的白血病前期状态，并增加了急性巨核细胞白血病的发病率。人类 21 三体多能细胞来自不同的来源，包括人类胚胎干细胞（hES）和诱导多能干细胞（iPS）细胞，它们在体外分化为模型，以再现三体对造血的影响。为了减轻克隆变异，我们从同一家系的 iPS 细胞系中分离出二倍体和三倍体亚克隆，从而生成除 21 号染色体外的同源亚克隆。在有利于胎儿肝脏样、γ-珠蛋白表达、确定性造血发育的分化条件下，我们发现 hES、iPS 或同源起源的三倍体细胞中，CD43(+)(Leukosialin)/CD235(+)(Glycophorin A)造血细胞的群体增加了两到五倍，伴有集落形成试验中多谱系集落形成潜能的增加。这些发现确立了 21 三体在胎儿肝脏阶段多谱系髓系造血的内在紊乱。
