Trisomy 21 expands the megakaryocyte-erythroid progenitor compartment in human fetal liver-implications for down syndrome AMKL.
Trisomy 21 expands the megakaryocyte-erythroid progenitor compartment in human fetal liver-implications for down syndrome AMKL.
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21 三体扩大了人胎儿肝脏中的巨核细胞-红系祖细胞区室 - 对唐氏综合症 AMKL 的影响。
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发表时间：
2006
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影响因子：
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通讯作者：
I. Roberts
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作者：
Oliver Tunstall;J. Fuente;P. Bennett;N. Fisk;P. Vyas;I. Roberts
患有唐氏综合症 (DS) 的儿童患急性巨核细胞白血病 (AMKL) 的频率特别高，与没有 21 三体性 (T21) 的儿童相比，增加了约 500 倍。 DS-AMKL 至少需要两个遗传事件，但还不够：关键巨核细胞转录因子 GATA1 中的 T21 和 N 端截短突变。 T21 与 GATA1 突变的这种紧密关联以及 AMKL 在狭窄时间窗口（胎儿寿命 - 5 岁）内的发展使得 DS-AMKL 成为多打击白血病发生的信息丰富的模型，其中第一步发生在子宫内。然而，T21 和突变型 GATA1 在白血病发生中的各自作用尚不清楚。为了具体研究 T21 在 DS-AMKL 中的作用以及为什么白血病起始仅限于胎儿（或产后早期），我们研究了 16 个胎儿（胎龄 15-37 周）在妊娠中期和晚期 DS 的胎儿造血情况，其中通过羊水胎儿细胞核型分析对 DS 伴 T21 进行产前诊断。通过 DHPLC 或直接测序（DHPLC 检测 GATA1 突变的灵敏度为 1-5%），筛查胎儿血液 (n=13)、胎儿肝脏 (n=9) 和胎儿骨髓 (n=8) 样本中 GATA1 基因基因组 DNA 的突变。未检测到 GATA1 突变。这使我们能够研究独立于 GATA1 突变的 T21 对胎儿造血的影响。 DS胎儿在造血功能上表现出明显的定性和定量异常。虽然 DS 和正常胎儿肝脏中的 CD34+ 细胞总数相当，但 DS 胎儿的双能巨核细胞-红系祖细胞 (MEP；CD34+CD38+FcgloCD45RA+− 胎儿肝脏 CD34+/CD38+ 细胞为 74.4% vs 27.0%) 显着增加。与正常胎儿血液样本相比，所有研究的 DS 胎儿的外周血显示巨核细胞生成障碍（形状异常和/或巨型血小板和 MK 碎片）、红细胞生成障碍（巨细胞、异色红细胞、嗜碱性点画）、母细胞数量增加，MEP 百分比也增加 - 40.3% vs 26.9% 相比之下，与正常胎儿骨相比，DS 胎儿骨髓中的 MEP、红系或 MK 谱系形态没有差异。来自 DS 胎儿肝脏和胎儿血液的 CD34+ 细胞均表达 fl GATA1 和 GATA1s mRNA，表明巨核细胞生成障碍和红细胞生成并非由于 fl GATA1 表达缺乏所致。这些数据首次表明，T21 本身会严重干扰巨核细胞生成和红细胞生成，并导致 MEP 频率增加，因为它为T21 在 AMKL 的起始步骤中，即 T21 扩展了胎儿肝脏来源的祖细胞区室，该区室形成了 GATA1 突变的底物，然后赋予了进一步的选择优势。
Children with Down syndrome (DS) have a uniquely high frequency of acute megakaryoblastic leukemia (AMKL)- ~500-fold increased compared to children without trisomy 21 (T21). At least two genetic events are required but are not sufficient for DS-AMKL: T21 and N-terminal truncating mutations in the key megakaryocytic transcription factor GATA1. This tight association of T21 with GATA1 mutations and the development of AMKL in a narrow temporal window (fetal life-5yrs) makes DS-AMKL a highly informative model of multi-hit leukemogenesis in which the first steps occur in utero. However, the individual contributions of T21 and mutant GATA1 in the leukemogenesis are unclear. To specifically investigate the role of T21 in DS-AMKL and why leukemia-initiation is confined to fetal (or early post-natal) life we have studied fetal hemopoiesis in DS during the second and third trimester in 16 fetuses (gestational age 15–37 weeks) where an antenatal diagnosis of DS with T21 was made by amniotic fluid fetal cell karyotyping. Samples of fetal blood (n=13), fetal liver (n=9) and fetal bone marrow (n=8) were screened for mutations in the GATA1 gene genomic DNA by DHPLC or direct sequencing (sensitivity of detecting a GATA1 mutation is 1–5% by DHPLC). No GATA1 mutations were detected. This allowed us to study the impact of T21 independent of GATA1 mutation on fetal hemopoiesis. DS fetuses showed marked qualitative and quantitative abnormalities in hemopoiesis. While the total number of CD34+ cells in DS and normal fetal liver were comparable, DS fetuses had a striking increase in bi-potential megakaryocyte-erythroid progenitors (MEP; CD34+CD38+FcgloCD45RA+− 74.4% vs 27.0% of fetal liver CD34+/CD38+ cells. Peripheral blood from all DS fetuses studied compared to normal fetal blood samples showed dysmegakaryopoiesis (abnormally shaped and/or giant platelets and MK fragments), dyserythropoiesis (macrocytes, poikilocytes, basophilic stippling), increased numbers of blast cells and also had an increased percentage of MEPs − 40.3% vs 26.9%. By contrast, there was no difference in the number of MEP nor erythroid or MK lineage morphology in DS fetal bone marrow compared to normal fetal bone marrow. CD34+ cells from DS fetal liver and fetal blood expressed both fl GATA1 and GATA1s mRNA indicating that dysmegakaryopoiesis and erythropoiesis were not due to lack of expression of fl GATA1. These data indicate, for the first time, that T21 by itself profoundly disturbs megakaryopoiesis and erythropoiesis and leads to an increased of frequency of MEP. This has important implications since it provides a testable hypothesis for the role of T21 in the initiating step of AMKL, namely that T21 expands a fetal liver-derived progenitor compartment which forms a substrate upon which GATA1 mutations then confer a further selective advantage.