Deciphering the complex, deregulated transcription network in the development of leukemia in children with Down syndrome

21号染色体的结构和数量畸变是儿童急性白血病中最常见的细胞遗传学改变，而患有唐氏综合症（DS， 21三体）的儿童发生髓性白血病（ML-DS）的风险增加了约500倍。大约95%的ML-DS患儿携带造血转录因子GATA1突变，导致截断蛋白（GATA1s）的独家表达。在正在进行的项目中，我们阐明了致病GATA1s突变在白血病过程中的未知分子作用。通过对人原代细胞和新生成的ML-DS小鼠模型的复杂功能研究，我们能够发现GATA1s无法控制胎儿巨核细胞和嗜酸性粒细胞祖细胞增殖率的增加。同时，GATA1诱导嗜酸性粒细胞和巨核细胞基因的功能保持不变。增殖速率的增加似乎主要是由IGF2通过激活e2f细胞周期调节因子诱导的。IGF2由胎儿肝脏分泌。在机制上，我们发现GATA1s突变损害了蛋白质与E2F1的相互作用。由于胎儿巨核细胞祖细胞的生长依赖于IGF2，而表面上相似的成人巨核细胞的生长不依赖于IGF2，因此我们的研究阐明了胎儿和成人造血之间重要但未知的差异。此外，我们的研究解释了ML-DS的胎儿起源。尽管有这些新的见解，但仍有两个问题没有得到解答，我们将在后续项目中加以解决。首先，什么样的内在遗传网络决定了胎儿造血祖细胞对IGF2的依赖性和对GATA1s突变的敏感性？第二，为什么GATA1s能诱导巨核细胞基因，而不能诱导红系基因？回答这些问题对于制定针对婴儿白血病的靶向治疗方案至关重要。

Structural and numerical aberrations of chromosome 21 are the most common cytogenetic changes in pediatric acute leukemias, whereas children with Down syndrome (DS, trisomy 21) have an approximately 500-fold increased risk to develop myeloid leukemia (ML-DS). About 95% of children with ML-DS carry mutations in the hematopoietic transcription factor GATA1, resulting in the exclusive expression of a truncated protein (GATA1s).In the running project, we elucidated the as yet unknown molecular role of pathognomonic GATA1s mutation in the process of leukemia. By complex functional studies in human primary blasts and a newly generated mouse model for ML-DS, we were able to discover that GATA1s fails to control the increased proliferation rate of fetal megakaryocytic and eosinophil progenitor cells. At the same time the function of GATA1 to induce eosinophil and megakaryocytic genes remains intact. The increased proliferation rate seems to be mainly induced by IGF2 via activation of the E2F-cell cycle regulators. , IGF2 is secreted by the fetal liver. Mechanistically, we showed that the GATA1s mutation impairs the protein interactions with E2F1. As the growth of fetal megakaryocytic progenitor cells but not of their ostensibly similar adult counterparts is dependent on IGF2, our study elucidates important yet unknown differences between fetal and adult hematopoiesis. Furthermore, our study explains the fetal origin of ML-DS. Despite these new insights two questions remain unanswered, which we will address in the follow-up project. First, what intrinsic genetic network determines the dependency of fetal hematopoietic progenitor cells on IGF2 and the sensitivity to the GATA1s mutation? Second, why does GATA1s induce megakaryocytic, but not erythroid genes? Answering these questions is essential to develop targeted therapeutic options for infant leukemias.