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

破译唐氏综合症儿童白血病发展过程中复杂的、失调的转录网络

基本信息

批准号：
159893279
负责人：
Professor Dr. Jan-Henning Cornelius Klusmann
金额：
--
依托单位：
Department of Medical Oncology
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2009
资助国家：
德国
起止时间：
2008-12-31 至 2018-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/159893279?language=en
关键词：
Deciphering complex deregulated transcription network

项目摘要

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.

21号染色体的结构和数目畸变是儿童急性白血病中最常见的细胞遗传学变化，而唐氏综合征（DS，21三体）儿童发生髓性白血病（ML-DS）的风险增加约500倍。大约95%的ML-DS患儿携带造血转录因子GATA 1突变，导致一种截短蛋白（GATA 1 s）的特异性表达。通过对人原代母细胞和新产生的ML-DS小鼠模型的复杂功能研究，我们能够发现GATA 1不能控制胎儿巨核细胞和嗜酸性粒细胞祖细胞的增殖速率增加。同时，GATA 1诱导嗜酸性粒细胞和巨核细胞基因的功能保持完整。增殖速率的增加似乎主要是由IGF 2通过激活E2 F细胞周期调节因子诱导的。IGF 2由胎儿肝脏分泌。从机制上讲，我们发现GATA 1 s突变损害了蛋白质与E2 F1的相互作用。由于胎儿巨核细胞祖细胞的生长依赖于IGF 2，而其表面上相似的成人祖细胞的生长则不依赖于IGF 2，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回答，我们将在后续项目中解决。首先，什么样的内在遗传网络决定了胎儿造血祖细胞对IGF 2的依赖性和对GATA 1 s突变的敏感性？第二，为什么GATA 1诱导巨核细胞基因，而不是红细胞基因？解决这些问题对于开发婴儿白血病的靶向治疗方案至关重要。