Deciphering the genetic interactive network of the DLK1-DIO3 ncRNA locus in the hematopoietic system and in infant leukemias

近年来，大量研究证实非编码RNAs(NcRNAs)，尤其是microRNAs(MiRNAs)的异常表达是白血病的致病因素。这些研究在很大程度上考察了单个miRNAs或长非编码RNA(LncRNAs)的功能。然而，我们以前对miR-99/100~125b簇的工作证明了基因组环境对非编码基因功能的重要性。我们发现，多顺反子组织的ncRNAs既可以具有协同功能，也可以具有互补功能，相互加强和控制。由于42%的miRNA基因是以多顺反子转录本的形式组织的，因此必须了解它们在控制基本细胞功能和细胞命运决定方面的相互作用。这对于在肿瘤学、血液学或再生医学中服从治疗性miRNA干扰的后果是至关重要的。为了对人类血液系统中ncRNA/信使核糖核酸簇的结构、调控和功能有一个具体而全面的了解，我们将在这个项目中(伴随着海森堡计划)剖析巨核细胞生成过程中的DLK1-dio3基因座，以及急性巨核细胞白血病的病原学。DLK1-dio3基因座包含人类基因组中最大的miRNA簇(54个miRNAs；称为miRNA-mega簇)，大量的box C/D snoRNAs和来自母系等位基因的lncRNAs。对我们的造血系统的本源性人类ncRNA表达图谱的综合分析发现，该基因在巨核细胞中有特异的表达。这种表达模式也在婴儿中频繁发生的巨核细胞白血病中发现。因此，这个项目的总体目标是阐明复杂的器官系统是如何被相互作用的遗传网络调节的，以及这些网络的失调如何影响共生。这些见解现在可以通过基因组编辑和全基因组转录调控的最新进展来实现。此外，用于患者来源异种移植的新的人源化小鼠模型将允许对婴儿白血病的创新治疗概念进行有效的临床前测试，从而迅速过渡到临床。

Numerous studies have recently established the dysregulated expression of non-coding RNAs (ncRNAs), in particular of microRNAs (miRNAs), as a causative factor in leukemogen-esis. These studies have largely examined the function of individual miRNAs or long non-coding RNAs (lncRNAs). However, our previous work on the miR-99/100~125b clusters demonstrated the importance of the genomic context for the function of non-coding genes. We showed that polycistronically organized ncRNAs can have both synergistic and comple-mentary functions, reinforcing and controlling each other. Since 42% of the miRNA genes are organized in polycistronic transcripts, their interaction in controlling essential cellular functions and cell-fate decisions has to be understood. This is essential to obey the consequences of therapeutic miRNA-interference in oncology, hematology or regenerative medicine. To gain specific and general insights into the structure, regulation and function of ncRNA/ mRNA clusters in the human blood system, we will dissect in this project (accompanying the Heisenberg Programme), the DLK1-DIO3 locus during megakaryopoiesis and the pathogen-esis of acute megakaryoblastic leukemias. The DLK1-DIO3 locus contains the largest miRNA cluster of the human genome (54 miRNAs; called miRNA-mega cluster), numerous box C / D snoRNAs and lncRNAs expressed from the maternal allele. Integrative analyses of our onto-genetic human ncRNA expression atlas of the hematopoietic system have uncovered a spe-cific expression of this locus in megakaryocytes. This expression pattern is also found in megakaryoblastic leukemias that frequently occur in infants. Thus, the overall aim of this project is to elucidate how complex organ systems are regu-lated by interactive genetic networks and how dysregulation of these networks impacts on-cogenesis. These insights now become reachable by recent advances in the genome editing and genome-wide transcriptional regulation. In addition, novel humanized mouse models for patient-derived xenografts will allow efficient preclinical testing of innovative treatment con-cepts for infant leukemias, and therefore the rapid transition to the clinics.