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

近年来，大量研究已经证实非编码rna (ncRNAs)，特别是microRNAs （miRNAs）的表达失调是白血病发生的一个致病因素。这些研究主要考察了单个mirna或长链非编码rna （lncRNAs）的功能。然而，我们之前对miR-99/100~125b簇的研究表明了基因组背景对非编码基因功能的重要性。我们发现，多顺反组织的ncrna既具有协同功能，又具有互补功能，相互加强和控制。由于42%的miRNA基因以多顺反子转录本组织，因此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必须被理解。在肿瘤学、血液学或再生医学中，这对于服从治疗性mirna干扰的后果是必不可少的。为了深入了解人类血液系统中ncRNA/ mRNA集群的结构、调控和功能，我们将在这个项目（伴随Heisenberg计划）中解剖巨核形成过程中的DLK1-DIO3位点和急性巨核母细胞白血病的发病机制。DLK1-DIO3位点包含人类基因组中最大的miRNA簇（54个miRNA，称为miRNA-mega cluster），以及大量来自母体等位基因的box C / D snorna和lncrna。我们对造血系统的个体遗传人类ncRNA表达图谱的综合分析揭示了该位点在巨核细胞中的特异性表达。这种表达模式也见于经常发生在婴儿中的巨核母细胞白血病。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控的，以及这些网络的失调是如何影响基因发生的。随着基因组编辑和全基因组转录调控的最新进展，这些见解现在变得触手可及。此外，用于患者来源的异种移植的新型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，从而快速过渡到临床。

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.