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

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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.