Unraveling miR-15 function in health and disease

MicroRNAs (miRNAs) are a type of short, non-protein-coding RNAs that have been shown to have a tremendous influence on almost all biological processes in mammals. While it has become clear that these miRNAs exert their function by regulating a defined set of genes, we are far from understanding how exactly this works neither on the global nor on the molecular level. In this proposal, I plan to provide a comprehensive functional analysis of the miR-15 family, a prominent group of miRNAs that is known mainly for the fact that it is lost in about 60 % of all cases of chronic lymphocytic leukemia (CLL), the most common adult leukemia in the western world. From these observations, one can conclude that the miR-15 family has the ability to suppress cancer, at least under certain circumstances. However, little is known about what these miRNAs do under normal conditions. Data by other groups and by us point into the direction that the members of the miR-15 family regulate whether a cell survives or dies, whether it divides or whether it stops to grow, and whether it develops into a slightly different cell type, a process referred to as differentiation. These decisions are especially important in organisms that consist of billions of cells, such as the human body. Given that the miR-15 family is present in almost all our tissues, we hypothesize that it plays an important role in in diverse processes throughout life, but this has not been addressed experimentally yet. Here, we plan to investigate the role of the miR-15 family by simply taking away some or all miR- 15 family members at the same time and by monitoring the biological processes that become compromised upon this action. In particular, we will analyze the effect of this loss in several tissues such as the immune system, the organ that allows us to defend pathogens such as viruses and bacteria. In addition, we will try to unravel the role of the miR-15 family in different types of cancer, as aberrant cell growth, a process that appears to be controlled by the miR-15 family, is tightly linked to this malady. Using this experimental setup, I expect that our work will allow us to better understand the miR-15 family under normal conditions, but also in case of disease. In the long term, this may be crucial for the development of miRNA-based therapeutic approaches.

MicroRNAs (miRNAs) are a type of short, non-protein-coding RNAs that have been shown to have a tremendous influence on almost all biological processes in mammals. While it has become clear that these miRNAs exert their function by regulating a defined set of genes, we are far from understanding how exactly this works on the global and the molecular level. Within this project, we aimed to provide a comprehensive functional analysis of the miR-15 family, a prominent group of six miRNAs that is known mainly for the fact that some members are lost in about 60 % of all cases of chronic lymphocytic leukemia (CLL), the most common adult leukemia in the western world. From these observations, one can conclude that the miR-15 family has the ability to suppress cancer, but little is known about what these miRNAs do under normal conditions. By taking away some or all miR-15 family members at the same time and by monitoring the biological processes that consequently become compromised, we have been able to define their individual roles. In particular, we could show that two members of the miR-15 family appear dispensable, suggesting that other family members can compensate for their loss. The other four family members, however, turned out to play an important function in the immune system, which is organ that allows us to defend pathogens such as viruses and bacteria. Here, the miR-15 family regulates and limits the development of different subsets of B cells, immune cells that are specialized in antibody production upon infection. Our findings explain how the miR-15 family members control whether these cells divide or stop to grow, and whether they differentiate into a slightly different cell type. Interestingly, one of those B cell subsets that becomes enlarged when we take the miR-15 family away is considered to be the origin for at least a subtype of CLL. We therefore hypothesize that loss of the miR-15 family in immune cells establishes a pre-cancerous setting that allows the accumulation of cells that possibly give rise to full-blown leukemia. Beyond CLL, we furthermore confirm that loss of the miR-15 family primes the immune system for myeloid leukemia, in which another type of immune cells looses its normal growth control. However, we do not know yet how the miR-15 family specifically restricts these myeloid cells under normal circumstances. Taken together, our work has provided us with a better understanding of the miR-15 family under normal conditions, but also in case of disease. This has not only shed light on the regulation of the immune system and how miRNAs affect specific cell types in general, but has also helped us to mechanistically link aberrant miR-15 expression to leukemia.