The pathogenic role of MSI1 and MSI2 in myeloid malignancies

• Applicant: Privatdozentin Dr. Jessica Höll
• Subject Area: Pediatric and Adolescent Medicine ; Hematology, Oncology
• Term: from 2015 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 281781283

Leukemias represent the most common cancer type in children and are among the ten most common malignancies in adults. The overall 5-year survival is estimated at 59%, although of course dependent on subtype and age.Despite significant progress in recent years, the underlying pathogenic mechanisms of the clonal expansion in leukemogenesis are still not very well understood. As of now leukemia research has covered such diverse topics as identifying chromosomal rearrangements or sequence mutations by next generation sequencing, studying tyrosine kinase signaling, and disruption of transcriptional control. So far, however, the role of RNA biology and post-transcriptional gene regulation in leukemogenesis has not been studied extensively.This proposal focuses on illuminating the role of post-transcriptional gene regulation by the Musashi family of RNA-binding proteins that are linked to (pediatric) leukemias.Post-transcriptional regulatory networks modulate all steps in the life cycle of any messenger RNAs. These networks stem from complex interactions between RNA-binding proteins, microRNAs and mRNA transcripts. Not surprisingly, deregulation of these networks results in cancer and other diseases, although the vast majority of reports to date have dealt with the role of microRNAs in cancer and only few with that of RNA-binding proteins.For dissecting the role of post-transcriptional gene regulation it is crucial to identify the mRNA targets of individual RNA-binding proteins. This can be achieved by PAR-CLIP (Photoactivatable-Ribonucleoside-Enhanced Crosslinking and Immunoprecipitation), a method making use of next-generation sequencing.Among the many important RNA-binding protein families, the Musashi family has emerged with promising roles in stem cell maintenance, nervous system development and tumorigenesis. Its two members MSI1 and MSI2 contain two tandem RNA recognition motifs and are evolutionary well conserved.Additionally it could be shown that the expression of both MSI1 and MSI2 is dysregulated in a variety of cancers including acute and chronic myeloid leukemias.Since its expression correlates with prognosis, MSI2 has recently also been proposed as a novel prognostic marker for acute myeloid leukemia.However, neither the RNA binding properties nor the mRNA binding partners of these two proteins have been extensively studied to date. By using PAR-CLIP and other next-generation sequencing-based techniques, this proposal therefore aims at describing the regulated mRNA targets as well as the RNA recognition elements (those sequences which are specifically recognized by each protein) of both MSI1 and MSI2. Next, the leukemogenic potential of the identified targets will be tested to better understand the consequences of MSI1/2 dysregulation in hematologic malignancies.

• DFG Programme: Research Grants