Description:
Post-transcriptional control of gene expression is emerging as a new frontier in the regulating stemness, differentiation and malignant transformation. Mutations in spliceosomal genes are a common cause of acute myeloid leukemia. In addition, RNA processing, splicing, and feedback loops to transcriptional regulation represent opportunities for drug development, therapeutic targeting, as well as immunotherapy. This session will present cutting-edge developments in how the regulation of splicing, RNA stability, and RNA processing impact fundamental processes in hematopoiesis. In addition, it will address how dysregulation of these processes induces or contribute to leukemia, and how it can be modulated for therapeutic purposes. 

Dr. Christopher Burge will focus on mechanism of RNA-processing and their impact on gene expression, including feedback loops to promoter regulation. Almost all human genes undergo alternative processing of their primary transcripts, including alternative splicing and/or alternative cleavage and polyadenylation, with RNA-binding proteins playing key regulatory roles. Pre-mRNA processing can impact the expression levels of genes in a variety of ways, including by producing alternative mRNA isoforms that differ in their stability, nuclear export, or translation. He will discuss recent work showing that splicing of internal exons near the 5' ends of genes can activate transcription from proximal upstream promoters, and exploring the mechanisms underlying this and other connections between RNA processing and gene expression. This work has implications for understanding programs of gene regulation in T cells and other immune cell types, and also opens up new approaches for therapeutic manipulation of gene expression.

Dr. Omar Abdel Wahab will focus on mutations in slicing factors and their contribution to hematologic malignancies. He will describe the role of genomic as well as transcriptomic and proteomic studies in defining critical events altered by mutant splicing factors in myeloid and lymphoid leukemias. Mutations in the spliceosomal genes SRSF2, U2AF1, SF3B1, and ZRSR2 are commonly found in patients with leukemia and are among the most common class of genetic alterations in clonal hematopoiesis, myelodysplastic neoplasms, and chronic lymphocytic leukemia. These mutations that occur at highly restricted amino acid residues, are always heterozygous, and rarely co-occur with one another. These data suggest that splicing mutations confer an alteration of splicing function and/or that cells may only tolerate a certain degree of splicing modulation.

Dr. Kristin Hope will focus on the role of RNA processing in determining cell states. This has broad implications for hematopoietic development, differentiation, and malignant transformation. RNA based mechanisms are contributing to proper enforcement of the stemness state in hematopoiesis. Dysregulation of these processes can underpin the pathogenesis of hematopoietic malignancies and acute myeloid leukemia in particular. RNA binding protein (RBP)-directed control of the post-transcriptional landscape is beginning to be appreciated for its importance in control of cell states. Dr. Hope will describe new strategies to both define key RBP regulators of normal vs leukemic stem cells (LSC) as well as unbiased approaches such as integrative RBP-interactome mapping, transcriptomics and proteomics, to identify their RNA substrates and the nature of their effects on RNA metabolism. She will also discuss the potential for carrying out rational manipulations of these circuitries to advance hematopoietic stem cell regeneration or target LSCs.