Michael G. Kharas: Overview
The world of RNA regulators in stem cell biology and their potential as therapeutic targets in cancer and regenerative medicine are virtually unexplored. The Kharas lab aims to uncover novel RNA regulators in stem cell biology and development in hopes of improving our understanding of cancer pathogenesis and treatment.
We know that hematopoietic stem cells (HSCs) must negotiate a delicate balance between symmetric division and asymmetric division in order to maintain self-renewal of the HSC compartment and continued development of terminally differentiated hematopoietic effector cells. However, the programs that modulate the switch from symmetric division to asymmetric division are not well understood. Lending particular urgency to the study of this cell-fate switch is recent work suggesting that these same cellular programs are critical to the fundamental process of stem cell disorders. Mechanistic insights into the regulation of cell-fate decisions may inform approaches to bone marrow failure syndromes, differentiation therapy of hematopoietic malignancies, and stem cell expansion for therapeutic benefits. By profiling gene expression in HSCs, we identified an RNA-binding protein called Musashi-2 that is required for normal hematopoietic stem cells and is overexpressed in patients with a worse clinical outcome in acute myeloid leukemia. The musashi gene was first identified in Drosophila in the sensory organ precursor cells regulating the cell-fate decision and modulating asymmetric cell division. Our projects have focused on understanding the MUSASHI RNA binding protein network in both normal and malignant hematopoietic biology.
Disruption of genetic and epigenetic mechanisms and altered signaling networks can promote cancer initiation and progression. While somatic alterations in these pathways leading to tumorigenesis are commonly studied, it remains to be established how processes that affect post-transcriptional and translational regulation of mRNA/protein expression impact cancer development. The wide discrepancy between transcriptional expression and the proteome highlights the importance of this regulation. RBPs are involved in post-transcriptional and co-translational regulation of RNA metabolism. There are over 1,500 distinct RBPs and tens of thousands of different coding and non-coding RNAs that are present in every cell. However, only a small number of these RBPs have been evaluated for their functional relevance. Altogether the RNA-protein and protein-protein interactions comprise the regulatory network of post-transcriptional regulation and mediate cell fate decisions in normal HSCs. Thus, we aim to define the oncogenic riboproteome and reveal the functionally relevant components to aid the discovery of novel therapeutic targets.
We have developed a platform to identify novel factors and RNA regulators that alter self-renewal, cell-fate decisions, and differentiation of HSCs and leukemia. We have established screening strategies to identify small molecules that block and inhibit RNA binding proteins.
Research projects include:
- Characterizing the role of MUSASHI family in normal and leukemic hematopoietic stem cells
- Identifying RNA regulators that have the potential to expand normal hematopoietic stem cells and convert embryonic stem cells to blood
- Developing screening approaches for self-renewal in both normal hematopoietic stem cells and leukemia stem cells in the context of myelodysplastic syndromes and acute myeloid leukemia
- Developing small molecules against RNA binding proteins
- Studying how RNA methylation controls cell fate
- Studying cellular pathways that are altered in induced pluripotent derived AML patient samples