The Kharas lab is working to identify critical pathways in both normal and leukemic hematopoietic stem cells (HSC).
Hematopoietic stem cells can undergo symmetric or asymmetric cell division. The Numb staining in the daughter cell marks cell fate for commitment and differentiation. The Musashi family regulates Numb translation, affecting asymmetric cell division.
More specifically, 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.
While in Gary Gilliland's and George Daley's laboratories, Dr. Kharas studied activated signaling pathways in myeloid leukemias. By profiling gene expression in HSCs, he identified an RNA-binding protein called Musashi-2 that is required for normal hematopoietic stem cells and is ovexpressed 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.
We know that 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.
The Kharas laboratory's focus will be to identify novel factors and RNA regulators that alter self-renewal, cell-fate decisions, and differentiation of HSCs and leukemia. We are also interested in how this program becomes altered in hematological malignancies.
Research projects include:
- Characterizing the role of Musashi-2 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