Life-long blood regeneration is critically dependent on self-renewing multipotent hematopoietic stem cells (HSCs). These cells’ nearly unlimited self-renewal potential and lifetime persistence in the body, in contrast to the committed progenitors (CPs), signifies the need for tight control of HSC genome integrity. Indeed, accumulation of unrepaired DNA damage in HSCs is associated with bone marrow (BM) failure and accelerated leukemogenesis. Recent findings from our and other laboratories have revealed striking differences in DNA-damage response (DDR) characteristics between HSCs and CPs, especially in their DNA-repair activities and propensity for apoptosis. However, the molecular basis and physiological significance of the HSC-specific DDR characteristics are only partially understood.
In our experiments we utilize novel cell-purification strategies, powerful loss- and gain-of-function genetic manipulations and the most sensitive in-vivo xenotransplantation assays for human hematopoiesis.
In our laboratory we pursue the following projects to address the molecular basis underlying HSC-specific responses to DNA damage:
1. DDR characterization in human HSCs isolated at different ontogenic stages.
2. Examination of DNA double strand break repair pathways in human HSCs.
3. Identification and characterization of molecular mechanisms connecting the DDR with self-renewal pathway in human HSCs.
4. Construction of gene regulatory networks responsible for the acquisition of a DNA-damage-tolerant state in human leukemia stem cells.
2. Detection and targeting of leukemia stem cells in human blood cancers
All stem cells can multiply, proliferate and differentiate. Because of these qualities, leukemic stem cells are the most malignant of all leukemic cells. The major reason for the dismal survival rate in blood cancers is the inherent resistance of these leukemic stem cells to cancer treatment. Understanding how leukemic stem cells are regulated has become an important area of cancer research. A lack of tools to specifically isolate leukemic stem cells has precluded the comprehensive study and specific targeting of these stem cells until now. Our team has devised a novel biosensor that can isolate and target leukemic stem cells (Yassin et al., Leukemia 2019, Aqaqe et al., Cancer research 2019).
By labeling leukemia cells on the basis of their stem character alone, our sensor manages to overcome surface marker-based issues. In this research project we isolate leukemia stem cells from human leukemia sick mice and characterize their unique vulnerabilities by profiling specific regions in their genome known as super-enhancers. Usually, such super-enhancers control expression of the most cell-valuable proteins, thus providing a unique address to identify the Achilles heel of human leukemia stem cells. Then we will pursue experimental targeting of these vulnerability genes to prove that leukemia stem cells cannot survive without them while the normal stem cells will be spared.
We believe that our biosensor can provide a prototype for precision oncology efforts to target patient-specific leukemic stem cells to fight this deadly disease.
Flowchart of experiments to identify and validate LSCs vulnerability genes using stemness-reporter and epigenome-related profiling approaches
For more details on this research direction check out our publications: