Cellular Crosstalk In The Normal And Malignant Bone Marrow
Cincinnati Children's Hospital Medical Center
Project Term: October 1, 2021 - September 30, 2026
We want to understand how leukemia inhibits blood production as this is one of the main causes of death in leukemia patients. We use new microscopy techniques developed by our group to image—for the first time—all types of blood cells and how they are eradicated by leukemia cells. Identification of the mechanisms through which leukemia inhibits blood production will be the foundation for new studies to develop drugs to maintain normal blood levels and prevent death in leukemia patients.
In the marrow of the bone, specialized blood progenitor cells divide to generate all the cells in the blood. Different types of progenitors are responsible for giving rise to different types of blood cells. For example, erythroid progenitors generate red blood cells, neutrophil progenitors give rise to neutrophils, and monocyte progenitors produce monocytes and macrophages. Leukemia kills by destroying these and other progenitors and preventing their function. How this occurs is not known. Researchers have proposed that leukemia stem cells inhibit blood production by homing to and displacing the normal progenitors, producing toxic molecules, passive displacement due to limited space in the marrow cavity, or by destroying other cells (collectively known as the microenvironment) that support and nurture the normal blood progenitors. It has not been possible to test these hypotheses due to the lack of methods to image the different cells in the bone marrow using a microscope. Dual objectives of my research program are to find how normal blood progenitors function to produce blood in the steady-state and after stress and understand how leukemia cells destroy these progenitors. My laboratory specializes in using state of the art microscopy of the bone marrow to understand how blood cell production is regulated. We recently developed methods to image—for the first time—the different types of blood progenitors and how they generate all types of blood cells in the marrow. We have also developed methods to image the leukemia stem cells using mouse models of acute myeloid leukemia. We will combine these tools to image and examine the relationships between growth of the leukemia and loss of normal blood progenitors in the bone marrow. These experiments will tell us which of the proposed mechanisms above is responsible for inhibiting blood production. Once we find this, the next step will be to start new projects aimed at identifying and validating targets that can be therapeutically exploited to protect the normal progenitors from the leukemia. Hopefully, this will lead to increased quality of life and improved survival of cancer patients. A second benefit of our research is that we will generate a map of how the leukemia grows in the bone marrow and how it inhibits blood production. This will be very helpful to all leukemia researchers when designing experiments or testing new hypotheses.