Modulating Signaling Pathways in Endothelial Cells to Abate Leukemic Progression
Jason Butler
PhDHackensack Meridian Health
Project Term: July 1, 2018 - June 30, 2023
We seek to elucidate the mechanisms by which aging of the vascular system contributes to the decline in blood stem cell function and leads to diseases such as hematopoietic malignancies. We have developed novel model systems that have led to the discovery of rejuvenation factors that can restore the functional capacity of an aging blood and vascular system. These studies lay the foundation for the development of therapeutic strategies to not only rejuvenate an aged blood system, but to also give a competitive advantage to non-malignant blood cells while directly targeting cancer cells following chemotherapy regimens commonly utilized to treat hematological malignancies.
The aging process leads to an increased susceptibility of acquiring a variety of life-threatening diseases. The growth of the elderly population around the globe has resulted in an increase in age-related blood disorders, for which there are really no effective treatments. Most reports describing age-related blood alterations have focused exclusively on changes within blood stem cells. However, an increasing body of evidence has demonstrated that the blood vessels surrounding blood stem cells in the bone marrow can nurture and instruct their ability to function properly. Understanding the intimate relationship between blood vessels and blood stem cells during aging may provide a novel opportunity to slow down and potentially reverse the age-related functional decline observed in the blood system. The goal of my research is to determine how aging of the blood vessels leads to the disruption of healthy blood stem cell function and if these age-related deficiencies of the blood vessels can enhance the progression of blood cancers such as acute myeloid leukemia (AML). Our group has shown that blood vessels are absolutely essential for supporting blood stem cell function. We have recently demonstrated that aged blood vessels can train young blood stem cells to function as aged stem cells, whereas young blood vessels can rejuvenate and increase the functionality of aged blood stem cells. Cells within the blood vessels interact with the AML cells, particularly through the secretion of soluble factors that influence the leukemia cells. We have also shown that AML cells can hijack the ability of blood vessels to support healthy blood stem cells and induce their own expansion leading to aggressive disease. We have devised novel experimental models of blood vessel cells grown in the laboratory that will allow us to determine if we can manipulate blood vessels to safeguard healthy blood stem cells while also increasing the susceptibility of AML cells to anti-cancer regimens. We will utilize our model systems to test if aged blood vessels support aggressive leukemic cells and if altering the instructive capacity of these blood vessels can reverse age-related blood disorders and give a competitive advantage to healthy blood stem cells. The success of these studies may lead to the development of therapeutic strategies designed to augment the sensitivity of leukemic cells to chemotherapy thereby reducing AML-associated side effects. Furthermore, these studies will begin to unravel the mechanisms by which aged blood vessels can lose their natural capacity to support normal blood production and become accessories to the development of blood cancer.