Targeting mitophagy of leukemia stem cells for therapy
Keisuke Ito
PhD, MDAlbert Einstein College of Medicine
Project Term: July 1, 2018 - June 30, 2023
Enhancing the commitment of leukemia stem cells (LSCs) is a promising therapeutic strategy against blood cancer, but tracking the division pattern of individual cells has proved difficult. We have established a novel technical regimen to assess the behavior of individual LSCs and their cell fate in vivo. Genetic mouse models and mouse models engrafted with leukemia patient samples are also used. Our project seeks to elucidate the role of mitophagy in the control of LSC division balance, which may facilitate new therapy targeting these cells.
Leukemia stem cells (LSCs) are thought to be responsible for leukemia initiation, maintenance and recurrence. Like healthy hematopoietic stem cells (HSC), LSCs have a fate choice when they divide. They can self-renew, producing new LSCs, or they can produce cells that will mature to become leukemia cells. Single LSCs have proven extremely difficult to track and observe. To fill this gap, we have established a novel technical regimen that includes the isolation of purified LSCs, a method of single-cell transplantation, and the extraction of individual daughter cells. These technical advances will allow us to study the behavior of individual LSCs in their native environment. We and others have shown the importance of mitochrondria in tumors. Mitochondria are the storehouses of energy for the cell, and their population in the cell is tightly regulated to achieve the proper balance. To control the population of mitochondria, a cell uses a regulatory pathway called mitophagy, which reduces the number of mitochondria. LSCs depend on active mitophagy for their self-renewal capacity. Our project seeks to elucidate the role of mitophagy in the control of LSC division balance, which may facilitate novel therapeutic strategies targeting these cells. We will identify the molecular mechanisms of mitochondrial quality control to understand its impact on LSC division balance. Our high-resolution imaging will assess the behavior of LSCs, which will lead to a better understanding of the molecular basis of LSC fate decisions. We will also develop new therapies aimed at eradicating leukemic cells by targeting mitophagy. Finally, genetic mouse models and mouse models engrafted with leukemia patient samples will be used to examine whether defective mitophagy inhibits LSC self-renewal. As the metabolic pathways affecting mitophagy are conserved in human hematopoiesis, we hypothesize that the quality control of mitochondria by mitophagy will prove a key target for enhancing LSC commitment in human leukemia patients. The proposed research should contribute to therapeutic strategies targeting mitochondrial autophagy, which will directly enhance and extend the health and well-being of patients with leukemia and may possibly contribute to new forms of curative therapy for a range of hematological malignancies.