Barcoding Pediatric Leukemia for Therapeutic Purposes
Ross Levine, MD, Memorial Sloan Kettering Cancer Center
Scott A. Armstrong, MD/PhD, Dana-Farber/Boston Children's Cancer and Blood Disorders Center
Vijay G. Sankaran, MD/PhD, Boston Children's Hospital
Fernando Camargo, PhD, Boston Children's Hospital
Jay Shendure, MD/PhD, University of Washington
Serine Avagyan, MD/PhD, Dana-Farber Cancer Institute
Juerg Schwaller, MD, University Children's Hospital and Department of Biomedicine, University of Basel, Switzerland
Peter Campbell, MD/PhD, Wellcome Sanger Institute
We hypothesize that pediatric leukemias develop from blood stem cells that arise during fetal life. The normal fetal cells possess a unique characteristic which allows them to persist during fetal life and early adolescence. Over the past three years, new techniques using genetic fingerprinting of stem cells developed by our team allows investigators to study how normal blood development occurs. Using these fingerprinting approaches in zebrafish and mice, we have surprisingly found that fetal blood cells persist into adulthood. We believe that a subset of these fetal stem cells is the origin of pediatric leukemias. Our team plans to use the new genetic fingerprinting techniques to map which type of blood stem cells are the origin of different types of pediatric leukemia. We plan to compare these approaches in model systems ranging from animals to human blood cells. We will perform chemical and genetic disruptions in search of key genes and pathways that alter stem cell function and which can kill leukemia cells. We have implemented these methods in a new cell culture system which will allow us to simultaneously perform thousands of treatments in a petri dish, probing for new therapeutics. We will further examine the most effective therapies in preclinical animal models and human pediatric leukemia samples. If successful, our approach could be useful to map the origins of all pediatric cancers including solid tumors and to find therapeutics that alter the balance between normal and leukemic stem cells.
Our team has developed technologies to genetically fingerprint cells using a variety of techniques across multiple animal models. We believe these methods will uncover when and where pediatric leukemias develop and how their origins impact disease course. For the zebrafish, we use a method where every stem cell is a different color and in mice, we have a DNA based approach. The zebrafish approach was named the Breakthrough of the Year in Science Magazine in 2018. We also developed CRISPR based fingerprinting approaches that offer unprecedented resolution into the ancestry of leukemic cells. These approaches have never been applied to cancer. Over the first two years of the grant, we will explore these cellular fingerprinting techniques in normal blood development to understand how normal fetal stem cells contribute to blood production in adulthood. We will then study how genes mutated in leukemia change this process. We plan to use new informatic technologies to determine how mutations change when genes are activated and molecular events controlling their dysregulation. We hypothesize that these changes will identify which pathways are altered in developing blood cells after a mutated leukemic gene is activated. We will examine how to interrupt the pathways with genes or chemicals, and test drugs in animal models and human pediatric leukemia samples in search of therapies which disrupt leukemic stem cells and not normal blood stem cells. Our studies will identify when and where pediatric leukemias arise in development and will find new mechanism-based therapies to treat patients.