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Role of Protocadherin-9 in Enabling Leukemia Cell Colonization of the CNS

National Jewish Health
Jordan Jacobelli, PhD
Grant Type: 
Innovation Grants
Year Awarded: 
Type of Childhood Cancer: 
Acute Lymphoblastic Leukemia (ALL), Spinal Cord Tumors
Project Description: 

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Current therapies lead to high remission rates, but many patients relapse, often with the involvement of the brain and spinal cord – the Central Nervous System (CNS). Specific CNS-directed treatments limit these CNS relapses but do not eliminate them. Additionally, these CNS-directed treatments have severe short- and long-term side effects, particularly in children. 

Project Goal
Our goal is to prevent relapses by inhibiting the ability of leukemia cells to colonize the CNS. Instead of using toxic treatments to kill the leukemia cells in the CNS (such as radiation or chemotherapy delivered directly to the brain and spinal cord), our work aims to stop leukemia colonization of the CNS by inhibiting proteins that enable leukemia cells to enter the brain and spinal cord and grow there. We have identified a candidate protein that is selectively present on the surface of leukemia cells that invade the CNS. We will determine if inhibiting this protein can prevent or reverse CNS colonization by leukemia cells and stop CNS relapses, thereby improving long-term survival. Inhibiting CNS colonization by leukemia cells would be a valuable tool to reduce leukemia relapse and could significantly improve patients’ quality of life by reducing or eliminating the need for CNS-directed therapies that have serious side-effects in pediatric patients. 

Project Update - June 2020
During the first year of the project, we have confirmed that interfering with Protocadherin-9 expression in acute lymphoblastic leukemia cells reduces their ability to cause central nervous system pathology. We have also validated our results in a human acute lymphoblastic leukemia xenograft model (by transferring human leukemia cells into mice). Furthermore, we have found that in acute lymphoblastic leukemia patients higher Protocadherin-9 expression can correlate with an increased incidence of central nervous system relapse. Ongoing work is now aimed at determining if inhibiting Protocadherin-9 can prevent or reverse colonization of the central nervous system by leukemia cells and avoid relapses.