Immune Evasion as a Mechanism of Clonal Escape in Aplastic Anemia
Abstract
Aplastic anemia (AA) is a serious disorder of the bone marrow which can lead to many complications and ultimately, death. This disease affects both young and old patients when immune cells, normally responsible for our body’s defense from infections and cancers, turn against its own bone marrow stem cells, the mother cells responsible for blood production. This abnormal reaction of one’s immune system is called autoimmunity (or autoimmune attack) and plays a role in many diseases in which other organs are affected, for example joints in arthritis. The most effective treatments for aplastic anemia involve inhibition of the immune system (called immunosuppression) or patients may also receive a bone marrow transplant. There is a great need to improve treatments for aplastic anemia, but this can only happen when we better understand how this disease evolves. While immunosuppression is effective to some degree in a majority of patients, some patients with aplastic anemia may not improve, or experience another deadly complication of this disease; they progress to a type of leukemia called myelodysplastic syndrome. The causes for aplastic anemia and its progression to myelodysplastic syndrome remain unclear. However, we know that distinct changes to proteins regulating the strength of immune attack can occur in aplastic anemia stem cells and allow for recovery of bone marrow despite a persistent autoimmune reaction. These changes may also help abnormal leukemia stem cells to “escape” the immune attack in aplastic anemia and develop to a deadly leukemia. In this proposal we will investigate the genetic changes occurring in bone marrow stem cells in aplastic anemia to better understand how this disease evolves, and to predict whether immunosuppression as a treatment will be successful. Furthermore, we will also study the changes in immunoregulatory proteins, called HLA, on leukemic stem cells to understand how leukemia (including the type of leukemia, which may occur in aplastic anemia patients) evades immune defenses against cancer. The findings of the proposed research may help to understand disease mechanisms and thus develop better drugs or more effective use of the currently available drugs. Most importantly, because the immune system has the ability to prevent cancer, our study of leukemia developing after aplastic anemia will help to understand the way leukemia and cancer evades our immunity, or conversely, how we can enhance our immunity to prevent or treat leukemia. In summary, the proposed investigations will have direct impact on how we treat not only aplastic anemia but also other cancers, including leukemia.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110149
Entities
People
- Jaroslaw P. Maciejewski
Organizations
- Cleveland Clinic
- United States Army