Role of Novel Myeloma Subpopulations in Disease Progression and Drug Resistance
Abstract
Background: Multiple myeloma (MM) is an incurable and devastating blood-related cancer in which plasma cells, a type of white blood cell, become malignant. Normally, plasma cells produce specific antibodies (also called immunoglobulins) that fight infections; however, in MM, plasma cells that produce a unique antibody grow uncontrollably and accumulate in the bone marrow. The main symptoms and complications of MM include bone pain, bone fractures, anemia, reduced kidney function, and susceptibility to infections due to an impaired immune system. Although the cause of MM is unknown, several potential environmental risk factors for MM are relevant to military Veterans, including exposure to irradiation, pesticides (e.g., Agent Orange), benzene, petroleum, and mineral oil products. Additional risk factors include genetic background and obesity. Currently, over 32,000 people in the US are diagnosed with MM each year. Despite novel therapies, most patients relapse, require long-term care, and eventually die due to disease complications. Scientific Objectives and Rationale: A study that used samples collected from active-duty Service Members (accessed through the US Department of Defense Serum Repository) revealed that all MM cases develop from a premalignant stage called MGUS (monoclonal gammopathy of undetermined significance). From MGUS, the disease progresses through multiple steps to smoldering MM, to active MM, and to an end-stage disease in which tumor cells spread outside the bone marrow and rapidly grow in other organs. In the general population, MGUS occurs in approximately 3% of individuals who are at least 50 years old, and the incidence increases with age. The prevalence of MGUS and MM is higher in men than women and in African Americans than in whites/Caucasians. Approximately 1% of MGUS and 10% of smoldering MM cases progress to active MM every year. Thus, understanding the mechanisms by which the disease progresses will help develop novel therapies that can be used at early stages of the disease and may cure MM. The overall objective of the proposed project is to exploit an innovative experimental model to study the roles of novel subpopulations of MM tumor cells in an effort to cure MM and prevent its progression to high-risk disease. Hypothesis: MM cells from a given patient vary widely in terms of their expression of genes related to cell growth and survival and in terms of the factors present on the cell surfaces. As with other cancers, the diverse characteristics of MM cells led to the idea that a small subpopulation of cancer stem cells is responsible for the disease. However, recent studies indicate that MM cells are capable of changing their characteristics in response to stress or other stimuli. By analyzing our extensive databases with information from thousands of patients samples, we identified novel cell-surface factors (LY6E and C1QBP) that each define a subpopulation of MM cells within a patient s total tumor sample. Our preliminary results demonstrated our ability to detect these small subpopulations in patients samples. These cell-surface factors are regulated by proteins that regulate many cancers, suggesting that these subpopulations of MM cells are important to the progression of the whole MM tumor bulk. We hypothesize that small subpopulations of MM cells contribute to disease progression of the whole tumor bulk and that therapies targeting the most significant contributors will help control MM at early stages and may sensitize tumor cells to current treatments at progressive stages of the disease. Experimental Settings: The exploitation of our novel in vitro model and our in vivo mouse model allows us to grow and study MM cells from patients with benign or active MM and to use MM cell lines that grow restrictively in bone, as seen clinically. With state-of-the-art techniques, we will determine whether LY6E+ and C1QBP+ MM cell subpopulations exist at different stages of the disease,
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110601
Entities
People
- Shmuel Yaccoby
Organizations
- United States Army
- University of Arkansas for Medical Sciences