The University of Alabama at Birmingham
Project Term: July 1, 2022 - June 30, 2025
The proposed studies will identify alterations in hematopoietic regulation that predict for risk for therapy-related myeloid neoplasm (TMN) and improve understanding of disease evolution to guide strategies to prevent TMN in patients receiving autologous hematopoietic cell transplantation (aHCT) for lymphoma. They will investigate alterations in hematopoietic function in peripheral blood stem cell used for aHCT, and serial evolution of hematopoietic defects leading to development of TMN.
Therapy-related myeloid neoplasm (TMN) is a devastating complication of cancer treatment. Patients receiving autologous hematopoietic cell transplantation (aHCT) for Hodgkin lymphoma (HL) and non-Hodgkin lymphoma NHL) have a high risk for developing TMN. There is a pressing need to develop methods to identify patients at high risk for developing TMN so that alternative treatment options for their lymphoma can be considered, and for improved understanding of mechanisms underlying development of TMN to inform the design of new strategies to prevent this complication from happening. To address this need, we have followed a large cohort of HL/NHL patients undergoing aHCT for development of TMN, and banked blood and marrow samples at different time points. Our previous studies show that abnormalities in blood stem cell function and gene regulation are seen in peripheral blood stem cell (PBSC) obtained pre-aHCT, long before onset of TMN. Clonal hematopoiesis of indeterminate potential (CHIP) is a condition characterized by expansion of blood cells bearing acquired mutations. CHIP is known to predispose to myeloid neoplasms and atherosclerotic disease, and its prevalence is increased in cancer patients treated with chemotherapy, radiation and aHCT. Presence of CHIP in the PBSC product used for transplant was associated with increased rate of TMN and inferior overall survival. However, several unanswered questions remain regarding the relationship between CHIP and TMN, since all patients with CHIP do not subsequently develop TMN, and some patients without detectable CHIP in PBSC go on to develop TMN. These observations suggest that CHIP may be a marker of hematopoietic system damage in patients predisposed to develop TMN. The goals of the proposed studies are to identify markers of alterations in hematopoietic development and regulation in PBSC that may be used to better identify patients at high risk for development of TMN post-aHCT, and to study serial alterations in hematopoietic development and regulation post-aHCT in patients who develop TMN. These studies will use recently developed powerful single cell technologies that allow high throughput analysis of alterations in different blood cell type distribution and function. The results of these studies will be applied to develop better predictors of risk for developing TMN and to identify mechanisms of TMN evolution that may potentially be targeted to prevent this complication from developing.