The role of adverse social-biological interactions in acute myeloid leukemia disparities - acute myeloid leukemia (AML) is a hematologic cancer with a generally poor prognosis, and mutations in TP53…

The role of adverse social-biological interactions in acute myeloid leukemia disparities - acute myeloid leukemia (AML) is a hematologic cancer with a generally poor prognosis, and mutations in TP53 define one of the most adverse risk molecular subsets. National and CO-operative group datasets suggest that sociodemographic characteristics (social deprivation index, education, poverty, insurance) influence survival in AML. We established the multi-institution chicago AML registry that has collected demographic and clinical data on 822 AML patients. In our published analysis, composite census tract-based socioeconomic measures of disadvantage and affluence were found to be potent mediators of observed AML survival differences. These tract-based measures may be markers for specific aspects of patients' social and physical environments (SPE) that contribute etiologically to poor AML outcomes. Our preliminary data confirms an increased prevalence of adverse genomic characteristics in AML patients living in adverse SPE, specifically TP53 mutations and complex cytogenetic abnormalities. In aim 1 we will develop a neighborhood stress scale, incorporating area deprivation index and gun violence data, and link this to adverse genomic characteristics of AML as well as more distal outcomes including treatment response and relapse-free and overall survival. We also develop a prospective study of preleukemic patients bearing small clones of TP53 mutated hematopoietic stem cells and examine the effects of self-reported social stress on inflammation and clonal evolution. We next address mechanisms by which factors within the SPE drive TP53 mutant clonal expansion. Our preliminary data confirm that an increased burden of social stressors results in activation of the innate immune system. Leveraging models of social stress in transgenic murine models of mutant TP53 clonal hematopoiesis, as well as serial patient samples we will study dynamic interactions between social environment, ancestry, and clonal trajectories in AML. Importantly, our analyses will consider both self-identified race/ethnicity (sire) and genetic ancestry based on ancestry informative markers (aims) to appreciate the overlapping, but independent effects of social constructs and genetic ancestry that may influence inflammation and immune response. Our preliminary studies suggest that the NLRP1 inflammasome/IL-1Β axis may represent a mechanistic link between social stressors and TP53 mutant clonal evolution and we will develop xenografts from AML patients from a range of social backgrounds to determine the therapeutic impact of targeting the NLRP1 inflammasome/IL-1Β axis. The goal of this project is to triangulate registry data, patient samples and animal models to establish social stress as a biologic determinant of clonal trajectories in AML development.