Objective
The overall goal of this proposal is to determine the genetic and epidemiological relationships between type 1 diabetes (T1D), childhood acute lymphoblastic leukemia (cALL), and hematopoietic traits; determine the molecular impact of genetic predisposition to T1D and cALL on hematopoietic function and to harness cALL-related hematopoietic function to treat T1D.
Background Rationale
Many epidemiological and genetic factors are shared between type 1 diabetes (T1D) and childhood acute lymphoblastic leukemia (cALL). At the genetic level, the two diseases show opposing genetic correlations and causal associations with leukocyte counts, in particular, lymphocytes. At the population, level, the two diseases also exhibit opposing racial/ethnic disparities; in the United States, Hispanics have lower T1D risk but higher cALL risk than non-Hispanic Whites (NHWs). On the other hand, NHWs have higher prevalence of T1D but lower cALL risk than Hispanics. These differences are imparted due to disproportionate prevalence of inherited mutations. Meanwhile, at the environment level, significant spatial clustering and comorbidity between T1D and cALL risk exist that cannot be explained by chance and common infectious origins have been implicated. Based on these intriguing convergent and divergent observations, this study will investigate the genetic and the epidemiological associations between T1D, cALL, and hematopoietic traits and whether genetic factors related to cALL account for racial/ethnic disparities in T1D prevalence; jointly study the impact of genetic predisposition to T1D and cALL on hematopoietic function; and harness cALL-related hematopoietic function to treat T1D.
Description of Project
Type 1 diabetes (T1D) is one of the most common autoimmune diseases in childhood. Interestingly, several genetic and epidemiological factors of T1D are shared with childhood acute lymphoblastic leukemia (cALL), the most common cancer in childhood. In both diseases, lymphocytes form a central stage, whereby lymphocyte-mediated destruction of insulin-producing beta cells leads to T1D, while uncontrolled proliferation of lymphoblasts characterizes cALL. Many genes, such as GATA3, IKZF1, IKZF3, that are associated with cALL risk are involved in hematopoiesis, especially lymphopoiesis or the production of lymphocytes. Some of these genes are also associated with T1D and T1D risk variants are most active in regulatory DNA regions of lymphocytes and hematopoietic stem and progenitor cells (HSPCs). Our previous studies showed that whereas T1D has a negative global genetic correlation with lymphocyte count, cALL has a positive genome-wide genetic correlation with lymphocyte count. Additionally, T1D has a positive global genetic correlation with eosinophil count whereas cALL has a positive global genetic correlation with neutrophil count. We also showed that whereas genetically predicted increase in lymphocyte count reduces the risk of T1D, this increases the risk of ALL. At the population level, T1D and cALL also exhibit divergent racial/ethnic disparities in the United States. For instance, non-Hispanic Whites (NHWs) have higher prevalence of T1D and lower prevalence of cALL compared to Hispanics/Latinos. On the other hand, the reverse is true for cALL, whereby Hispanics have a higher prevalence of cALL and lower T1D prevalence than NHWs. These racial disparities are in part due to genetic factors. For instance, we recently found a common genetic variant in the IKZF1 gene that is prevalent among Hispanics but rare among NHWs, which contributes to the higher incidence of cALL among Hispanics than NHWs. Unlike the genetic level, studies have demonstrated spatial clustering and comorbidity between T1D and cALL than it would be by chance. Although common infectious origins for both diseases have been proposed as a possible reason for the spatial clustering and comorbidity, the molecular and cellular mechanisms are unknown. The genetic correlations and causal associations of T1D and cALL with leukocytes from multiple distinct blood cell lineages suggests that the genetic risk for these diseases affect hematopoietic stem and progenitor cells (HSPCs) to direct multi-lineage blood production, as well as mature hematopoietic cell function. We hypothesize that genetic predisposition to T1D and cALL affect hematopoietic differentiation and function divergently, which can be harnessed to treat T1D. We will first determine the genetic epidemiology of the associations between T1D, cALL, and hematopoietic traits and the contribution of IKZF1 genetic variation to T1D disparities. Next, we will perform paired multiome single-nucleus chromatin accessibility and single-nucleus gene expression in human HSPCs and peripheral blood mononuclear cells from patients with and without T1D. We will then integrate T1D and cALL genetic variants with chromatin accessibility and gene expression to identify the DNA elements, gene regulatory networks, and the hematopoietic differentiation trajectories and functions that are impacted by genetic susceptivity to these diseases. Lastly, we will use genetic and pharmacologic tools to simulate cALL-associated lymphopoiesis in the NOD mouse, a model of human T1D, to test whether cALL-associated enhancement of lymphopoiesis could be harnessed to prevent T1D. These studies could uncover new insights into molecular pathogenesis of T1D and cALL through hematopoietic differentiation and function and identify novel targets for diagnosis and therapeutic repurposing.
Anticipated Outcome
This study is expected to uncover new insights into how type 1 diabetes (T1D) and childhood acute lymphoblastic leukemia (cALL) divergently or similarly impact hematopoietic function, identify molecular markers for disease prediction and therapeutic repurposing, and a potential treatment strategy for T1D.
Relevance to T1D
This study could shed light on new disease mechanisms and therapeutic avenues for type 1 diabetes through joint analysis of a disease that shares divergent and convergent genetic and environmental features.