Single-cell Profiling of Childhood Acute Lymphoblastic Leukemia
Lay Summary: This project will perform single-cell analysis of tumor cells and tumor microenvironment cells in 30 cases of acute lymphoblastic leukemia (ALL). The goal is to identify tumor intrinsic and microenvironmental determinants of tumor formation and progression.
Previous single-cell gene expression and mutational profiling studies of ALL have shown that both the tumor cells and bone marrow non-tumor cells are heterogeneous (variable) in the patterns of gene expression and tumor mutations. For example, tumor mutations can be mapped to subpopulations of cells within a single sample specific, and gene expression signatures in non-tumor cells are associated with disease relapse. In addition, single-cell profiling has shown that ALL tumor cells acquire characteristics associated with treatment resistance when cultured with bone marrow stroma. Single-cell profiling approaches can identify non-tumor T cells that show distinct patterns of activity, and potential reactivity against the tumor cells, highlighting a potential avenue for therapy. However, there are no systematic data using single-cell profiling in carefully selected cohorts of good-risk and high-risk ALL to dissect the relationship of tumor cells and the tumor microenvironment at single-cell resolution. This proposal will perform such a study in a cohort of ALL samples that have detailed characterization of the bulk tumor population, and available xenografts (tumor cells propagated in mice) to enable the data and samples to be useful as a resource for the general research community.
Lay Summary Project Goal: The goal of the proposal is to generate a comprehensive resource of single-cell tumor, tumor microenvironment and T-cell data in a cohort of childhood ALL samples representative of key ALL genetic subtypes and risk groups. The proposal will examine at least 30 cases of ALL spanning six standard and high-risk subtypes. The single-cell profiling will study the tumor microenvironment and T cell compartment at single-cell resolution. The proposal will incorporate sequencing of sequential samples obtained at diagnosis and relapse. All samples have existing whole genome and transcriptome sequencing data already in hand and publicly available. All samples have xenografts available. Data will be deposited to the ALSF-supported Childhood Cancer Data Lab (CCDL), at public genomic data repositories, and will be hosted on the St. Jude website linked to the primary patients' samples, xenografts, and genomic data. Together, this study will provide a valuable resource for the leukemia research community, and will provide important insights into the tumor intrinsic and extrinsic factors that drive tumor formation and response.
