ABSTRACT
T-cell malignancies comprise a heterogeneous group of cancers resulting from the clonal expansion of T-cells at different developmental stages [...].
ABSTRACT
Cell differentiation is accompanied by epigenetic changes leading to precise lineage definition and cell identity. Here we present a comprehensive resource of epigenomic data of human T cell precursors along with an integrative analysis of other hematopoietic populations. Although T cell commitment is accompanied by large scale epigenetic changes, we observed that the majority of distal regulatory elements are constitutively unmethylated throughout T cell differentiation, irrespective of their activation status. Among these, the TCRA gene enhancer (Eα) is in an open and unmethylated chromatin structure well before activation. Integrative analyses revealed that the HOXA5-9 transcription factors repress the Eα enhancer at early stages of T cell differentiation, while their decommission is required for TCRA locus activation and enforced αß T lineage differentiation. Remarkably, the HOXA-mediated repression of Eα is paralleled by the ectopic expression of homeodomain-related oncogenes in T cell acute lymphoblastic leukemia. These results highlight an analogous enhancer repression mechanism at play in normal and cancer conditions, but imposing distinct developmental constraints.
Subject(s)
Enhancer Elements, Genetic , Hematopoiesis/genetics , Receptors, Antigen, T-Cell/genetics , Thymus Gland/cytology , Animals , Apoptosis Regulatory Proteins/genetics , Cell Differentiation/genetics , Cell Nucleus/metabolism , Chromatin/metabolism , DNA Demethylation , DNA Methylation/genetics , Epigenome , Gene Expression Regulation , Gene Rearrangement, T-Lymphocyte , Histones/metabolism , Homeodomain Proteins/genetics , Humans , Lymphocyte Activation/immunology , Mice , Protein Binding , Protein Processing, Post-Translational , Stem Cells/cytology , T-Lymphocytes/cytology , Thymocytes/metabolismABSTRACT
Chimeric antigen receptor (CAR) T-cells targeting CD19 demonstrated remarkable efficacy for the treatment of B-cell malignancies. The development of CAR T-cells against T-cell malignancies appears more challenging due to the similarities between the therapeutic, normal and malignant T-cells. The obstacles include CAR T-cell fratricide, T-cell aplasia, and contamination of CAR T-cell products with malignant T-cells. Here, we review these challenges and propose solutions to overcome these limitations.