Abstract
3D genome alternations can dysregulate gene expression by rewiring enhancer-promoter interactions and lead to diseases. We report integrated analyses of 3D genome alterations and differential gene expressions in 18 newly diagnosed T-lineage acute lymphoblastic leukemia (T-ALL) patients and 4 healthy controls. 3D genome organizations at the levels of compartment, topologically associated domains and loop could hierarchically classify different subtypes of T-ALL according to T cell differentiation trajectory, similar to gene expressions-based classification. Thirty-four previously unrecognized translocations and 44 translocation-mediated neo-loops are mapped by Hi-C analysis. We find that neo-loops formed in the non-coding region of the genome could potentially regulate ectopic expressions of TLX3, TAL2 and HOXA transcription factors via enhancer hijacking. Importantly, both translocation-mediated neo-loops and NUP98-related fusions are associated with HOXA13 ectopic expressions. Patients with HOXA11-A13 expressions, but not other genes in the HOXA cluster, have immature immunophenotype and poor outcomes. Here, we highlight the potentially important roles of 3D genome alterations in the etiology and prognosis of T-ALL.
Highlights
Cell precursor acute lymphoblastic leukemia (ALL) (ETP ALL) is a high-risk subtype, which is characterized by an immature immunophenotype and a gene expression profile similar to early T-cell precursors[3,4]
Principal component analysis (PCA) at the levels of the compartment, topologically associated domains (TADs), and loop structures demonstrated that the T-lineage acute lymphoblastic leukemia (T-ALL) samples could be separated from the control samples by PC1, while ETP and non-ETP ALL could be separated by PC2 at all three architectural levels (Fig. 1a, upper panels) and be further delineated by hierarchical clustering analysis (Fig. 1a, lower panels)
By detailed comparisons of the 3D chromosomal organizations of the T-ALL samples and the healthy controls, we identified compartment switches corresponding to 3% of genome, ~700 differential TAD boundaries and more than 6000 differential looping events (Supplementary Fig. 1a)
Summary
Cell precursor ALL (ETP ALL) is a high-risk subtype, which is characterized by an immature immunophenotype and a gene expression profile similar to early T-cell precursors[3,4]. Whether the noncoding region of the genome and 3D-genomic structure play important roles in T-ALL development are largely unknown. The genomes are hierarchically organized by multi-scaled structural units, including compartments, topologically associated domains (TADs), and loops, which can be identified by Hi-C9. Loops frequently bridge promoter and enhancer interaction[9] and are further organized into individual TADs13. Each of these layers of organization have pronounced effects on gene expression[9,10,16,17]. Kloetgen et al discovered that recurrent TAD boundary changes in the MYC locus are associated with MYC dysregulation while NOTCH pathway activation can regulate 3D genome organization in T-ALL18
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