T Cell Acute Lymphoblastic Leukemia as a Consequence of Thymus Autonomy

Abstract

Thymus autonomy is the capacity of the thymus to maintain T lymphocyte development and export independently of bone marrow contribution. Prolonging thymus autonomy was shown to be permissive to the development of T cell acute lymphoblastic leukemia (T-ALL), similar to the human disease. In this study, performing thymus transplantation experiments in mice, we report that thymus autonomy can occur in several experimental conditions, and all are permissive to TALL. We show that wild type thymi maintain their function of T lymphocyte production upon transplantation into recipients with several genotypes (and corresponding phenotypic differences), i.e., Rag2 2/2 g c 2/2 , g c 2/2 , Rag2 2/2 IL-7ra 2/2 , and IL-7ra 2/2. We found that the cellularity of the thymus grafts is influenced exclusively by the genotype of the host, i.e., IL-7ra 2/2 versus g c 2/2. Nonetheless, the difference in cellularity detected in thymus autonomy bore no impact on onset, incidence, immunophenotype, or pathologic condition of TALL. In all tested conditions, TALL reached an incidence of 80%, demonstrating that thymus autonomy bears a high risk of leukemia. We also analyzed the microbiota composition of the recipients and their genetic background, but none of the differences found influenced the development of TALL. Taken together, our data support that IL-7 drives cellular turnover non-cell autonomously, which is required for prevention of TALL. We found no influence for TALL in the specific combination of the genotypic mutations tested (including the developmental block caused by Rag deficiency), in microbiota composition, or minor differences in the genetic background of the strains.

Specific Eco-evolutionary Contexts in the Mouse Gut Reveal Escherichia coli Metabolic Versatility

“…(https://qiime2.org) with default parameters. DADA2 was used for quality filtering, denoising, paired-end merging, and amplicon sequence variant (ASV, i.e., sub-Operational Taxonomic Units) calling using QIIME dada2 denoise-paired method [85,86]. ASVs represented by less than 10 reads were removed from corresponding samples.…”

Self-renewal of double negative 3 (DN3) early thymocytes allows for thymus autonomy but compromises the β-selection checkpoint

“…Thymus autonomy, sustained by DN3e that self-renew and differentiate, is deleterious if prolonged in time as leukemia emerges as a final consequence 8,10 . This highlights the importance of cell competition in the thymus to clear DN3e.…”

“…These are likely the cells giving rise to leukemia. The fact that T-ALL has an onset starting at 15-week post-transplantation 8,10 suggests that leukemogenesis is a long process, and probably involves a series of events. Future studies will be important to detail the mechanisms that are on the genesis of T-ALL following thymus autonomy.…”

“…8c, d), confirming that such cells indeed emerge in these conditions. This suggests that in parallel with the normal differentiation, there is an additional program that operates in distinct, individual cells potentially creating the conditions for the malignant transformation that later causes leukemia 8,10 . Altogether, we could identify an aberrant gene expression program running in parallel with normal thymopoiesis that was characterized by thymocytes escaping the β-selection checkpoint and expressing an unusual pattern of Notch target genes, potentially the earliest cells on the path to T-ALL.…”

“…We further showed that in the steady state thymus autonomy is inhibited by cell competition 8 occurring at early stages of T lymphocyte differentiation 9 . When cell competition was impaired, thymus autonomy was triggered and later resulted in T cell acute lymphoblastic leukemia (T-ALL) with an incidence of up to 80% and onset at 15 weeks post-transplantation 8,10 . T-ALL emerging in this experimental setting closely resembled the human pediatric disease in immunophenotype, genetic and genomic alterations, transcriptome and pathological condition 8 .…”