Limited bone marrow chimerism impairs cell competition in the thymus and causes leukemia

Abstract

Cell competition in the thymus is a critical tumor suppressor process that prevents leukemia. We show that suboptimal bone marrow correction of {gamma}c-deficient mice disrupts this process, inducing thymus autonomy and promoting T cell acute lymphoblastic leukemia (T-ALL). {gamma}c-deficiency causes severe combined immunodeficiency in mice and humans and is treated by hematopoietic stem and progenitor cell (HSPC) transplantation. However, inefficient correction led to intermittent thymic activity, consistent with sporadic thymus seeding. This was accompanied by altered thymocyte composition and the emergence of an aberrant TCR{beta}{square}CD4{square}CD8{square} population that preceded overt leukemia. Leukemia incidence and latency were exacerbated when HSPCs were pre-cultured under conditions mimicking gene-editing protocols, whereas delaying thymopoietic support in the host mitigated disease. Critically, the extent of bone marrow reconstitution determined the ability to suppress thymus autonomy and leukemia development. Together, these findings demonstrate that inadequate bone marrow correction directly compromises thymic cell competition, creating a permissive niche for malignant transformation. Our work highlights thymus autonomy as a risk in immunodeficiency treatment and underscores the need to ensure robust hematopoietic reconstitution to prevent leukemogenesis.