A tumor suppressor function for prosurvival BCL-2 proteins in the thymus

Defective cell competition has been linked to tumorigenesis in various cancers, including acute lymphoblastic leukemia (T-ALL), but the underlying mechanisms remain unclear. In the thymus, we found marked elevation in the amount of prosurvival BCL-2 protein in “new” progenitors competing with “old” counterparts, suggesting an apoptotic mechanism. However, in a thymic transplant model of disrupted cell competition, Bcl2 deletion paradoxically accelerated the onset of leukemia resembling T-ALL. Mechanistically, the loss of BCL-2 did not alter competitive outcomes but induced heightened apoptosis and increased IL-7-driven compensatory proliferation in the surviving progenitors. This elevated cell turnover accelerated the acquisition of oncogenic mutations but did not change the mutational burden or landscape of T-ALL. More broadly, we found that even modest reduction in the related prosurvival proteins, MCL-1 or BCL-XL, also accelerated T-ALL-like disease in the transplant model. In a separate setting, conditional ablation of Mcl1 early in thymic lymphopoiesis caused profound thymocyte loss, elevated progenitor proliferation and spontaneous T-ALL. These findings define a tumor-suppressive function for BCL-2 family proteins in settings of defective cell competition, with important implications for the therapeutic use of BH3 mimetics in cancer.