Significance The Mre11 complex core, consisting of Mre11, Rad50, and Nbn/Nbs1, is essential for viability. Accordingly, hematopoietic-specific Nbn deficiency leads to perinatal lethality. In contrast, destabilizing the interaction of Nbn with the core Mre11−Rad50 ( Nbn ^mid8 allele) in hematopoietic cells permits viability but leads to severe defects in hematopoiesis. Viability requires gene amplification of MRE11 and CHK1 . We propose that the MRE11 overexpression compensates for weakened Nbn interaction, and that selection for CHK1 overexpression mitigates the genomic instability and loss of ATM-dependent checkpoint functions. The surviving animals develop highly penetrant T-ALL, the mutational features of which resemble human T-ALL. Hence, Nbn meets the definition of a tumor suppressor in this context.