Nbn-Mre11 interaction is required for tumor suppression and genomic integrity.

We derived a mouse model in which a mutant form of Nbn/Nbs1 (hereafter Nbn) exhibits severely impaired binding to the Mre11-Rad50 core of the Mre11 complex. The allele was expressed exclusively in hematopoietic lineages (in mice). Unlike mice with Nbn deficiency in the bone marrow, mice were viable. mice hematopoiesis was profoundly defective, exhibiting reduced cellularity of thymus and bone marrow, and stage-specific blockage of B cell development. Within 6 mo, mice developed highly penetrant T cell leukemias. leukemias recapitulated mutational features of human T cell acute lymphoblastic leukemia (T-ALL), containing mutations in , , , , and , suggesting that mice may provide a venue to examine the relationship between the Mre11 complex and oncogene activation in the hematopoietic compartment. Genomic analysis of malignancies showed focal amplification of 9qA2, causing overexpression of and We propose that overexpression of compensates for the metastable Mre11-Nbn interaction, and that selective pressure for overexpression reflects the essential role of Nbn in promoting assembly and activity of the Mre11 complex.