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

We derived a mouse model in which a mutant form of Nbn/Nbs1^mid8 (hereafter Nbn^mid8) exhibits severely impaired binding to the Mre11-Rad50 core of the Mre11 complex. The Nbn allele was expressed exclusively in hematopoietic lineages (in Nbn mice). Unlike Nbn mice with Nbn deficiency in the bone marrow, Nbn mice were viable. Nbn mice hematopoiesis was profoundly defective, exhibiting reduced cellularity of thymus and bone marrow, and stage-specific blockage of B cell development. Within 6 mo, Nbn mice developed highly penetrant T cell leukemias. Nbn leukemias recapitulated mutational features of human T cell acute lymphoblastic leukemia (T-ALL), containing mutations in NOTCH1, TP53, BCL6, BCOR, and IKZF1, suggesting that Nbn mice may provide a venue to examine the relationship between the Mre11 complex and oncogene activation in the hematopoietic compartment. Genomic analysis of Nbn malignancies showed focal amplification of 9qA2, causing overexpression of MRE11 and CHK1 We propose that overexpression of MRE11 compensates for the metastable Mre11-Nbn^mid8 interaction, and that selective pressure for overexpression reflects the essential role of Nbn in promoting assembly and activity of the Mre11 complex.

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