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

Abstract

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 <i>Nbn</i>^<i>mid8</i> allele was expressed exclusively in hematopoietic lineages (in <i>Nbn</i>^{<i>-/mid8vav</i>} mice). Unlike <i>Nbn</i>^{<i>flox/floxvav</i>} mice with Nbn deficiency in the bone marrow, <i>Nbn</i>^{<i>-/mid8vav</i>} mice were viable. <i>Nbn</i>^{<i>-/mid8vav</i>} mice hematopoiesis was profoundly defective, exhibiting reduced cellularity of thymus and bone marrow, and stage-specific blockage of B cell development. Within 6 mo, <i>Nbn</i>^{<i>-/mid8</i>} mice developed highly penetrant T cell leukemias. <i>Nbn</i>^{<i>-/mid8vav</i>} leukemias recapitulated mutational features of human T cell acute lymphoblastic leukemia (T-ALL), containing mutations in <i>NOTCH1</i>, <i>TP53</i>, <i>BCL6</i>, <i>BCOR</i>, and <i>IKZF1</i>, suggesting that <i>Nbn</i>^<i>mid8</i> mice may provide a venue to examine the relationship between the Mre11 complex and oncogene activation in the hematopoietic compartment. Genomic analysis of <i>Nbn</i>^{<i>-/mid8vav</i>} malignancies showed focal amplification of 9qA2, causing overexpression of <i>MRE11</i> and <i>CHK1</i> We propose that overexpression of <i>MRE11</i> 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.