| First Author | Kim JH | Year | 2019 |
| Journal | Proc Natl Acad Sci U S A | Volume | 116 |
| Issue | 30 | Pages | 15178-15183 |
| PubMed ID | 31285322 | Mgi Jnum | J:277750 |
| Mgi Id | MGI:6333039 | Doi | 10.1073/pnas.1905305116 |
| Citation | Kim JH, et al. (2019) Nbn-Mre11 interaction is required for tumor suppression and genomic integrity. Proc Natl Acad Sci U S A 116(30):15178-15183 |
| abstractText | 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 (mid8) allele was expressed exclusively in hematopoietic lineages (in Nbn (-/mid8vav) mice). Unlike Nbn (flox/floxvav) mice with Nbn deficiency in the bone marrow, Nbn (-/mid8vav) mice were viable. Nbn (-/mid8vav) 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 (-/mid8) mice developed highly penetrant T cell leukemias. Nbn (-/mid8vav) 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 (mid8) mice may provide a venue to examine the relationship between the Mre11 complex and oncogene activation in the hematopoietic compartment. Genomic analysis of Nbn (-/mid8vav) 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. |
