期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2019
卷号：116
期号：30
页码：15178-15183
DOI：10.1073/pnas.1905305116
出版社：The National Academy of Sciences of the United States of America
摘要：We derived a mouse model in which a mutant form of Nbn/Nbs1mid8 (hereafter Nbnmid8) 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−Nbnmid8 interaction, and that selective pressure for overexpression reflects the essential role of Nbn in promoting assembly and activity of the Mre11 complex.
