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GENETICS
Artemis and p53 cooperate to suppress oncogenic N-myc amplification in progenitor B cells

Sean Rooney ^*, JoAnn Sekiguchi ^*, Scott Whitlow ^*, Mark Eckersdorff ^*, John P. Manis ^*, Charles Lee , David O. Ferguson ^*, and Frederick W. Alt ^* 

^*Howard Hughes Medical Institute, Children's Hospital, Department of Genetics, Harvard Medical School, and Center for Blood Research, Boston, MA 02115; and Division of Cytogenetics, Department of Pathology, Brigham and Woman's Hospital, Harvard Medical School, Boston, MA 02115

Communicated by Frederick W. Alt, Harvard Medical School, Boston, MA, December 31, 2003 (received for review December 30, 2003)

The nonhomologous DNA end-joining (NHEJ) pathway contains six known components, including Artemis, a nuclease mutated in a subset of human severe combined immunodeficient patients. Mice doubly deficient for the five previously analyzed NHEJ factors and p53 inevitably develop progenitor B lymphomas harboring der(12)t(12;15) translocations and immunoglobin heavy chain (IgH)/c-myc coamplification mediated by a breakage-fusion-bridge mechanism. In this report, we show that Artemis/p53-deficient mice also succumb reproducibly to progenitor B cell tumors, demonstrating that Artemis is a tumor suppressor in mice. However, the majority of Artemis/p53-deficient tumors lacked der(12)t(12;15) translocations and c-myc amplification and instead coamplified IgH and N-myc through an intra- or interchromosome 12 breakage-fusion-bridge mechanism. We discuss this finding in the context of potential implications for mechanisms that may target IgH locus translocations to particular oncogenes.

To whom correspondence should be addressed. E-mail: alt{at}enders.tch.harvard.edu.

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