Artemis and p53 cooperate to suppress oncogenic N-myc amplification in progenitor B cells.
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.
Rooney
Sean
S
Howard Hughes Medical Institute, Children's Hospital, Department of Genetics, Harvard Medical School, and Center for Blood Research, Boston, MA 02115, USA.
Sekiguchi
JoAnn
J
Whitlow
Scott
S
Eckersdorff
Mark
M
Manis
John P
JP
Lee
Charles
C
Ferguson
David O
DO
Alt
Frederick W
FW
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000502:physiology*; D001483:Base Sequence; D002874:Chromosome Mapping; D004260:DNA Repair; D004720:Endonucleases; D016259:Genes, myc; D016158:Genes, p53; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D015448:Leukemia, B-Cell / Q000235:genetics; D016393:Lymphoma, B-Cell / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009374:Neoplasms, Experimental / Q000235:genetics*; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics*; D013489:Suppression, Genetic / Q000235:genetics*; D015996:Survival Rate; D014178:Translocation, Genetic; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics*
D007143:Immunoglobulin Heavy Chains; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; D004720:Endonucleases; C473337:Dclre1c protein, mouse