Selection against PUMA gene expression in Myc-driven B-cell lymphomagenesis.
The p53 tumor suppressor pathway limits oncogenesis by inducing cell cycle arrest or apoptosis. A key p53 target gene is PUMA, which encodes a BH3-only proapoptotic protein. Here we demonstrate that Puma deletion in the Emu-Myc mouse model of Burkitt lymphoma accelerates lymphomagenesis and that approximately 75% of Emu-Myc lymphomas naturally select against Puma protein expression. Furthermore, approximately 40% of primary human Burkitt lymphomas fail to express detectable levels of PUMA and in some tumors this is associated with DNA methylation. Burkitt lymphoma cell lines phenocopy the primary tumors with respect to DNA methylation and diminished PUMA expression, which can be reactivated following inhibition of DNA methyltransferases. These findings establish that PUMA is silenced in human malignancies, and they suggest PUMA as a target for the development of novel chemotherapeutics.
Garrison
Sean P
SP
Department of Biochemistry, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105, USA.
Jeffers
John R
JR
Yang
Chunying
C
Nilsson
Jonas A
JA
Hall
Mark A
MA
Rehg
Jerold E
JE
Yue
Wen
W
Yu
Jian
J
Zhang
Lin
L
Onciu
Mihaela
M
Sample
Jeffery T
JT
Cleveland
John L
JL
Zambetti
Gerard P
GP
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D001374:Azacitidine / Q000494:pharmacology; D001402:B-Lymphocytes / Q000473:pathology*; D001483:Base Sequence; D002051:Burkitt Lymphoma / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D044127:Epigenesis, Genetic / Q000187:drug effects; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D006801:Humans; D008745:Methylation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; D006657:Histones; C488588:PUMA protein, mouse; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D001374:Azacitidine