Mdm2 haplo‐insufficiency profoundly inhibits Myc‐induced lymphomagenesis
Open accessAbstract
Mdm2 harnesses the p53 tumor suppressor, yet loss of one Mdm2 allele in Mdm2(+/-) mice has heretofore not been shown to impair tumor development. Here we report that Mdm2 haplo-insufficiency profoundly suppresses lymphomagenesis in E micro -myc transgenic mice. Mdm2(+/-)E micro -myc transgenics had greatly protracted rates of B cell lymphoma development with life spans twice that of wild-type transgenic littermates. Im paired lymphoma development was associated with drastic reductions in peripheral B cell numbers in Mdm2(+/-)E micro -myc transgenics, and primary pre-B cells from Mdm2(+/-)E micro -myc transgenics and Mdm2(+/-) littermates were extremely susceptible to spontaneous apoptosis. Loss of p53 rescued all of the effects of Mdm2 haplo-insufficiency, indicating they were p53 dependent. Furthermore, half of the lymphomas that ultimately emerged in Mdm2(+/-)E micro -myc transgenics harbored inactivating mutations in p53, and the majority overcame haplo-insufficiency by overexpressing Mdm2. These results support the concept that Mdm2 functions are rate limiting in lymphomagenesis and that targeting Mdm2 will enhance p53-mediated apoptosis, compromising tumor development and/or maintenance.
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A third of the lymphomas arising in Eμ-myc transgenic mice that have mutated p53 or lack p53 also overexpress Mdm2.
“a third of the lymphomas arising in Eμ-myc transgenic mice that have mutated p53 or lack p53 also overexpress Mdm2 (2, 15)”
From Mdm2 Promotes Genetic Instability and Transformation Independent of p53 (2008) · cites this paper as [2]
In “The effects of Mdm2 haplo-insufficiency are p53 dependent” (page unavailable), the paper reports Mdm2 overexpression in many lymphomas with mutated p53. It does not give a one-third figure for lymphomas with mutated or deleted p53 that also overexpress Mdm2; the percentages it reports use all analyzed lymphomas as the denominator. (LLM, conf=0.84)
Experimental — accuracy not yet measuredSome tumors in mice and humans contain mutant p53 and overexpress Mdm2, which suggests Mdm2 may have p53-independent functions.
“In addition, some tumors in mice and humans contain mutant p53 and overexpress Mdm2, indicating that Mdm2 may have functions independent of p53 (Alt, et al., 2003; Cordon-Cardo, et al., 1994; Eischen, et al., 1999; Lu, et al., 2002; Peng, et al., 2001; Sigalas, et al., 1996).”
From The Mdm network and its regulation of p53 activities: a rheostat of cancer risk (2014) · cites this paper as Alt, et al., 2003
Gamma radiation or Myc overexpression causes cell death when cells are haploinsufficient for Mdm2.
“Consequently, gamma radiation or overexpression of the Myc oncogene leads to cell death when cells are haploinsufficient for Mdm2 (Alt, et al., 2003; O’Leary, et al., 2004; Terzian, et al., 2007).”
From The Mdm network and its regulation of p53 activities: a rheostat of cancer risk (2014) · cites this paper as Alt, et al., 2003
In Mdm2+/− and Mdmx+/− heterozygous mice, the threshold for p53 activation in response to MYC is lowered, resulting in lower rates of MYC-induced lymphoma.
“In Mdm2+/−- and Mdmx+/−-heterozygous mice, the threshold for p53 activation in response to MYC is lowered, resulting in lower rates of MYC-induced lymphoma26,27.”
From MDM2, MDMX and p53 in oncogenesis and cancer therapy (2013) · cites this paper as [26]
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- Authors
- Alt, J. R., Greiner, T. C., Cleveland, J. L., & Eischen, C. M.
- Affiliations
- University of Nebraska Medical Center (US)
- St. Jude Children's Research Hospital (US)
- Corresponding author
- Eischen, Christine M.
- Venue
- The EMBO Journal
- Published
- 2003-03-17
- Volume
- 22
- Issue
- 6
- Pages
- 1442-1450
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC151074
- OpenAlex
- W2117736191
- Cited by
- 129
- References
- 48
- Citations by year
- 2025: 2 · 2024: 4 · 2023: 3 · 2022: 5 · 2021: 1 · 2020: 2 · 2019: 3 · 2018: 1 · 2017: 1 · 2016: 5 · 2015: 6 · 2014: 9 · 2013: 3 · 2012: 9
- FWCI
- 4.19
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Lebanese Syrian Associated Charities
- National Institutes of Health
- National Cancer Institute (CA-76379, T32-CA09476, R01CA076379, T32CA009476)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 44158, R01DK044158)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- MDM2, c-Myc, lymphomagenesis, B-cell lymphoma, p53, p53-dependent apoptosis, pre-B cells, Eμ-myc transgenic mice, tumor suppressor, MDM2 overexpression
- MeSH terms
- Animals, B-Lymphocytes, Cell Survival, Cells, Cultured, Longevity, Mice, Transgenic, Neoplasm Proteins, Nuclear Proteins, Proto-Oncogene Proteins, Gene Expression Regulation, Neoplastic, Genes, Tumor Suppressor, Genes, p53, Genes, myc, Lymphoma, B-Cell, Apoptosis, Mice, Knockout, Mice, Proto-Oncogene Proteins c-mdm2
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