p53 loss promotes acute myeloid leukemia by enabling aberrant self-renewal

Zhao, Z., Zuber, J., Diaz-Flores, E., Lintault, L., Kogan, S. C., Shannon, K., Lowe, S. W. (July 2010) p53 loss promotes acute myeloid leukemia by enabling aberrant self-renewal. Genes Dev, 24 (13). pp. 1389-1402. ISSN 1549-5477 (Electronic) 0890-9369 (Linking)

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URL: http://www.ncbi.nlm.nih.gov/pubmed/20595231
DOI: 10.1101/gad.1940710

Abstract

The p53 tumor suppressor limits proliferation in response to cellular stress through several mechanisms. Here, we test whether the recently described ability of p53 to limit stem cell self-renewal suppresses tumorigenesis in acute myeloid leukemia (AML), an aggressive cancer in which p53 mutations are associated with drug resistance and adverse outcome. Our approach combined mosaic mouse models, Cre-lox technology, and in vivo RNAi to disable p53 and simultaneously activate endogenous Kras(G12D)-a common AML lesion that promotes proliferation but not self-renewal. We show that p53 inactivation strongly cooperates with oncogenic Kras(G12D) to induce aggressive AML, while both lesions on their own induce T-cell malignancies with long latency. This synergy is based on a pivotal role of p53 in limiting aberrant self-renewal of myeloid progenitor cells, such that loss of p53 counters the deleterious effects of oncogenic Kras on these cells and enables them to self-renew indefinitely. Consequently, myeloid progenitor cells expressing oncogenic Kras and lacking p53 become leukemia-initiating cells, resembling cancer stem cells capable of maintaining AML in vivo. Our results establish an efficient new strategy for interrogating oncogene cooperation, and provide strong evidence that the ability of p53 to limit aberrant self-renewal contributes to its tumor suppressor activity.

Item Type: Paper
Uncontrolled Keywords: Animals Cell Proliferation Gene Knockdown Techniques Gene Silencing Genetic Vectors Green Fluorescent Proteins/genetics/metabolism Hematopoietic Stem Cells/metabolism Integrases/genetics/metabolism Leukemia, Myeloid, Acute/ physiopathology Mice Mice, Inbred C57BL Proto-Oncogene Proteins p21(ras)/genetics/metabolism RNA/genetics Sequence Deletion/genetics Tumor Cells, Cultured Tumor Suppressor Protein p53/ deficiency/genetics/ metabolism
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > RNAi
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > green fluorescent protein
diseases & disorders > cancer > cancer types > leukemia
organism description > animal > mammal > rodent > mouse
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > p53
therapies > stem cells
CSHL Authors:
Communities: CSHL labs > Lowe lab
CSHL Cancer Center Shared Resources > Animal Services
CSHL Cancer Center Shared Resources > DNA Sequencing Service
CSHL Cancer Center Shared Resources > Flow Cytometry Service
Depositing User: CSHL Librarian
Date: 1 July 2010
Date Deposited: 26 Oct 2011 19:19
Last Modified: 26 Dec 2014 20:42
PMCID: PMC2895198
Related URLs:
URI: http://repository.cshl.edu/id/eprint/15595

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