p53 loss promotes acute myeloid leukemia by enabling aberrant self-renewal
| Autor: | Kevin Shannon, Scott W. Lowe, Johannes Zuber, Zhen Zhao, Scott C. Kogan, Laura Lintault, Ernesto Diaz-Flores |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Genetic Vectors
Green Fluorescent Proteins Biology medicine.disease_cause Proto-Oncogene Proteins p21(ras) Mice Cancer stem cell Genetics medicine Tumor Cells Cultured Gene silencing Animals Gene Silencing Cell Proliferation Sequence Deletion Oncogene Integrases Myeloid leukemia medicine.disease Hematopoietic Stem Cells Mice Inbred C57BL Leukemia Leukemia Myeloid Acute Gene Knockdown Techniques Cancer research RNA KRAS Stem cell Tumor Suppressor Protein p53 Carcinogenesis Developmental Biology Research Paper |
| Popis: | 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 KrasG12D—a common AML lesion that promotes proliferation but not self-renewal. We show that p53 inactivation strongly cooperates with oncogenic KrasG12D 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|