title: p53 loss promotes acute myeloid leukemia by enabling aberrant self-renewal.
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.
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhao
authors.forename: Johannes
authors.initials: J
authors.lastname: Zuber
authors.forename: Ernesto
authors.initials: E
authors.lastname: Diaz-Flores
authors.forename: Laura
authors.initials: L
authors.lastname: Lintault
authors.forename: Scott C
authors.initials: SC
authors.lastname: Kogan
authors.forename: Kevin
authors.initials: K
authors.lastname: Shannon
authors.forename: Scott W
authors.initials: SW
authors.lastname: Lowe
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D012313:RNA / Q000235:genetics; D017384:Sequence Deletion / Q000235:genetics; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53; D049452:Green Fluorescent Proteins; D012313:RNA; C045073:Cre recombinase; D019426:Integrases; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)