Proliferative status of primitive hematopoietic progenitors from patients with acute myelogenous leukemia (AML)

Guan, Yanfei; Hogge, Donna E.

doi:10.1038/sj.leu.2401975

Cited by 51 publications

(37 citation statements)

References 31 publications

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“…Accordingly, loss of p53 might contribute to the formation of leukemia-initiating cells, which by definition have maintained or reacquired the capacity for indefinite selfrenewal through accumulated mutations and/or epigenetic changes (Passegue and Weisman 2005). Such cells have properties reminiscent of cancer stem cells, which are considered to be inherently more aggressive and refractory to chemotherapy (Guan and Hogge 2000;Jordan and Guzman 2004;Holtz et al 2005). Consequently, our results suggest a biological explanation for the occurrence of p53 mutations in the most aggressive and drugresistant AMLs.…”

Section: Prevention Of Aberrant Self-renewal and Tumor Suppression Bymentioning

confidence: 75%

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

Zuber²,

et al. 2010

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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 selfrenewal contributes to its tumor suppressor activity.[Keywords: AML; Ras; cancer stem cells; leukemia; p53; self-renewal; tumor suppressor] Supplemental material is available at http://www.genesdev.org.

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Section: Prevention Of Aberrant Self-renewal and Tumor Suppression Bymentioning

confidence: 75%

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

Zuber²,

et al. 2010

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“…Normal stem cells cycle less frequently than the more differentiated transit-amplifying cells (thus, the designation of normal stem cells as label retaining). CSCs from acute and chronic myelogenous leukemias are relatively quiescent 58,59 , contributing to therapeutic resistance. Similar results have not been confirmed in CSCs derived from solid tumors.…”

Section: Cscs and Chemotherapy Resistancementioning

confidence: 99%

Survival of the Fittest: Cancer Stem Cells in Therapeutic Resistance and Angiogenesis

Eyler

Rich

2008

JCO

656

484

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In an increasing number of cancers, tumor populations called cancer stem cells (CSCs) or tumor initiating cells have been defined in functional assays of self-renewal and tumor initiation. Moreover, recent work in several different cancers has suggested the CSC population as a source of chemo-and radiation-therapy resistance within tumors. Work in glioblastoma and breast cancers supports the idea that CSCs may possess innate resistance mechanisms against radiation-and chemotherapyinduced cancer cell death, allowing them to survive and initiate tumor recurrence. Several resistance mechanisms have been proposed, including amplified checkpoint activation and DNA damage repair as well as increased Wnt/β-Catenin and Notch signalling. Novel targeted therapies against the DNA damage checkpoint or stem cell maintenance pathways may sensitize CSCs to radiation or other therapies. Another important category of cancer therapies are anti-angiogenic and vascular targeting agents which are also becoming integrated in the treatment paradigm of an increasing number of cancers. Recent results from our laboratory and others support a role for CSCs in the angiogenic drive as well as the mechanism of anti-angiogenic agents. Identifying and targeting the molecular mechanisms responsible for CSC therapeutic resistance may improve the efficacy of current cancer therapies.

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“…[15][16][17] Hatfield et al 18 reported the production of IL-3 from microvascular endothelium of bone marrow resulting in the proliferation and inhibition of apoptosis of AML blasts. Bone marrow stromal cells also produce IL-6 and stem cell factor (SCF).…”

Section: Introductionmentioning

confidence: 99%