Long-term haematopoietic reconstitution by Trp53-/-p16Ink4a-/-p19Arf-/- multipotent progenitors

Akala, Omobolaji Oyekunle; Park, Inkyung; Qian, Dalong; Pihalja, Michael; Becker, Michael W.; Clarke, Michael F.

doi:10.1038/nature06869

Cited by 160 publications

(149 citation statements)

References 26 publications

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“…14 Indeed, activation of DNA damage response genes appears more prominent where p53 is intact (i.e., NHD13; Puma −/− ) in comparison with cases where p53 is lost (Figure 7d). Loss of p53 might also enhance progression to AML by promoting aberrant self-renewal 29 or a switch to oxidative metabolism causing DNA damage. 27 In response to DNA damage (e.g., γ-irradiation) and cytokine withdrawal, PUMA appears to be more important than NOXA for apoptosis of normal hematopoietic stem and progenitor cells.…”

Section: Discussionmentioning

confidence: 99%

PUMA promotes apoptosis of hematopoietic progenitors driving leukemic progression in a mouse model of myelodysplasia

et al. 2016

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Myelodysplastic syndrome (MDS) is characterized by ineffective hematopoiesis with resultant cytopenias. Increased apoptosis and aberrantly functioning progenitors are thought to contribute to this phenotype. As is the case for other malignancies, overcoming apoptosis is believed to be important in progression toward acute myeloid leukemia (AML). Using the NUP98-HOXD13 (NHD13) transgenic mouse model of MDS, we previously reported that overexpression of the anti-apoptotic protein BCL2, blocked apoptosis and improved cytopenias, paradoxically, delaying leukemic progression. To further understand this surprising result, we examined the role of p53 and its pro-apoptotic effectors, PUMA and NOXA in NHD13 mice. The absence of p53 or PUMA but not NOXA reduced apoptosis and expanded the numbers of MDS-repopulating cells. Despite a similar effect on apoptosis and cell numbers, the absence of p53 and PUMA had diametrically opposed effects on progression to AML: absence of p53 accelerated leukemic progression, while absence of PUMA significantly delayed progression. This may be explained in part by differences in cellular responses to DNA damage. The absence of p53 led to higher levels of γ-H2AX (indicative of persistent DNA lesions) while PUMA-deficient NHD13 progenitors resolved DNA lesions in a manner comparable to wild-type cells. These results suggest that targeting PUMA may improve the cytopenias of MDS without a detrimental effect on leukemic progression thus warranting further investigation. Cell Death and Differentiation (2016) 23, 1049-1059 doi:10.1038/cdd.2015; published online 8 January 2016Myelodysplastic syndromes (MDS) are a genetically and clonally heterogeneous group of myeloid malignancies, likely arising from the hematopoietic stem cell. 1-3 Despite their genetic heterogeneity, they share common phenotypic features including low peripheral blood counts (cytopenias) in spite of a hypercellular bone marrow (ineffective hematopoiesis), dysplasia and a variable propensity for transformation to acute myeloid leukemia (AML). 4 Programmed cell death or apoptosis of white blood cells is a common feature, and is thought to contribute to the cytopenias particularly in early stages of the disease. The basis of ineffective hematopoiesis in MDS may also lie in the dysfunction of hematopoietic progenitors and their inability to support adequate bone marrow function. Apoptosis can be triggered by extrinsic factors, such as FAS ligand or TNF-α, or by cell-intrinsic factors such as ribosomal stress or increased reactive oxygen species. A cell extrinsic mechanism for apoptosis in MDS has been favored for many years; 5 however, recent evidence suggests a cell-intrinsic trigger, especially in del(5q) MDS for which there is evidence for activation of the tumor suppressor p53 by ribosomal dysfunction. 6,7 More aggressive stages of MDS have less apoptosis than earlier stages, 8 supporting the paradigm that acquired resistance to apoptosis of malignant progenitors is an important step in cancer progression. 9 Among hematological...

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Section: Discussionmentioning

confidence: 99%

PUMA promotes apoptosis of hematopoietic progenitors driving leukemic progression in a mouse model of myelodysplasia

et al. 2016

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“…Mutations that inactivate the p53 tumour suppressor network occur in most natural human tumours, thus, remarkable similarities must exist between the genetic and epigenetic processes involved in the generation of cancer, and the acquisition of a less differentiated phenotype and self-renewal ability in induced pluripotency. Loss of p53 confers stem-like properties in committed progenitors in the haematopoietic system (Akala et al, 2008), and loss of p53 increases the size of the mammary repopulating compartment in mice by 10-fold, suggesting that p53 may act as a regulator of stem cell self-renewal in vivo (Cicalese et al, 2009). Therefore, it is possible that the acquisition of the self-renewal ability of CSCs arises by some of the mechanisms shared with those involved in pluripotency reprogramming, in cells that harbour permissive mutations, such as inactivation of the p53 pathway.…”

Section: Sox2 Activation In Breast Cancer Stem Cellsmentioning

confidence: 99%

Sox2 expression in breast tumours and activation in breast cancer stem cells

Leis¹,

Eguiara²,

et al. 2011

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The cancer stem cell (CSC) model does not imply that tumours are generated from transformed tissue stem cells. The target of transformation could be a tissue stem cell, a progenitor cell, or a differentiated cell that acquires selfrenewal ability. The observation that induced pluripotency reprogramming and cancer are related has lead to the speculation that CSCs may arise through a reprogramming-like mechanism. Expression of pluripotency genes (Oct4, Nanog and Sox2) was tested in breast tumours by immunohistochemistry and it was found that Sox2 is expressed in early stage breast tumours. However, expression of Oct4 or Nanog was not found. Mammosphere formation in culture was used to reveal stem cell properties, where expression of Sox2, but not Oct4 or Nanog, was induced. Over-expression of Sox2 increased mammosphere formation, effect dependent on continuous Sox2 expression; furthermore, Sox2 knockdown prevented mammosphere formation and delayed tumour formation in xenograft tumour initiation models. Induction of Sox2 expression was achieved through activation of the distal enhancer of Sox2 promoter upon sphere formation, the same element that controls Sox2 transcription in pluripotent stem cells. These findings suggest that reactivation of Sox2 represents an early step in breast tumour initiation, explaining tumour heterogeneity by placing the tumour-initiating event in any cell along the axis of mammary differentiation.

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“…These findings might reflect the presence of tumor initiating cells in the WBM of p53 null mice. Interestingly, loss of p53 could promote acquisition of self-renewal by early hematopoietic progenitor cells [48], suggesting that progenitor reprogramming might contribute to the increased frequency of reconstitution and to the lymphomas of the p53 null bone marrow.…”

Section: Opinionmentioning

confidence: 99%