Deletion of Puma protects hematopoietic stem cells and confers long-term survival in response to high-dose γ-irradiation

Yu, Hui; Shen, Hongmei; Yuan, Youzhong; XuFeng, Richard; Hu, Xiaoxia; Garrison, Sean; Zhang, Lin; Yu, Jian; Zambetti, Gerard P.; Cheng, Tao

doi:10.1182/blood-2009-10-248278

Cited by 122 publications

(121 citation statements)

References 40 publications

(55 reference statements)

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“…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. [30][31][32][33][34] Here, we provide the first evidence of a similar predominant role for PUMA in oncogene-induced apoptosis of hematopoietic stem and progenitor cells in vivo. Interestingly, the absence of PUMA but not loss of p53 rescued myeloid progenitors, suggesting that the mechanism of apoptosis is not a simple linear pathway from p53 to PUMA.…”

Section: Discussionmentioning

confidence: 59%

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: 59%

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

et al. 2016

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“…More recently, several groups of investigators reported that Puma, a downstream target of p53 and a proapoptotic BH3-only protein, plays a critical role in mediating IR-induced HSC apoptosis and ARS (140,172). They showed that Puma was selectively induced by IR in LSK cells and LSK cells from Puma knockout mice were insensitive to IR-induced apoptosis.…”

Section: Ir-induced Apoptosis In Hscsmentioning

confidence: 99%

Hematopoietic Stem Cell Injury Induced by Ionizing Radiation

Shao

Luo

Zhou

2014

Antioxidants & Redox Signaling

265

218

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Significance: Exposure to ionizing radiation (IR) as the result of nuclear accidents or terrorist attacks is a significant threat and a major medical concern. Hematopoietic stem cell (HSC) injury is the primary cause of death after accidental or intentional exposure to a moderate or high dose of IR. Protecting HSCs from IR should be a primary goal in the development of novel medical countermeasures against radiation. Recent Advances: Significant progress has been made in our understanding of the mechanisms by which IR causes HSC damage. The mechanisms include (i) induction of HSC apoptosis via the p53-Puma pathway; (ii) promotion of HSC differentiation via the activation of the G-CSF/Stat3/BATF-dependent differentiation checkpoint; (iii) induction of HSC senescence via the ROS-p38 pathway; and (iv) damage to the HSC niche. Critical Issues: Induction of apoptosis in HSCs and hematopoietic progenitor cells is primarily responsible for IR-induced acute bone marrow (BM) injury. Long-term BM suppression caused by IR is mainly attributable to the induction of HSC senescence. However, the promotion of HSC differentiation and damage to the HSC niche can contribute to both the acute and long-term effects of IR on the hematopoietic system. Future Directions: In this review, we have summarized a number of recent findings that provide new insights into the mechanisms whereby IR damages HSCs. These findings will provide new opportunities for developing a mechanism-based strategy to prevent and/or mitigate IR-induced BM suppression.

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“…However, very recent studies provide surprising new information on the role of PUMA in certain cancer types, emphasizing the "dark side" of the function of this proapoptotic molecule. Surprisingly, it turns out that genetic ablation of PUMA paradoxically leads to a protective effect for hematopoietic stem/progenitor cells (HSPCs) against γ radiation and the induction of mutations in these cells [104,105]. This inhibits the development of lymphomas [106,107] and hepatocellular carcinoma under certain conditions [108].…”

Section: Puma In Carcinogenesismentioning

confidence: 99%

“…In wild-type cells, DNA damage caused by IR induced p53-dependent activation of PUMA. PUMA protein induced apoptosis of HSPCs with damaged DNA thereby promoting the formation of thymic lymphomas [104][105][106][107]. Interesting results were obtained in a diethylnitrosamine-induced (DEN-induced) liver carcinogenesis model.…”

Section: Puma In Carcinogenesismentioning

confidence: 99%

Puma, a critical mediator of cell death — one decade on from its discovery

Hikisz

Kiliańska

2012

Cellular and Molecular Biology Letters

109

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Abbreviations used: ADI/II -activation domain I/II; Apaf-1 -apoptosis protease activating factor-1; Bad -Bcl-2 associated death promoter; Bak -Bcl-2 antagonist killer; Bax -Bcl-2 associated protein x; Bcl-2 -B-cell leukemia/lymphoma-2; BH1-4 -Bcl-2 homology domains 1-4; Bid -BH3 interacting domain death agonist; Bik -Bcl-2 interacting killer; Bim -Bcl-2 interacting mediator of cell death; Bmf -Bcl-2 modifying factor; Bod -Bcl-2-related ovarian death gene; Bok -Bcl-2 ovarian killer; BS1/2 -p53 binding site 1/2; CHOP -C/EBP homologous protein; DEN -diethylnitrosamine; GSK-3 -glycogen synthase kinase-3; HRK -harakiri, activator of apoptosis ; HSPCs -hematopoietic stem/progenitor cells; HSV-1 -human herpes virus; IKK -IκB kinase; IL-3 -interleukin 3; Lys -lysine; Mcl-1 -myeloid cell leukemia-1; MEFs -mouse embryo fibroblasts; miRNA/miR -microRNA; MLS -mitochondrial localization signal; MOMPmitochondrial outer membrane permeabilization; NOXA (PMAP1) -phorbol-12-myristate-13-acetate-induced protein 1; OMM -outer mitochondrial membrane; PCDprogrammed cell death; PI3K -phosphoinositide 3-kinase; PUMA -p53 upregulated modulator of apoptosis; ROS -reactive oxygen species; Ser -serine; Smac/DIABLOsecond mitochondria-derived activator or caspases/direct IAP binding protein with low pI; TRB3 -tribbles 3 homolog; UV-IR -ultraviolet-gamma irradiation Abstract: PUMA (p53 upregulated modulator of apoptosis) is a pro-apoptotic member of the BH3-only subgroup of the Bcl-2 family. It is a key mediator of p53-dependent and p53-independent apoptosis and was identified 10 years ago. The PUMA gene is mapped to the long arm of chromosome 19, a region that is frequently deleted in a large number of human cancers. PUMA mediates apoptosis thanks to its ability to directly bind known anti-apoptotic members of the Bcl-2 family. It mainly localizes to the mitochondria. The binding of PUMA to the inhibitory members of the Bcl-2 family (Bcl-2-like proteins) via its BH3 domain seems to be a critical regulatory step in the induction of apoptosis. It results in the displacement of the proteins Bax and/or Bak. This is followed by their activation and the formation of pore-like structures on the mitochondrial Unauthenticated Download Date | 5/11/18 3:27 AM CELLULAR & MOLECULAR BIOLOGY LETTERS 647 membrane, which permeabilizes the outer mitochondrial membrane, leading to mitochondrial dysfunction and caspase activation. PUMA is involved in a large number of physiological and pathological processes, including the immune response, cancer, neurodegenerative diseases and bacterial and viral infections.

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Deletion of Puma protects hematopoietic stem cells and confers long-term survival in response to high-dose γ-irradiation

Cited by 122 publications

References 40 publications

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

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

Hematopoietic Stem Cell Injury Induced by Ionizing Radiation

Puma, a critical mediator of cell death — one decade on from its discovery

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