Inhibition of apoptosis by BCL2 prevents leukemic transformation of a murine myelodysplastic syndrome

Slape, Christopher; Saw, Jesslyn; Jowett, Jeremy B. M.; Aplan, Peter D.; Strasser, Andreas; Jane, Stephen M.; Curtis, David J.

doi:10.1182/blood-2012-05-430736

Cited by 43 publications

(40 citation statements)

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“…Using the NUP98-HOXD13 (NHD13) transgenic mouse model of MDS, we demonstrated previously that enforced expression of BCL2 could rescue oncogenic stress-induced apoptosis of hematopoietic stem and myeloid progenitors and found this prevented progression to AML. 17 To define the hematopoietic subsets affected by apoptosis in NHD13 mice, we measured the numbers and percentages of cells undergoing apoptosis among defined hematopoietic stem and progenitor cells by flow cytometry. As previously reported, 18,19 the proportions of Lineage neg Sca-1 + c-Kit + (LSK) stem/multi-potent progenitor cells and Lineage neg Sca-1 − c-Kit + (LK) progenitor cells were reduced approximately three-fold and two-fold, respectively (Figure 1a).…”

Section: Resultsmentioning

confidence: 99%

“…16 NHD13 mice also show evidence of increased apoptosis of bone marrow stem and progenitor cells. 17 In this model, we have demonstrated that apoptosis is driven by cell-intrinsic factors because it is effectively blocked by enforced expression of BCL2. 17 Challenging the paradigm that overcoming apoptosis is an important step toward malignant transformation, we have found that blocking apoptosis by BCL2 in this mouse model actually prevents transformation to AML.…”

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confidence: 91%

“…17 In this model, we have demonstrated that apoptosis is driven by cell-intrinsic factors because it is effectively blocked by enforced expression of BCL2. 17 Challenging the paradigm that overcoming apoptosis is an important step toward malignant transformation, we have found that blocking apoptosis by BCL2 in this mouse model actually prevents transformation to AML. However, several caveats need to be considered for the effects seen with transgenic expression of BCL2.…”

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confidence: 91%

“…14 To address the mechanism and relevance of apoptosis in MDS, we have used the NUP98-HOXD13 (NHD13) transgenic mouse in which the t(2;11)(q31;p15) fusion protein is expressed in hematopoietic stem and progenitor cells under the control of the hematopoietic specific promoter, Vav. 15 Although this translocation is rare in human MDS, these mice Abbreviations: AML, acute myeloid leukemia; BFU-E, burst-forming units-erythroid; CFU-E, colony-forming units-erythroid; CFU-GM, colony-forming units-granulocyte/ macrophage; GMP, granulocyte-macrophage progenitors; LK cells, lineage neg Sca-1-c-Kit+; LSK cells, lineage neg Sca-1+c-Kit+; LT-HSCs, long-term hematopoietic stem cells; MDS, myelodysplastic syndromes; MLL, mixed-lineage leukemia; MPPs, multipotent progenitors; NHD13, Nup98-HoxD13; SLAM, Signaling Lymphocyte Activation Molecules; ST-HSCs, short-term hematopoietic stem cells; TNF, tumor necrosis factor; WT, wild-type 17 In this model, we have demonstrated that apoptosis is driven by cell-intrinsic factors because it is effectively blocked by enforced expression of BCL2. 17 Challenging the paradigm that overcoming apoptosis is an important step toward malignant transformation, we have found that blocking apoptosis by BCL2 in this mouse model actually prevents transformation to AML.…”

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confidence: 99%

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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: Resultsmentioning

confidence: 99%

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confidence: 91%

mentioning

confidence: 91%

mentioning

confidence: 99%

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

et al. 2016

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“…In a ramped-up process of Darwinian selection, rounds of these events, may lead to the development of aggressive and apoptosis resistant AML. Indeed, supporting this idea, inhibiting apoptosis, either through ectopic BCL-2 expression or loss of PUMA expression delays leukemia progression in mouse models of MDS 59,60 . As the authors suggest, if these findings hold These results, together with transcriptomic and in vitro co-culture experiments led the authors to propose a model whereby tumour cell apoptosis reprogram TAM towards a wound-healing type response that fuels tumourigenesis 68 .…”

Section: Apoptosis Cell Competition and Cancermentioning

confidence: 90%

A fate worse than death: apoptosis as an oncogenic process

2016

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Myelodysplastic syndromes

2021

Haematology

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FAS gene, a direct target for NFκB transcription factor, is repressed in solid tumors including colon carcinomas. We have previously reported that, while overexpressed in low risk myelodysplastic syndromes (MDS), the Fas death receptor becomes undetectable on CD34 + progenitors when the disease progresses to secondary acute myeloid leukaemia (sAML). This study aimed at investigating the interplay between NFκB and Fas during MDS progression.We first observed that Fas was inducible by TNFα in the HL60 cell line. In these cells, p65/RelA bound to the chromatin at FAS promoter, while inhibition of NFκB pathway by IKKα inhibitor BAY11-7082 or lentiviral expression of a non-degradable mutant of IκBα, IκSR blocked the expression of Fas. By contrast, TNFα failed to induce Fas expression in the colon carcinoma cell line SW480, due to hypermethylation of the FAS promoter. In vitro use of azacitidine rescued p65/RelA binding on FAS promoter and, subsequently Fas expression in SW480 cells. We also show that, inhibition of NFκB pathway decreased the expression of Fas in MDS CD45 lo CD34 + bone marrow cells. However, despite of the nuclear expression of p65/RelA, Fas was often low on CD45 lo CD34 + AML cells. TNFα failed to stimulate its expression, while azacitidine efficiently rescued p65/RelA binding and Fas reexpression. Our data suggest that DNA methylation at NFκB sites is responsible for FAS gene silencing. Rescuing FAS gene expression by azacitidine could contribute to slacken the progression to leukaemia.

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Inhibition of apoptosis by BCL2 prevents leukemic transformation of a murine myelodysplastic syndrome

Cited by 43 publications

References 39 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

A fate worse than death: apoptosis as an oncogenic process

Myelodysplastic syndromes

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