Apoptosis of leukocytes triggered by acute DNA damage promotes lymphoma formation

Labi, Verena; Erlacher, Miriam; Krumschnabel, Gerhard; Manzl, Claudia; Tzankov, Alexandar; Pinon, Josephina; Egle, Alexander; Villunger, Andreas

doi:10.1101/gad.1940210

Cited by 102 publications

(128 citation statements)

References 28 publications

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“…9 Previously, it has been shown that the absence of PUMA (or overexpression of BCL-2) could greatly delay or even prevent development of γ-radiation-induced thymic lymphoma, a malignancy that is, like MDS, also derived from bone marrow HSCs. 31,37 We previously showed that overexpression of BCL-2 with consequent blocking of apoptosis could have a similar effect in the presence of an established MDS-initiating cell. 16 The effects seen with loss of PUMA extend our previous work by identifying the BH3-only protein that is essential for initiating apoptosis in this setting.…”

Section: Discussionmentioning

confidence: 97%

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: 97%

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

et al. 2016

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“…The BH3-only protein PUMA is essential for p53-mediated apoptosis in thymocytes and its loss enhances myc-induced lymphomagenesis [48][49][50][51] . Counter-intuitively, loss of PUMA prevents rather than promotes thymic lymphoma following irradiation 52,53 . Similarly, in a carcinogen-induced liver cancer model, deletion of PUMA or overexpression of anti-apoptotic BCL-2 protein also delays tumour development 54,55 .…”

Section: Apoptosis Cell Competition and Cancermentioning

confidence: 99%

A fate worse than death: apoptosis as an oncogenic process

2016

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“…55 Remarkably, loss of PUMA completely abrogated γ-radiation-induced thymic lymphoma development. 111,112 This striking finding could be attributed to the profound resistance of PUMA-deficient white blood cells to DNA damage-induced apoptosis. The persistence of these cells obviated the need for mobilisation and burst of proliferation of haematopoietic stem/ progenitor cells that would normally occur to repopulate the depleted haematopoietic system, 111,112 a process that appears to be required for lymphoma development in this model.…”

Section: Mcl1mentioning

confidence: 99%

“…111,112 This striking finding could be attributed to the profound resistance of PUMA-deficient white blood cells to DNA damage-induced apoptosis. The persistence of these cells obviated the need for mobilisation and burst of proliferation of haematopoietic stem/ progenitor cells that would normally occur to repopulate the depleted haematopoietic system, 111,112 a process that appears to be required for lymphoma development in this model. 109 These observations suggest that accumulation of DNA lesions, some of them potentially oncogenic, is not sufficient to induce tumour formation unless it is also accompanied by a drive for proliferative expansion of the mutation bearing leukaemia/lymphoma-initiating cells.…”

Section: Mcl1mentioning

confidence: 99%

The BCL-2 protein family, BH3-mimetics and cancer therapy

2015

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Escape from apoptosis is a key attribute of tumour cells and facilitates chemo-resistance. The 'BCL-2-regulated' or 'intrinsic' apoptotic pathway integrates stress and survival signalling to govern whether a cancer cell will live or die. Indeed, many pro-apoptotic members of the BCL-2 family have demonstrated tumour-suppression activity in mouse models of cancer and are lost or repressed in certain human cancers. Conversely, overexpression of pro-survival BCL-2 family members promotes tumorigenesis in humans and in mouse models. Many of the drugs currently used in the clinic mediate their therapeutic effects (at least in part) through the activation of the BCL-2-regulated apoptotic pathway. However, initiators of this apoptotic pathway, such as p53, are mutated, lost or silenced in many human cancers rendering them refractory to treatment. To counter such resistance mechanisms, a novel class of therapeutics, 'BH3-mimetics', has been developed. These drugs directly activate apoptosis by binding and inhibiting select antiapoptotic BCL-2 family members and thereby bypass the requirement for upstream initiators, such as p53. In this review, we discuss the role of the BCL-2 protein family in the development and treatment of cancer, with an emphasis on mechanistic studies using well-established mouse models of cancer, before describing the development and already recognised potential of the BH3-mimetic compounds.

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Apoptosis of leukocytes triggered by acute DNA damage promotes lymphoma formation

Cited by 102 publications

References 28 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

The BCL-2 protein family, BH3-mimetics and cancer therapy

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