Targeting of MCL-1 kills MYC-driven mouse and human lymphomas even when they bear mutations in <i>p53</i>

Kelly, Gemma L.; Grabow, Stephanie; Glaser, Stefan; Fitzsimmons, Leah; Aubrey, Brandon J.; Okamoto, Tomoyoshi; Valente, Liz J.; Robati, Mikara; Tai, Lin; Fairlie, W. Douglas; Lee, Erinna F.; Lindström, Mikael S.; Wiman, Klas G.; Huang, David C.S.; Bouillet, Philippe; Rowe, Martin; Rickinson, Alan B.; Herold, Marco J.; Strasser, Andreas

doi:10.1101/gad.232009.113

Cited by 159 publications

(142 citation statements)

References 59 publications

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“…Mouse models have proven invaluable in helping define the role of apoptosis in tumour suppression, anti-cancer therapy and as a bone fide therapeutic target 19,20,[109][110][111] . Investigating the pro-oncogenic potential of apoptosis, we propose that mouse models should be extended to address the following interrelated questions: 1) can apoptosis exert a prooncogenic function during tumourigenesis ?…”

Section: Modeling Oncogenic Effects Of Apoptosismentioning

confidence: 99%

A fate worse than death: apoptosis as an oncogenic process

2016

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Section: Modeling Oncogenic Effects Of Apoptosismentioning

confidence: 99%

A fate worse than death: apoptosis as an oncogenic process

2016

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“…96 Interestingly, although BCL-XL is critical for the development of pre-B/B lymphoma in Eμ-Myc mice, it is dispensable for the sustained survival and expansion of these tumours. 97 Instead, MCL-1 is essential, with loss of even a single allele of Mcl-1 abrogating the in vivo growth of malignant Eμ-Myc lymphomas, unless they have acquired a mutation in the tumour-suppressor gene p53. 97 p53-deficient mice, a model of Li-Fraumeni syndrome.…”

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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“…Consequent studies demonstrated that c-MYC synergizes with any of the anti-apoptotic BCL-2 proteins in transforming leukocytes in overexpression models in vivo, 49 whereas the dependence appears more selective at the level of endogenous pro-survival proteins. 50 Consistently, the loss of various pro-apoptotic BH3-only proteins results in acceleration of c-MYC-driven lymphomagenesis. [51][52][53] Similar synergies between c-MYC and anti-apoptotic BCL-2 proteins have been observed in other tissues such as the pancreas or the mammary gland.…”

Section: The Apoptosis Paradox In Tumor Developmentmentioning

confidence: 53%

How cell death shapes cancer

Erlacher

2015

Klin Padiatr

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Apoptosis has been established as a mechanism of anti-cancer defense. Members of the BCL-2 family are critical mediators of apoptotic cell death in health and disease, often found to be deregulated in cancer and believed to lead to the survival of malignant clones. However, over the years, a number of studies pointed out that a model in which cell death resistance unambiguously acts as a barrier against malignant disease might be too simple. This is based on paradoxical observations made in tumor patients as well as mouse models indicating that apoptosis can indeed drive tumor formation, at least under certain circumstances. One possible explanation for this phenomenon is that apoptosis can promote proliferation critically needed to compensate for cell loss, for example, upon therapy, and to restore tissue homeostasis. However, this, at the same time, can promote tumor development by allowing expansion of selected clones. Usually, tissue resident stem/progenitor cells are a major source for repopulation, some of them potentially carrying (age-, injury-or therapy-induced) genetic aberrations deleterious for the host. Thereby, apoptosis might drive genomic instability by facilitating the emergence of pathologic clones during phases of proliferation and subsequent replication stress-associated DNA damage. Tumorigenesis initiated by repeated cell attrition and repopulation, as confirmed in different genetic models, has parallels in human cancers, exemplified in therapy-induced secondary malignancies and myelodysplastic syndromes in patients with congenital bone marrow failure syndromes. Here, we aim to review evidence in support of the oncogenic role of stress-induced apoptosis.

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Targeting of MCL-1 kills MYC-driven mouse and human lymphomas even when they bear mutations in p53

Cited by 159 publications

References 59 publications

A fate worse than death: apoptosis as an oncogenic process

A fate worse than death: apoptosis as an oncogenic process

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

How cell death shapes cancer

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