期刊
LEUKEMIA
卷 30, 期 7, 页码 1520-1530出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2016.49
关键词
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资金
- DFG [FOR2036, FOR1961 (HE3553/4-1), FOR1961 (NE1438/4-1)]
- Max Eder-Program grants from the Deutsche Krebshilfe [109310, 111738, 108029]
- Human Frontiers Science Program grant [RGY0073/ 2012]
- German Jose Carreras Leukemia Foundation grant [DJCLS R 12/22]
- Else Korner Fresenius-Stiftung [2014-A185]
- NHMRC
- Redstone Foundation Trust
- LLS
- ERC starting grant (LiverCancerMechanisms)
- Stiftung Experimentelle Biomedizin
- Cancer Council of Victoria
- Helmholtz-Zentrum
T lymphocyte non-Hodgkin's lymphoma (T-NHL) represents an aggressive and largely therapy-resistant subtype of lymphoid malignancies. As deregulated apoptosis is a frequent hallmark of lymphomagenesis, we analyzed gene expression profiles and protein levels of primary human T-NHL samples for various apoptotic regulators. We identified the apoptotic regulator MCL-1 as the only pro-survival BCL-2 family member to be highly expressed throughout all human T-NHL subtypes. Functional validation of pro-survival protein members of the BCL-2 family in two independent T-NHL mouse models identified that the partial loss of Mcl-1 significantly delayed T-NHL development in vivo. Moreover, the inducible reduction of MCL-1 protein levels in lymphoma-burdened mice severely impaired the continued survival of T-NHL cells, increased their susceptibility to chemotherapeutics and delayed lymphoma progression. Lymphoma viability remained unaffected by the genetic deletion or pharmacological inhibition of all alternative BCL-2 family members. Consistent with a therapeutic window for MCL-1 treatment within the context of the whole organism, we observed an only minimal toxicity after systemic heterozygous loss of Mcl-1 in vivo. We conclude that re-activation of mitochondrial apoptosis by blockade of MCL-1 represents a promising therapeutic strategy to treat T-cell lymphoma.
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