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Leukemia. 2016 Jul;30(7):1520-30. doi: 10.1038/leu.2016.49. Epub 2016 Mar 8.

Re-activation of mitochondrial apoptosis inhibits T-cell lymphoma survival and treatment resistance.

Author information

1
III. Medical Department of Hematology and Oncology, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany.
2
The Laboratory of Lymphocyte Signaling and Oncoproteome, Department I of Internal Medicine, Center for Integrated Oncology (CIO) Köln-Bonn, and CECAD, University of Cologne, Cologne, Germany.
3
Dr Senckenberg Institute of Pathology, Goethe Universität, Frankfurt am Main, Germany.
4
Institute for Clinical Chemistry and Pathobiochemistry, Technical University of Munich, Munich, Germany.
5
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
6
Institute for Virology, Technical University Munich/ Helmholtz Zentrum, Munich, Germany.
7
Division of Chronic Inflammation and Cancer, German Cancer Research Center Heidelberg (DKFZ), Heidelberg, Germany.
8
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
9
Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.

Abstract

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.

PMID:
27055871
DOI:
10.1038/leu.2016.49
[Indexed for MEDLINE]

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