Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
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Spinner, S; Crispatzu, G; Yi, JH; Munkhbaatar, E; Mayer, P; Höckendorf, U; Müller, N; Li, Z; Schader, T; Bendz, H; Hartmann, S; Yabal, M; Pechloff, K; Heikenwalder, M; Kelly, GL; Strasser, A; Peschel, C; Hansmann, ML; Ruland, J; Keller, U; Newrzela, S; Herling, M; Jost, PJ.
Re-activation of mitochondrial apoptosis inhibits T-cell lymphoma survival and treatment resistance.
Leukemia. 2016; 30(7):1520-1530
Doi: 10.1038/leu.2016.49
Web of Science
PubMed
FullText
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- Führende Autor*innen der Med Uni Graz
- Jost Philipp
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- 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.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals -
- Apoptosis -
- Apoptosis Regulatory Proteins - analysis
- Apoptosis Regulatory Proteins - genetics
- Cell Survival -
- Drug Resistance, Neoplasm -
- Gene Expression Profiling -
- Humans -
- Lymphoma, T-Cell - chemistry
- Lymphoma, T-Cell - pathology
- Mice -
- Myeloid Cell Leukemia Sequence 1 Protein - analysis
- Myeloid Cell Leukemia Sequence 1 Protein - antagonists & inhibitors
- Myeloid Cell Leukemia Sequence 1 Protein - genetics
- Myeloid Cell Leukemia Sequence 1 Protein - physiology
- Proto-Oncogene Proteins c-bcl-2 - genetics