Re-activation of mitochondrial apoptosis inhibits T-cell lymphoma survival and treatment resistance
- Author(s)
- Spinner, S; Crispatzu, G; Yi, JH; Munkhbaatar, E; MAYER, P; Hockendorf, U; Muller, 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;
- Journal Title
- Leukemia
- Publication Type
- Journal Article in press
- 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.Leukemia advance online publication, 8 April 2016; doi:10.1038/leu.2016.49.
- Publisher
- NPG
- Research Division(s)
- Molecular Genetics Of Cancer
- PubMed ID
- 27055871
- Publisher's Version
- https://doi.org/10.1038/leu.2016.49
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2016-04-28 02:06:58
Last Modified: 2016-05-02 08:40:33