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

S. Spinner, G. Crispatzu, J. H. Yi, E. Munkhbaatar, P. Mayer, U. Höckendorf, N. Müller, Z. Li, T. Schader, H. Bendz, S. Hartmann, M. Yabal, K. Pechloff, M. Heikenwalder, G. L. Kelly, A. Strasser, C. Peschel, M. L. Hansmann, J. Ruland, U. KellerS. Newrzela, M. Herling, P. J. Jost

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

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.

Original languageEnglish
Pages (from-to)1520-1530
Number of pages11
JournalLeukemia
Volume30
Issue number7
DOIs
StatePublished - 1 Jul 2016
Externally publishedYes

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