Lymphoma

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

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.

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Acknowledgements

We thank Stephanie Rott and Smaro Beskeli for excellent technical assistance. PJJ was supported by the DFG Research Unit FOR2036, Max Eder-Program grants from the Deutsche Krebshilfe (program nos. 109310 and 111738), a Human Frontiers Science Program grant (program no. RGY0073/ 2012), the German Jose Carreras Leukemia Foundation grant (DJCLS R 12/22) and a grant from the Else Kröner Fresenius-Stiftung (2014-A185). MH (Cologne) was supported by the DFG Research Unit 'CONTROL-T' FOR1961 (HE3553/4-1) and Max Eder-Program grants from the Deutsche Krebshilfe (program no. 108029). SN was supported by the DFG Research Unit 'CONTROL-T' FOR1961 (NE1438/4-1). GLK and AS were supported by fellowships and grants from the NHMRC and the Redstone Foundation Trust; AS by LLS and Cancer Council of Victoria. MH (Munich) was supported by an ERC starting grant (LiverCancerMechanisms), the Stiftung Experimentelle Biomedizin and the Helmholtz-Zentrum.

Author contributions

Sabine Spinner performed experiments and wrote the manuscript. Ji-Hee Yi, Tim Schrader, Henriette Bendz, Petra Mayer, Ulrike Höckendorf, Nicole Müller and Monica Yabal performed experiments. Gemma L Kelly and Andreas Strasser generated the CreERT2 Mcl-1fl/+ and CreERT2 Mcl-1+/+ lymphoma cells. Enkhtsetseg Munkhbaatar performed histological analysis of murine T-NHL samples. Giuliano Crispatzu and Marco Herling integrated and summarized the mRNA expression data on human T-NHL samples. Sylvia Hartman and Martin-Leo Hansmann provided and stained histological sections of human PTCL, ALCL and AITL samples. Zoulei Lei evaluated PET-CT results on mice transplanted with T-NHL cells. Konstanze Pechloff and Jürgen Ruland generated ITK-SYK CD4Cre mice and provided critical reagents. Mathias Heikenwälder and Sebastian Newrzela provided critical reagents and advice. Christian Peschel, Andreas Strasser, Marco Herling, Ulrich Keller and Jürgen Ruland supported the project by critical discussion. Philipp J Jost designed and supervised the project and wrote the manuscript.

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Correspondence to P J Jost.

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Competing interests

GLK and AS work at the Walter and Eliza Hall Institute. This Institute receives milestone payments from Genentech Inc. and AbbVie for the development of BH3 mimetic drugs for cancer therapy. All the other authors declare no conflict of interest.

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Spinner, S., Crispatzu, G., Yi, J. et al. Re-activation of mitochondrial apoptosis inhibits T-cell lymphoma survival and treatment resistance. Leukemia 30, 1520–1530 (2016). https://doi.org/10.1038/leu.2016.49

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