PuSH - Publication Server of Helmholtz Zentrum München

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

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

Leukemia 30, 1520-1530 (2016)
Publ. Version/Full Text DOI PMC
Free by publisher
Open Access Green as soon as Postprint is submitted to ZB.
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.
Altmetric
Additional Metrics?
[➜Log in]
Edit extra informations Login
Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Bcl-2 Family Proteins; Gene-expression; Therapeutic Targets; Antiapoptotic Mcl-1; Thymic Lymphoma; Transgenic Mice; Lymphocytes; Leukemia; Deletion; Memory
ISSN (print) / ISBN 0887-6924
e-ISSN 1476-5551
Journal Leukemia
Quellenangaben Volume: 30, Issue: 7, Pages: 1520-1530 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Virology (VIRO)