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Re-activation of mitochondrial apoptosis inhibits T-cell lymphoma survival and treatment resistance.
Leukemia 30, 1520-1530 (2016)
DOI Verlagsversion bestellen
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Bcl-2 Family Proteins; Gene-expression; Therapeutic Targets; Antiapoptotic Mcl-1; Thymic Lymphoma; Transgenic Mice; Lymphocytes; Leukemia; Deletion; Memory
ISSN (print) / ISBN 0887-6924
Quellenangaben Band: 30, Heft: 7, Seiten: 1520-1530
Verlag Nature Publishing Group
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Virology (VIRO)