title: 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.
authors.affiliation: III. Medical Department of Hematology and Oncology, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Spinner
authors.affiliation: The Laboratory of Lymphocyte Signaling and Oncoproteome, Department I of Internal Medicine, Center for Integrated Oncology (CIO) Köln-Bonn, and CECAD, University of Cologne, Cologne, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Crispatzu
authors.affiliation: Dr Senckenberg Institute of Pathology, Goethe Universität, Frankfurt am Main, Germany.
authors.forename: J-H
authors.initials: JH
authors.lastname: Yi
authors.affiliation: III. Medical Department of Hematology and Oncology, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Munkhbaatar
authors.affiliation: The Laboratory of Lymphocyte Signaling and Oncoproteome, Department I of Internal Medicine, Center for Integrated Oncology (CIO) Köln-Bonn, and CECAD, University of Cologne, Cologne, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Mayer
authors.affiliation: III. Medical Department of Hematology and Oncology, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Höckendorf
authors.affiliation: III. Medical Department of Hematology and Oncology, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Müller
authors.affiliation: III. Medical Department of Hematology and Oncology, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany.
authors.forename: Z
authors.initials: Z
authors.lastname: Li
authors.affiliation: Dr Senckenberg Institute of Pathology, Goethe Universität, Frankfurt am Main, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Schader
authors.affiliation: III. Medical Department of Hematology and Oncology, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Bendz
authors.affiliation: Dr Senckenberg Institute of Pathology, Goethe Universität, Frankfurt am Main, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Hartmann
authors.affiliation: III. Medical Department of Hematology and Oncology, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Yabal
authors.affiliation: Institute for Clinical Chemistry and Pathobiochemistry, Technical University of Munich, Munich, Germany.|German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Pechloff
authors.affiliation: Institute for Virology, Technical University Munich/ Helmholtz Zentrum, Munich, Germany.|Division of Chronic Inflammation and Cancer, German Cancer Research Center Heidelberg (DKFZ), Heidelberg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Heikenwalder
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: G L
authors.initials: GL
authors.lastname: Kelly
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Strasser
authors.affiliation: III. Medical Department of Hematology and Oncology, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Peschel
authors.affiliation: Dr Senckenberg Institute of Pathology, Goethe Universität, Frankfurt am Main, Germany.
authors.forename: M-L
authors.initials: ML
authors.lastname: Hansmann
authors.affiliation: Institute for Clinical Chemistry and Pathobiochemistry, Technical University of Munich, Munich, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Ruland
authors.affiliation: III. Medical Department of Hematology and Oncology, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Keller
authors.affiliation: Dr Senckenberg Institute of Pathology, Goethe Universität, Frankfurt am Main, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Newrzela
authors.affiliation: The Laboratory of Lymphocyte Signaling and Oncoproteome, Department I of Internal Medicine, Center for Integrated Oncology (CIO) Köln-Bonn, and CECAD, University of Cologne, Cologne, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Herling
authors.affiliation: III. Medical Department of Hematology and Oncology, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany.|German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: P J
authors.initials: PJ
authors.lastname: Jost
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000032:analysis / Q000235:genetics*; D002470:Cell Survival; D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling; D006801:Humans; D016399:Lymphoma, T-Cell / Q000737:chemistry* / Q000473:pathology; D051379:Mice; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000032:analysis* / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2