Universität zu Köln

Spinner, S., Crispatzu, G., Yi, J-H, Munkhbaatar, E., Mayer, P., Hoeckendorf, U., Mueller, N., Li, Z., Schader, T., Bendz, H., Hartmann, S., Yabal, M., Pechloff, K., Heikenwalder, M., Kelly, G. L., Strasser, A., Peschel, C., Hansmann, M-L, Ruland, J., Keller, U., Newrzela, S., Herling, M. and Jost, P. J. (2016). Re-activation of mitochondrial apoptosis inhibits T-cell lymphoma survival and treatment resistance. Leukemia, 30 (7). S. 1520 - 1531. LONDON: NATURE PUBLISHING GROUP. ISSN 1476-5551

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Spinner, S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Crispatzu, G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Yi, J-H UNSPECIFIED UNSPECIFIED UNSPECIFIED Munkhbaatar, E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Mayer, P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoeckendorf, U. UNSPECIFIED UNSPECIFIED UNSPECIFIED Mueller, N. UNSPECIFIED UNSPECIFIED UNSPECIFIED Li, Z. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schader, T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Bendz, H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hartmann, S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Yabal, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Pechloff, K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Heikenwalder, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kelly, G. L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Strasser, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Peschel, C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hansmann, M-L UNSPECIFIED UNSPECIFIED UNSPECIFIED Ruland, J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Keller, U. UNSPECIFIED UNSPECIFIED UNSPECIFIED Newrzela, S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Herling, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Jost, P. J. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-271652
DOI:	10.1038/leu.2016.49
Journal or Publication Title:	Leukemia
Volume:	30
Number:	7
Page Range:	S. 1520 - 1531
Date:	2016
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	1476-5551
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language BCL-2 FAMILY PROTEINS; THYMIC LYMPHOMA; MCL-1; EXPRESSION; GENE; DELETION; GROWTH; MOUSE; MYC; PROGNOSTICATION Multiple languages Oncology; Hematology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/27165