Universität zu Köln

Hahn, M., Buerckert, J-P, Luttenberger, C. A., Klebow, S., Hess, M., Al-Maarri, M., Vogt, M., Reissig, S., Hallek, M., Wienecke-Baldacchino, A., Buch, T., Muller, C. P., Pallasch, C. P., Wunderlich, F. T., Waisman, A. and Hoevelmeyer, N. (2018). Aberrant splicing of the tumor suppressor CYLD promotes the development of chronic lymphocytic leukemia via sustained NF-kappa B signaling. Leukemia, 32 (1). S. 72 - 83. LONDON: NATURE PUBLISHING GROUP. ISSN 1476-5551

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Abstract

The pathogenesis of chronic lymphocytic leukemia (CLL) has been linked to constitutive NF-kappa B activation but the underlying mechanisms are poorly understood. Here we show that alternative splicing of the negative regulator of NF-kappa B and tumor suppressor gene CYLD regulates the pool of CD5(+) B cells through sustained canonical NF-kappa B signaling. Reinforced canonical NF-kappa B activity leads to the development of B1 cell-associated tumor formation in aging mice by promoting survival and proliferation of CD5(+) B cells, highly reminiscent of human B-CLL. We show that a substantial number of CLL patient samples express sCYLD, strongly implicating a role for it in human B-CLL. We propose that our new CLL-like mouse model represents an appropriate tool for studying ubiquitination-driven canonical NF-kappa B activation in CLL. Thus, inhibition of alternative splicing of this negative regulator is essential for preventing NF-kappa B-driven clonal CD5(+) B-cell expansion and ultimately CLL-like disease.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Hahn, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Buerckert, J-P UNSPECIFIED UNSPECIFIED UNSPECIFIED Luttenberger, C. A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Klebow, S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hess, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Al-Maarri, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Vogt, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Reissig, S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hallek, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wienecke-Baldacchino, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Buch, T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Muller, C. P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Pallasch, C. P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wunderlich, F. T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Waisman, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoevelmeyer, N. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-204697
DOI:	10.1038/leu.2017.168
Journal or Publication Title:	Leukemia
Volume:	32
Number:	1
Page Range:	S. 72 - 83
Date:	2018
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	1476-5551
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CELL RECEPTOR; ACTIVATION; SURVIVAL; GENE; EXPRESSION; APOPTOSIS; UBIQUITIN; PATHWAY; RELB; A20 Multiple languages Oncology; Hematology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/20469