Reference : Aberrant splicing of the tumor suppressor CYLD promotes the development of chronic ly...
Scientific journals : Article
Life sciences : Genetics & genetic processes
Aberrant splicing of the tumor suppressor CYLD promotes the development of chronic lymphocytic leukemia via sustained NF-kappaB signaling.
Hahn, M. [> >]
Burckert, J.-P. [> >]
Luttenberger, C. A. [> >]
Klebow, S. [> >]
Hess, M. [> >]
Al-Maarri, M. [> >]
Vogt, M. [> >]
Reissig, S. [> >]
Hallek, M. [> >]
Wienecke-Baldacchino, Anke mailto [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit]
Buch, T. [> >]
Muller, Claire mailto [University of Luxembourg > Faculty of Language and Literature, Humanities, Arts and Education (FLSHASE) > Luxembourg Centre for Educational Testing (LUCET)]
Pallasch, C. P. [> >]
Wunderlich, F. T. [> >]
Waisman, A. [> >]
Hovelmeyer, N. [> >]
Yes (verified by ORBilu)
[en] The pathogenesis of chronic lymphocytic leukemia (CLL) has been linked to constitutive NF-kappaB activation but the underlying mechanisms are poorly understood. Here we show that alternative splicing of the negative regulator of NF-kappaB and tumor suppressor gene CYLD regulates the pool of CD5(+) B cells through sustained canonical NF-kappaB signaling. Reinforced canonical NF-kappaB 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-kappaB activation in CLL. Thus, inhibition of alternative splicing of this negative regulator is essential for preventing NF-kappaB-driven clonal CD5(+) B-cell expansion and ultimately CLL-like disease.

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