[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.
Disciplines :
Genetics & genetic processes
Author, co-author :
Hahn, M.
Burckert, J.-P.
Luttenberger, C. A.
Klebow, S.
Hess, M.
Al-Maarri, M.
Vogt, M.
Reissig, S.
Hallek, M.
Wienecke-Baldacchino, Anke ; University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
Buch, T.
Muller, Claire ; University of Luxembourg > Faculty of Language and Literature, Humanities, Arts and Education (FLSHASE) > Luxembourg Centre for Educational Testing (LUCET)