Aberrant splicing of the tumor suppressor CYLD promotes the development of chronic lymphocytic leukemia via sustained NF-kappaB signaling.

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.