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

Abstract

The pathogenesis of chronic lymphocytic leukemia (CLL) has been linked to constitutive NF-κB activation but the underlying mechanisms are poorly understood. Here we show that alternative splicing of the negative regulator of NF-κB and tumor suppressor gene CYLD regulates the pool of CD5 B cells through sustained canonical NF-κB signaling. Reinforced canonical NF-κB 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-κB activation in CLL. Thus, inhibition of alternative splicing of this negative regulator is essential for preventing NF-κB-driven clonal CD5 B-cell expansion and ultimately CLL-like disease.

Epigenetic modifiers DNMT3A and BCOR are recurrently mutated in CYLD cutaneous syndrome

“…In humans, recurrent loss of functional CYLD is reported in diverse cancers, including myeloma 22 , leukemia 23,24 , hepatocellular carcinoma 25 , neuroblastoma 26 , and pancreatic cancer 27 , consistent with its role as a tumor suppressor expressed ubiquitously in normal tissues. In CCS patients, increased Wnt signalling has been shown to be an oncogenic dependency in cylindroma and spiradenoma tumors 7 .…”

Alternative Splice Forms of CYLD Mediate Ubiquitination of SMAD7 to Prevent TGFB Signaling and Promote Colitis

“…7 Furthermore, we and others have found that the naturally occurring short splice form of CYLD (sCYLD), lacking exons 7 and 8 coding for the binding sites of TRAF2 and NEMO, 8 plays a crucial role in regulating nuclear factor-kB signaling and controlling immune responses in T and B cells, dendritic cells, medullary thymic epithelial cells, and hepatocytes. [8][9][10][11][12][13] TGFB is a pleiotropic cytokine that regulates different cellular responses such as cell proliferation, differentiation, growth, and tumorigenesis. 14 TGFB signals through the SMAD proteins, following the serine-threonine kinase activity of its receptor, consisting of TGFB receptor types I and II.…”

NF-κB and Human Cancer: What Have We Learned over the Past 35 Years?

“…Mutations in promoter sequences that affect NFKB1 expression or NF-κB-dependent expression of target genes have been described in oral, bladder, and breast cancer [ 59 , 60 , 61 ]. Furthermore, aberrant alternative splicing of the NF-κB inhibitor CYLD may lead to chronic activaiton of NF-κB in some cases of chronic lymphocytic leukemia [ 62 ].…”