36 research outputs found
B cell-specific conditional expression of Myd88(p.L252P) leads to the development of diffuse large B cell lymphoma in mice
The adaptor protein MYD88 is critical to relay activation of Toll-like receptor signaling to NF-{kappa}B activation.MYD88 mutations, particularly the p.L265P mutation, have been described in numerous distinct B cell malignancies, including diffuse large B cell lymphoma (DLBCL). 29% of activated B cell (ABC)-type DLBCL, which is characterized by constitutive activation of the NF-{kappa}B pathway, carry the p.L265P mutation. In addition, ABC-DLBCL frequently displays focal copy number gains affecting BCL2. Here, we generated a novel mouse model, in which Cre-mediated recombination, specifically in B cells, leads to the conditional expression of Myd88(p.L252P)(the orthologous position of the human MYD88(p.L265P) mutation) from the endogenous locus. These animals develop a lympho-proliferative disease, and occasional transformation into clonal lymphomas. The clonal disease displays morphological and immunophenotypical characteristics of ABC-DLBCL. Lymphomagenesis can be accelerated by crossing in a further novel allele, which mediates conditional overexpression ofBCL2 Cross-validation experiments in human DLBCL samples revealed that bothMYD88andCD79Bmutations are substantially enriched in ABC-DLBCL, compared to germinal center B cell DLBCL. Furthermore, analyses of human DLBCL genome sequencing data confirmed that BCL2 amplifications frequently co-occur with MYD88 mutations, further validating our approach. Lastly,in silicoexperiments revealed that particularly MYD88-mutant ABC-DLBCL cells display an actionable addiction to BCL2. Altogether, we generated a novel autochthonous mouse model of ABC-DLBCL, which could be used as a preclinical platform for the development and validation of novel therapeutic approaches for the treatment of ABC-DLBCL
AKT activity orchestrates marginal zone B cell development in mice and humans.
The signals controlling marginal zone (MZ) and follicular (FO) B cell development remain incompletely understood. Here, we show that AKT orchestrates MZ B cell formation in mice and humans. Genetic models that increase AKT signaling in B cells or abolish its impact on FoxO transcription factors highlight the AKT-FoxO axis as an on-off switch for MZ B cell formation in mice. In humans, splenic immunoglobulin (Ig) D <sup>+</sup> CD27 <sup>+</sup> B cells, proposed as an MZ B cell equivalent, display higher AKT signaling than naive IgD <sup>+</sup> CD27 <sup>-</sup> and memory IgD <sup>-</sup> CD27 <sup>+</sup> B cells and develop in an AKT-dependent manner from their precursors in vitro, underlining the conservation of this developmental pathway. Consistently, CD148 is identified as a receptor indicative of the level of AKT signaling in B cells, expressed at a higher level in MZ B cells than FO B cells in mice as well as humans
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
Global DNA methylation levels are altered by modifiable clinical manipulations in assisted reproductive technologies
AKT ACTIVATION IN CHRONIC LYMPHOCYTIC LEUKEMIA CELLS PROMOTES TRANSFORMATION TOWARDS AGGRESSIVE RICHTER'S SYNDROME LYMPHOMA
AKT activation in Chronic Lymphocytic Leukemia cells promotes transformation towards aggressive Richter's syndrome lymphoma
Temporal and tissue-specific requirements for T-lymphocyte IL-6 signalling in obesity-associated inflammation and insulin resistance
Low-grade inflammation links obesity to insulin resistance through the activation of tissue-infiltrating immune cells. Interleukin-6 (IL-6) is a crucial regulator of T cells and is increased in obesity. Here we report that classical IL-6 signalling in T cells promotes inflammation and insulin resistance during the first 8 weeks on a high-fat diet (HFD), but becomes dispensable at later stages (after 16 weeks). Mice with T cell-specific deficiency of IL-6 receptor-alpha (IL-6R alpha(T-KO)) exposed to a HFD display improved glucose tolerance, insulin sensitivity and inflammation in liver and EWATafter 8 weeks. However, after 16 weeks, insulin resistance in IL-6R alpha(T-KO) epididymal white adipose tissue (EWAT) is comparable to that of controls, whereas the inflammatory profile is significantly worse. This coincided with a shift from classical T cell IL-6 signalling at 8 weeks, to enhanced IL-6 trans-signalling at 16 weeks. Collectively, our studies reveal that IL-6 action in T cells through classical IL-6 signalling promotes inflammation and insulin resistance early during obesity development, which can be compensated for by enhanced IL-6 trans-signalling at later stages
Aberrant splicing of the tumor suppressor CYLD promotes the development of chronic lymphocytic leukemia via sustained NF-kappa B signaling
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
Activated gp130 signaling selectively targets B cell differentiation to induce mature lymphoma and plasmacytoma
Aberrant splicing of the tumor suppressor CYLD promotes the development of chronic lymphocytic leukemia via sustained NF-κB signaling
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