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1.
Blood ; 137(5): 646-660, 2021 02 04.
Artículo en Inglés | MEDLINE | ID: mdl-33538798

RESUMEN

Richter's transformation (RT) is an aggressive lymphoma that occurs upon progression from chronic lymphocytic leukemia (CLL). Transformation has been associated with genetic aberrations in the CLL phase involving TP53, CDKN2A, MYC, and NOTCH1; however, a significant proportion of RT cases lack CLL phase-associated events. Here, we report that high levels of AKT phosphorylation occur both in high-risk CLL patients harboring TP53 and NOTCH1 mutations as well as in patients with RT. Genetic overactivation of Akt in the murine Eµ-TCL1 CLL mouse model resulted in CLL transformation to RT with significantly reduced survival and an aggressive lymphoma phenotype. In the absence of recurrent mutations, we identified a profile of genomic aberrations intermediate between CLL and diffuse large B-cell lymphoma. Multiomics assessment by phosphoproteomic/proteomic and single-cell transcriptomic profiles of this Akt-induced murine RT revealed an S100 protein-defined subcluster of highly aggressive lymphoma cells that developed from CLL cells, through activation of Notch via Notch ligand expressed by T cells. Constitutively active Notch1 similarly induced RT of murine CLL. We identify Akt activation as an initiator of CLL transformation toward aggressive lymphoma by inducing Notch signaling between RT cells and microenvironmental T cells.


Asunto(s)
Leucemia Linfocítica Crónica de Células B/patología , Linfoma de Células B Grandes Difuso/patología , Proteínas de Neoplasias/fisiología , Proteínas Proto-Oncogénicas c-akt/fisiología , Receptor Notch1/fisiología , Animales , Evolución Clonal , Progresión de la Enfermedad , Activación Enzimática , Regulación Neoplásica de la Expresión Génica , Genes p53 , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/fisiopatología , Linfocitos Infiltrantes de Tumor/inmunología , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/fisiopatología , Ratones , Ratones Endogámicos C57BL , Fenotipo , Fosfoproteínas/fisiología , Proteínas Proto-Oncogénicas c-akt/genética , Receptores de Antígenos de Linfocitos B/inmunología , Transducción de Señal/fisiología , Transcriptoma , Microambiente Tumoral , Proteína p53 Supresora de Tumor/fisiología , Regulación hacia Arriba
2.
Nat Commun ; 14(1): 7824, 2023 Nov 29.
Artículo en Inglés | MEDLINE | ID: mdl-38016943

RESUMEN

Dysregulation of hypothalamic ceramides has been associated with disrupted neuronal pathways in control of energy and glucose homeostasis. However, the specific ceramide species promoting neuronal lipotoxicity in obesity have remained obscure. Here, we find increased expression of the C16:0 ceramide-producing ceramide synthase (CerS)6 in cultured hypothalamic neurons exposed to palmitate in vitro and in the hypothalamus of obese mice. Conditional deletion of CerS6 in hypothalamic neurons attenuates high-fat diet (HFD)-dependent weight gain and improves glucose metabolism. Specifically, CerS6 deficiency in neurons expressing pro-opiomelanocortin (POMC) or steroidogenic factor 1 (SF-1) alters feeding behavior and alleviates the adverse metabolic effects of HFD feeding on insulin sensitivity and glucose tolerance. POMC-expressing cell-selective deletion of CerS6 prevents the diet-induced alterations of mitochondrial morphology and improves cellular leptin sensitivity. Our experiments reveal functions of CerS6-derived ceramides in hypothalamic lipotoxicity, altered mitochondrial dynamics, and ER/mitochondrial stress in the deregulation of food intake and glucose metabolism in obesity.


Asunto(s)
Obesidad , Proopiomelanocortina , Animales , Ratones , Ceramidas/metabolismo , Dieta Alta en Grasa/efectos adversos , Glucosa/metabolismo , Homeostasis , Hipotálamo/metabolismo , Ratones Obesos , Neuronas/metabolismo , Obesidad/metabolismo , Proopiomelanocortina/metabolismo
3.
Cell Rep ; 42(4): 112378, 2023 04 25.
Artículo en Inglés | MEDLINE | ID: mdl-37060566

RESUMEN

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+CD27+ B cells, proposed as an MZ B cell equivalent, display higher AKT signaling than naive IgD+CD27- and memory IgD-CD27+ 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.


Asunto(s)
Linfocitos B , Proteínas Proto-Oncogénicas c-akt , Humanos , Ratones , Animales , Tejido Linfoide , Transducción de Señal , Bazo
4.
Diabetes ; 67(12): 2695-2702, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30257974

RESUMEN

Hepatic and myocardial ectopic lipid deposition has been associated with insulin resistance (IR) and cardiovascular risk. Lipid overload promotes increased hepatic oxidative capacity, oxidative stress, and impaired mitochondrial efficiency, driving the progression of nonalcoholic fatty liver disease (NAFLD). We hypothesized that higher lipid availability promotes ischemia-induced cardiac dysfunction and decreases myocardial mitochondrial efficiency. Mice with adipose tissue-specific overexpression of sterol element-binding protein 1c as model of lipid overload with combined NAFLD-IR and controls underwent reperfused acute myocardial infarcts (AMIs). Whereas indexes of left ventricle (LV) contraction were similar in both groups at baseline, NAFLD-IR showed severe myocardial dysfunction post-AMI, with prominent LV reshaping and increased end-diastolic and end-systolic volumes. Hearts of NAFLD-IR displayed hypertrophy, steatosis, and IR due to 18:1/18:1-diacylglycerol-mediated protein kinase Cε (PKCε) activation. Myocardial fatty acid-linked respiration and oxidative stress were increased, whereas mitochondrial efficiency was decreased. In humans, decreased myocardial mitochondrial efficiency of ventricle biopsies related to IR and troponin levels, a marker of impaired myocardial integrity. Taken together, increased lipid availability and IR favor susceptibility to ischemia-induced cardiac dysfunction. The diacylglycerol-PKCε pathway and reduced mitochondrial efficiency both caused by myocardial lipotoxicity may contribute to the impaired LV compensation of the noninfarcted region of the myocardium.


Asunto(s)
Resistencia a la Insulina/fisiología , Infarto del Miocardio/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Estrés Oxidativo/fisiología , Animales , Modelos Animales de Enfermedad , Humanos , Ratones , Mitocondrias Cardíacas/metabolismo , Infarto del Miocardio/complicaciones , Miocardio/metabolismo , Enfermedad del Hígado Graso no Alcohólico/complicaciones
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