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Myeloproliferative neoplasms represent a group of clonal hematopoietic disorders of which myelofibrosis (MF) is the most aggressive. In the context of myeloid neoplasms, there is a growing recognition of the dysregulation of immune response and T-cell function as significant contributors to disease progression and immune evasion. We investigated cytotoxic T-cell exhaustion in MF to restore immune response against malignant cells. Increased expression of inhibitory receptors like CTLA-4 was observed on cytotoxic T cells from MF patients together with a reduced secretion of IFNÉ£ and TNFÉ. CTLA-4 ligands CD80 and CD86 were increased on MF granulocytes and monocytes highlighting a possible role for myeloid cells in suppressing T-cell activation in MF patients. Unlike healthy donors, the activation of cytotoxic T cells from MF patients was attenuated in the presence of myeloid cells and restored when T cells were cultured alone or treated with anti-CTLA-4. Moreover, anti-CTLA-4 treatment promoted elimination of neoplastic monocytes and granulocytes in a co-culture system with cytotoxic T cells. To test CTLA-4 inhibition in vivo, patient-derived xenografts were generated by transplanting MF CD34+ cells and by infusing homologous T cells in NSGS mice. CTLA-4 blockade reduced human myeloid chimerism and led to T-cell expansion in spleen and bone marrow. Overall, these findings shed light on T-cell dysfunction in MF and suggest that CTLA-4 blockade can boost the cytotoxic T cell-mediated immune response against tumor cells.
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Identification and characterisation of novel targets for treatment is a priority in the field of psychiatry. FKBP5 is a gene with decades of evidence suggesting its pathogenic role in a subset of psychiatric patients, with potential to be leveraged as a therapeutic target for these individuals. While it is widely reported that FKBP5/FKBP51 mRNA/protein (FKBP5/1) expression is impacted by psychiatric disease state, risk genotype and age, it is not known in which cell types and sub-anatomical areas of the human brain this occurs. This knowledge is critical to propel FKBP5/1-targeted treatment development. Here, we performed an extensive, large-scale postmortem study (n = 1024) of FKBP5/1, examining neocortical areas (BA9, BA11 and ventral BA24/BA24a) derived from subjects that lived with schizophrenia, major depression or bipolar disorder. With an extensive battery of RNA (bulk RNA sequencing, single-nucleus RNA sequencing, microarray, qPCR, RNAscope) and protein (immunoblot, immunohistochemistry) analysis approaches, we thoroughly investigated the effects of disease state, ageing and genotype on cortical FKBP5/1 expression including in a cell type-specific manner. We identified consistently heightened FKBP5/1 levels in psychopathology and with age, but not genotype, with these effects strongest in schizophrenia. Using single-nucleus RNA sequencing (snRNAseq; BA9 and BA11) and targeted histology (BA9, BA24a), we established that these disease and ageing effects on FKBP5/1 expression were most pronounced in excitatory superficial layer neurons of the neocortex, and this effect appeared to be consistent in both the granular and agranular areas examined. We then found that this increase in FKBP5 levels may impact on synaptic plasticity, as FKBP5 gex levels strongly and inversely correlated with dendritic mushroom spine density and brain-derived neurotrophic factor (BDNF) levels in superficial layer neurons in BA11. These findings pinpoint a novel cellular and molecular mechanism that has potential to open a new avenue of FKBP51 drug development to treat cognitive symptoms in psychiatric disorders.
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Trastornos Mentales , Neocórtex , Humanos , Trastornos Mentales/genética , Envejecimiento/genética , Neuronas , Genotipo , Polimorfismo de Nucleótido SimpleRESUMEN
Aging and psychosocial stress are associated with increased inflammation and disease risk, but the underlying molecular mechanisms are unclear. Because both aging and stress are also associated with lasting epigenetic changes, a plausible hypothesis is that stress along the lifespan could confer disease risk through epigenetic effects on molecules involved in inflammatory processes. Here, by combining large-scale analyses in human cohorts with experiments in cells, we report that FKBP5, a protein implicated in stress physiology, contributes to these relations. Across independent human cohorts (total n > 3,000), aging synergized with stress-related phenotypes, measured with childhood trauma and major depression questionnaires, to epigenetically up-regulate FKBP5 expression. These age/stress-related epigenetic effects were recapitulated in a cellular model of replicative senescence, whereby we exposed replicating human fibroblasts to stress (glucocorticoid) hormones. Unbiased genome-wide analyses in human blood linked higher FKBP5 mRNA with a proinflammatory profile and altered NF-κB-related gene networks. Accordingly, experiments in immune cells showed that higher FKBP5 promotes inflammation by strengthening the interactions of NF-κB regulatory kinases, whereas opposing FKBP5 either by genetic deletion (CRISPR/Cas9-mediated) or selective pharmacological inhibition prevented the effects on NF-κB. Further, the age/stress-related epigenetic signature enhanced FKBP5 response to NF-κB through a positive feedback loop and was present in individuals with a history of acute myocardial infarction, a disease state linked to peripheral inflammation. These findings suggest that aging/stress-driven FKBP5-NF-κB signaling mediates inflammation, potentially contributing to cardiovascular risk, and may thus point to novel biomarker and treatment possibilities.
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Envejecimiento/genética , Enfermedades Cardiovasculares/genética , Epigénesis Genética/genética , Inflamación/genética , FN-kappa B/genética , Estrés Psicológico/genética , Proteínas de Unión a Tacrolimus/genética , Regulación hacia Arriba/genética , Senescencia Celular/genética , Preescolar , Trastorno Depresivo Mayor/genética , Femenino , Estudio de Asociación del Genoma Completo/métodos , Humanos , Masculino , Factores de Riesgo , Transducción de Señal/genéticaRESUMEN
The C-terminal aminoacidic sequence from NPM1-mutated protein, absent in normal human tissues, may serve as a leukemia-specific antigen and can be considered an ideal target for NPM1-mutated acute myeloid leukemia (AML) immunotherapy. Different in silico instruments and in vitro/ex vivo immunological platforms have identified the most immunogenic epitopes from NPM1-mutated protein. Spontaneous development of endogenous NPM1-mutated-specific cytotoxic T cells has been observed in patients, potentially contributing to remission maintenance and prolonged survival. Genetically engineered T cells, namely CAR-T or TCR-transduced T cells, directed against NPM1-mutated peptides bound to HLA could prospectively represent a promising therapeutic approach. Although either adoptive or vaccine-based immunotherapies are unlikely to be highly effective in patients with full-blown leukemia, these strategies, potentially in combination with immune-checkpoint inhibitors, could be promising in maintaining remission or preemptively eradicating persistent measurable residual disease, mainly in patients ineligible for allogeneic hematopoietic stem cell transplant (HSCT). Alternatively, neoantigen-specific donor lymphocyte infusion derived from healthy donors and targeting NPM1-mutated protein to selectively elicit graft-versus-leukemia effect may represent an attractive option in subjects experiencing post-HSCT relapse. Future studies are warranted to further investigate dynamics of NPM1-mutated-specific immunity and explore whether novel individualized immunotherapies may have potential clinical utility in NPM1-mutated AML patients.
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Antígenos de Neoplasias/inmunología , Leucemia Mieloide Aguda/inmunología , Proteínas Nucleares/genética , Linfocitos T/inmunología , Animales , Humanos , Inmunoterapia/métodos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Mutación , Proteínas Nucleares/inmunología , NucleofosminaAsunto(s)
Leucemia Mieloide Aguda , Células Madre de Sangre Periférica , Humanos , Adulto , Estudios de Factibilidad , Estaurosporina/uso terapéutico , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/tratamiento farmacológico , Tirosina Quinasa 3 Similar a fms/genética , Mutación , Inhibidores de Proteínas Quinasas/uso terapéuticoAsunto(s)
Biomarcadores de Tumor/metabolismo , Proliferación Celular , Factores Reguladores del Interferón/genética , Leucemia Linfocítica Crónica de Células B/patología , Mutación , Proteínas Proto-Oncogénicas c-myc/metabolismo , Anciano , Biomarcadores de Tumor/genética , Estudios de Cohortes , Estudios de Seguimiento , Regulación Neoplásica de la Expresión Génica , Humanos , Factores Reguladores del Interferón/metabolismo , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/metabolismo , Masculino , Pronóstico , Proteínas Proto-Oncogénicas c-myc/genética , Células Tumorales CultivadasRESUMEN
Lenalidomide is an immunomodulatory agent clinically active in chronic lymphocytic leukemia patients. The specific mechanism of action is still undefined, but includes modulation of the microenvironment. In chronic lymphocytic leukemia patients, nurse-like cells differentiate from CD14(+) mononuclear cells and protect chronic lymphocytic leukemia cells from apoptosis. Nurse-like cells resemble M2 macrophages with potent immunosuppressive functions. Here, we examined the effect of lenalidomide on the monocyte/macrophage population in chronic lymphocytic leukemia patients. We found that lenalidomide induces high actin polymerization on CD14(+) monocytes through activation of small GTPases, RhoA, Rac1 and Rap1 that correlated with increased adhesion and impaired monocyte migration in response to CCL2, CCL3 and CXCL12. We observed that lenalidomide increases the number of nurse-like cells that lost the ability to nurture chronic lymphocytic leukemia cells, acquired properties of phagocytosis and promoted T-cell proliferation. Gene expression signature, induced by lenalidomide in nurse-like cells, indicated a reduction of pivotal pro-survival signals for chronic lymphocytic leukemia, such as CCL2, IGF1, CXCL12, HGF1, and supported a modulation towards M1 phenotype with high IL2 and low IL10, IL8 and CD163. Our data provide new insights into the mechanism of action of lenalidomide that mediates a pro-inflammatory switch of nurse-like cells affecting the protective microenvironment generated by chronic lymphocytic leukemia into tissues.
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Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Macrófagos/efectos de los fármacos , Monocitos/efectos de los fármacos , Fagocitosis/efectos de los fármacos , Talidomida/análogos & derivados , Microambiente Tumoral/efectos de los fármacos , Citoesqueleto de Actina/efectos de los fármacos , Inhibidores de la Angiogénesis/farmacología , Apoptosis/efectos de los fármacos , Biomarcadores de Tumor/genética , Western Blotting , Adhesión Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Técnicas de Cocultivo , Femenino , Citometría de Flujo , Perfilación de la Expresión Génica , Humanos , Inmunofenotipificación , Lenalidomida , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/metabolismo , Leucemia Linfocítica Crónica de Células B/patología , Activación de Linfocitos , Macrófagos/metabolismo , Macrófagos/patología , Monocitos/metabolismo , Monocitos/patología , Talidomida/farmacología , Células Tumorales CultivadasRESUMEN
Increasing evidence suggests that bariatric surgery (BS) patients are at risk for substance abuse disorders (SUD). The purpose of this systematic review and meta-analysis was to determine the relationship between BS and the development of new-onset substance abuse disorder (SUDNO) in bariatric patients. On October 31, 2023, we reviewed the scientific literature following PRISMA guidelines. A total of 3242 studies were analyzed, 7 met the inclusion criteria. The pooled incidence of SUDNO was 4.28%. Patients' characteristics associated with SUDNO included preoperative mental disorders, high pre-BS BMI, and public health insurance. Surgical factors associated with new SUDNOs included severe complications in the peri- or postoperative period. The occurrence of SUDNOs is a non-negligeable complication after BS. Predisposing factors may be identified and preventive actions undertaken.
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Cirugía Bariátrica , Obesidad Mórbida , Trastornos Relacionados con Sustancias , Humanos , Cirugía Bariátrica/efectos adversos , Cirugía Bariátrica/estadística & datos numéricos , Trastornos Relacionados con Sustancias/epidemiología , Obesidad Mórbida/cirugía , Obesidad Mórbida/complicaciones , Factores de Riesgo , Complicaciones Posoperatorias/epidemiología , Incidencia , Femenino , Masculino , Adulto , Persona de Mediana EdadRESUMEN
JAK2V617F is the most recurrent genetic mutation in Philadelphia-negative chronic Myeloproliferative Neoplasms (MPNs). Since the JAK2 locus is located on Chromosome 9, we hypothesized that Chromosome 9 copy number abnormalities may be a disease modifier in JAK2V617F-mutant MPN patients. In this study, we identified a subset of MPN patients with partial or complete Chromosome 9 trisomy (+9p patients), who differ from JAK2V617F-homozygous MPN patients as they carry three JAK2 alleles as well as three copies of all neighboring gene loci, including CD274, encoding immunosuppressive Programmed death-ligand 1 (PD-L1) protein. Investigation of the clonal hierarchy revealed that the JAK2V617F occurs first, followed by +9p. Functionally, CD34+ cells from +9p MPN patients demonstrated increased clonogenicity, generating a greater number of primitive colonies, due to high OCT4 and NANOG expression, with knock-down of these genes leading to a genotype-specific decrease in colony numbers. Moreover, our analysis revealed increased PD-L1 surface expression in malignant monocytes from +9p patients, while analysis of the T cell compartment unveiled elevated levels of exhausted cytotoxic T cells. Overall, here we identify a distinct novel subgroup of MPN patients, who feature a synergistic interplay between +9p and JAK2V617F that shapes immune escape characteristics and increased stemness in CD34+ cells.
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High levels of proinflammatory cytokines induce neurotoxicity and catalyze inflammation-driven neurodegeneration, but the specific release mechanisms from microglia remain elusive. Here we show that secretory autophagy (SA), a non-lytic modality of autophagy for secretion of vesicular cargo, regulates neuroinflammation-mediated neurodegeneration via SKA2 and FKBP5 signaling. SKA2 inhibits SA-dependent IL-1ß release by counteracting FKBP5 function. Hippocampal Ska2 knockdown in male mice hyperactivates SA resulting in neuroinflammation, subsequent neurodegeneration and complete hippocampal atrophy within six weeks. The hyperactivation of SA increases IL-1ß release, contributing to an inflammatory feed-forward vicious cycle including NLRP3-inflammasome activation and Gasdermin D-mediated neurotoxicity, which ultimately drives neurodegeneration. Results from protein expression and co-immunoprecipitation analyses of male and female postmortem human brains demonstrate that SA is hyperactivated in Alzheimer's disease. Overall, our findings suggest that SKA2-regulated, hyperactive SA facilitates neuroinflammation and is linked to Alzheimer's disease, providing mechanistic insight into the biology of neuroinflammation.
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Enfermedad de Alzheimer , Autofagia , Proteínas Cromosómicas no Histona , Proteína con Dominio Pirina 3 de la Familia NLR , Enfermedades Neuroinflamatorias , Animales , Femenino , Humanos , Masculino , Ratones , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Autofagia/genética , Proteínas Cromosómicas no Histona/metabolismo , Citocinas/metabolismo , Inflamasomas/metabolismo , Microglía/metabolismo , Enfermedades Neuroinflamatorias/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismoRESUMEN
The localization, number, and function of postsynaptic AMPA-type glutamate receptors (AMPARs) are crucial for synaptic plasticity, a cellular correlate for learning and memory. The Hippo pathway member WWC1 is an important component of AMPAR-containing protein complexes. However, the availability of WWC1 is constrained by its interaction with the Hippo pathway kinases LATS1 and LATS2 (LATS1/2). Here, we explored the biochemical regulation of this interaction and found that it is pharmacologically targetable in vivo. In primary hippocampal neurons, phosphorylation of LATS1/2 by the upstream kinases MST1 and MST2 (MST1/2) enhanced the interaction between WWC1 and LATS1/2, which sequestered WWC1. Pharmacologically inhibiting MST1/2 in male mice and in human brain-derived organoids promoted the dissociation of WWC1 from LATS1/2, leading to an increase in WWC1 in AMPAR-containing complexes. MST1/2 inhibition enhanced synaptic transmission in mouse hippocampal brain slices and improved cognition in healthy male mice and in male mouse models of Alzheimer's disease and aging. Thus, compounds that disrupt the interaction between WWC1 and LATS1/2 might be explored for development as cognitive enhancers.
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Hipocampo , Péptidos y Proteínas de Señalización Intracelular , Plasticidad Neuronal , Fosfoproteínas , Proteínas Serina-Treonina Quinasas , Receptores AMPA , Animales , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Masculino , Humanos , Receptores AMPA/metabolismo , Receptores AMPA/genética , Ratones , Plasticidad Neuronal/fisiología , Hipocampo/metabolismo , Vía de Señalización Hippo , Serina-Treonina Quinasa 3 , Transducción de Señal , Memoria/fisiología , Proteínas Supresoras de Tumor/metabolismo , Proteínas Supresoras de Tumor/genética , Factor de Crecimiento de Hepatocito/metabolismo , Ratones Endogámicos C57BL , Enfermedad de Alzheimer/metabolismo , Fosforilación , Neuronas/metabolismoAsunto(s)
Inmunidad Celular/efectos de los fármacos , Leucemia Linfocítica Crónica de Células B/inmunología , Purinas/farmacología , Quinazolinonas/farmacología , Linfocitos T/efectos de los fármacos , Antineoplásicos/farmacología , Movimiento Celular/efectos de los fármacos , Movimiento Celular/genética , Movimiento Celular/inmunología , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Supervivencia Celular/inmunología , Células Cultivadas , Perfilación de la Expresión Génica/métodos , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Regulación Leucémica de la Expresión Génica/inmunología , Humanos , Inmunidad Celular/genética , Inmunidad Celular/inmunología , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/patología , Linfocitos T/inmunología , Linfocitos T/metabolismoRESUMEN
Macrophages reside in tissues infiltrated by chronic lymphocytic leukemia B cells and the extent of infiltration is associated with adverse prognostic factors. We studied blood monocyte population by flow cytometry and whole-genome microarrays. A mixed lymphocyte reaction was performed to evaluate proliferation of T cells in contact with monocytes from patients and normal donors. Migration and gene modulation in normal monocytes cultured with CLL cells were also evaluated. The absolute number of monocytes increased in chronic lymphocytic leukemia patients compared to the number in normal controls (792 ± 86 cells/µL versus 485 ± 46 cells/µL, P=0.003). Higher numbers of non-classical CD14(+)CD16(++) and Tie-2-expressing monocytes were also detected in patients. Furthermore, we performed a gene expression analysis of monocytes in chronic lymphocytic leukemia patients, showing up-regulation of RAP1GAP and down-regulation of tubulins and CDC42EP3, which would be expected to result in impairment of phagocytosis. We also detected gene alterations such as down-regulation of PTGR2, a reductase able to inactivate prostaglandin E2, indicating immunosuppressive activity. Accordingly, the proliferation of T cells in contact with monocytes from patients was inhibited compared to that of cells in contact with monocytes from normal controls. Finally, normal monocytes in vitro increased migration and up-regulated CD16, RAP1GAP, IL-10, IL-8, MMP9 and down-regulated PTGR2 in response to leukemic cells or conditioned media. In conclusion, altered composition and deregulation of genes involved in phagocytosis and inflammation were found in blood monocytes obtained from chronic lymphocytic leukemia patients, suggesting that leukemia-mediated "education" of immune elements may also include the establishment of a skewed phenotype in the monocyte/macrophage population.
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Regulación hacia Abajo/genética , Regulación Neoplásica de la Expresión Génica , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/metabolismo , Prueba de Cultivo Mixto de Linfocitos , Monocitos/patología , Fagocitosis/genética , Adulto , Anciano , Anciano de 80 o más Años , Células Cultivadas , Femenino , Perfilación de la Expresión Génica/métodos , Humanos , Inflamación/genética , Inflamación/metabolismo , Inflamación/patología , Leucemia Linfocítica Crónica de Células B/patología , Prueba de Cultivo Mixto de Linfocitos/métodos , Masculino , Persona de Mediana Edad , Monocitos/metabolismoAsunto(s)
Angiopoyetina 2/metabolismo , Leucemia Linfocítica Crónica de Células B/metabolismo , Proteínas de Neoplasias/metabolismo , Receptor TIE-2/metabolismo , Transducción de Señal , Angiopoyetina 2/genética , Supervivencia Celular/genética , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/patología , Masculino , Proteínas de Neoplasias/genética , Receptor TIE-2/genética , Células Tumorales CultivadasRESUMEN
Deletion on the long arm of chromosome 11 occurs in 5-20% of chronic lymphocytic leukaemia (CLL) patients. We analysed clinical-biological characteristics of 131 CLL patients carrying 11q deletion documented before therapy (de novo 11q deleted CLL). De novo 11q deleted CLL were characterized by high frequencies of unmutated immunoglobulin variable heavy genes, multiple fluorescence in situ hybridization aberrations and lymph node involvement. Factors significantly associated with shorter time to first treatment (TTFT) were advanced Binet stages, high white blood cell count, increased ß2 -microglobulin levels, 17p in addition, splenomegaly and more extensive lymphadenopathy. We found that patients with <25% 11q deleted nuclei (n = 22) experienced longer TTFT compared with patients with ≥25% 11q deleted nuclei (n = 87; median TTFT, 40 vs. 14 months, p = 0.011) and also showed better response to treatments (complete response, 50% vs. 21%, p = 0.016). The variables identified by multivariate analysis as independently associated with reduced TTFT were advanced Binet stages [hazard ratio (HR) 4.69; p < 0.001] and ≥25% 11q deleted nuclei (HR 4.73; p = 0.004). De novo 11q deleted CLLs exhibit variable clinical outcome. The percentage of deleted nuclei inside leukemic clone should be included in the prognostic definition of therapy-naïve 11q deleted CLL patients.
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Deleción Cromosómica , Cromosomas Humanos Par 11 , Leucemia Linfocítica Crónica de Células B/genética , Adulto , Anciano , Anciano de 80 o más Años , Heterogeneidad Genética , Humanos , Leucemia Linfocítica Crónica de Células B/patología , Leucemia Linfocítica Crónica de Células B/terapia , Persona de Mediana Edad , Pronóstico , Eliminación de SecuenciaRESUMEN
Background and objective: The fourth dose the COVID-19 vaccine was first proposed to immunocompromised patients. The aim of the article is to systematically review the literature and report the humoral response and outcomes after the fourth dose administration in people with impaired immune system. Methods: Published studies on the humoral response, efficacy and safety of the fourth dose of the COVID-19 vaccine were analyzed in various settings of immunocompromised patients. We conducted systematic searches of PubMed, Cochrane Library and WHO COVID-19 Research Database for series published through January 31, 2023, using the search terms "fourth dose" or "second booster" or "4th dose" and "Coronavirus" or "COVID-19" or "SARS-CoV-2." All articles were selected according to the PRISMA guidelines. Results: A total of 24 articles including 2,838 patients were comprised in the systematic review. All the studies involved immunocompromised patients, including solid organ transplant recipients, patients with autoimmune rheumatic disease, patients with human immunodeficiency virus (HIV) and patients with blood cancers or diseases. Almost all patients received BNT162b2 or mRNA-1273 as fourth dose. All the studies demonstrated the increase of antibody titers after the fourth dose, both in patients who had a serological strong response and in those who had a weak response after the third dose. No serious adverse events after the 4th dose have been reported by 13 studies. COVID-19 infection after the fourth dose ranged from 0 to 21%. Conclusion: The present review highlights the importance of the fourth dose of covid-19 vaccines for immunocompromised patients. Across the included studies, a fourth dose was associated with improved seroconversion and antibody titer levels. In particular, a fourth dose was associated with increasing immunogenicity in organ transplant recipients and patients with hematological cancers, with a very low rate of serious side effects.
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Vacunas contra la COVID-19 , COVID-19 , Humanos , COVID-19/prevención & control , Vacuna BNT162 , SARS-CoV-2 , Huésped InmunocomprometidoRESUMEN
The trajectory of B cell development goes through subsequent steps governed by complex genetic programs, strictly regulated by multiple transcription factors. Interferon regulatory factor 4 (IRF4) regulates key points from pre-B cell development and receptor editing to germinal center formation, class-switch recombination and plasma cell differentiation. The pleiotropic ability of IRF4 is mediated by its "kinetic control", allowing different IRF4 expression levels to activate distinct genetic programs due to modulation of IRF4 DNA-binding affinity. IRF4 is implicated in B cell malignancies, acting both as tumor suppressor and as tumor oncogene in different types of precursors and mature B cell neoplasia. Here, we summarize the complexity of IRF4 functions related to different DNA-binding affinity, multiple IRF4-specific target DNA motif, and interactions with transcriptional partners. Moreover, we describe the unique role of IRF4 in acute leukemias and B cell mature neoplasia, focusing on pathogenetic implications and possible therapeutic strategies in multiple myeloma and chronic lymphocytic leukemia.
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Centro Germinal , Neoplasias , Humanos , Diferenciación Celular , Factores Reguladores del Interferón/genética , Factores Reguladores del Interferón/metabolismo , ADN/metabolismoRESUMEN
High levels of proinflammatory cytokines induce neurotoxicity and catalyze inflammation-driven neurodegeneration, but the specific release mechanisms from microglia remain elusive. We demonstrate that secretory autophagy (SA), a non-lytic modality of autophagy for secretion of vesicular cargo, regulates neuroinflammation-mediated neurodegeneration via SKA2 and FKBP5 signaling. SKA2 inhibits SA-dependent IL-1ß release by counteracting FKBP5 function. Hippocampal Ska2 knockdown in mice hyperactivates SA resulting in neuroinflammation, subsequent neurodegeneration and complete hippocampal atrophy within six weeks. The hyperactivation of SA increases IL-1ß release, initiating an inflammatory feed-forward vicious cycle including NLRP3-inflammasome activation and Gasdermin D (GSDMD)-mediated neurotoxicity, which ultimately drives neurodegeneration. Results from protein expression and co-immunoprecipitation analyses of postmortem brains demonstrate that SA is hyperactivated in Alzheimer's disease. Overall, our findings suggest that SKA2-regulated, hyperactive SA facilitates neuroinflammation and is linked to Alzheimer's disease, providing new mechanistic insight into the biology of neuroinflammation.
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The clinical relevance of angiopoietin-2 (Ang2) in chronic lymphocytic leukemia (CLL) was previously suggested by the association between high Ang2, and shorter progression-free survival reported in small series of patients. Here, we evaluated Ang2 glycoprotein levels in plasma samples collected from a multicentric cohort of CLL patients (n = 316) using an enzyme-linked immunosorbent assay method, and we investigated its prognostic role in relation to time to first treatment (TTFT) and overall survival. Based on a cutoff equal to 2459 pg/mL, we divided our cohort in 2 subsets (high and low Ang2) composing 100 (31.6%) and 216 (68.4%) patients, respectively. High Ang2 was predictive of reduced TTFT (P < .001) and overall survival (P = .002). Multivariate analysis confirmed that high Ang2 was an independent prognosticator for TTFT (hazard ratio = 1.739; 95% confidence interval, 1.059-2.857; P = .029). Significant associations were found between high Ang2 and advanced Binet stages (P < .001), high beta(2)-microglobulin (P < .001), unmutated variable region of immunoglobulin heavy chain gene status (P < .001), high CD38 and zeta-chain-associated protein kinase 70 expression (P < .001 and P = .003), and intermediate/high cytogenetic risk (P = .005). Moreover, Ang2 added prognostic power to other conventional prognosticators and helped to refine prognosis among CLL subsets with both high and low vascular endothelial growth factor plasma levels. Ang2 plasma level may be a useful independent prognosticator for CLL.
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Angiopoyetina 2/sangre , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/mortalidad , Leucemia Linfocítica Crónica de Células B/terapia , Adulto , Anciano , Anciano de 80 o más Años , Angiopoyetina 2/análisis , Biomarcadores de Tumor/sangre , Análisis Químico de la Sangre , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/sangre , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante , Pronóstico , Análisis de Supervivencia , Factores de TiempoRESUMEN
BACKGROUND: Chronic lymphocytic leukemia B cells display prolonged survival in vivo, but when cultured in vitro rapidly undergo spontaneous apoptosis. We hypothesize that interactions with endothelial cells in infiltrated tissues and during recirculation may have a pathogenic role in chronic lymphocytic leukemia. DESIGN AND METHODS: We evaluated apoptosis of leukemic cells after co-culture on a monolayer of human umbilical vein endothelial cells with addition of fludarabine and antibodies that block adhesion. Then, we compared microarray-based gene expression profiles between leukemic cells at baseline and after co-culture. RESULTS: We found that the endothelial layer protected leukemic cells from apoptosis inducing a 2-fold mean decrement in apoptotic cells after 2 days of co-culture. Moreover, the endothelial layer decreased the sensitivity of chronic lymphocytic leukemia B cells to fludarabine-induced apoptosis. Physical contact with endothelium mediated by both ß(1)- and ß(2)- integrins is essential for the survival advantage of leukemic cells. In particular, blocking CD106 on endothelial cells or CD18 on leukemic B cells led to the almost complete abrogation of the survival advantage (>70% inhibition of viability). However, a reduction of apoptosis was also measured in leukemic cells cultured in conditioned medium collected after 2 days of co-culture, implying that survival is partially mediated by soluble factors. Overall, the contact with endothelial cells modulated 1,944 genes in chronic lymphocytic leukemia B cells, establishing a peculiar gene expression profile: up-regulation of angiogenesis-related genes, an increase of genes involved in TGFß and Wnt signaling pathways, secretion of cytokines recruiting stromal cells and macrophages and up-regulation of anti-apoptotic molecules such as Bcl2 and Survivin. CONCLUSIONS: Our study supports the notion that endothelial cells are major players in the chronic lymphocytic leukemia microenvironment. Adhesion to endothelium strongly supports survival, protects from drug-induced apoptosis and extensively modifies the gene expression profile of leukemic cells.