RESUMEN
The contribution of γδ T cells to immune responses is associated with rapid secretion of interferon-γ (IFN-γ). Here, we show a perinatal thymic wave of innate IFN-γ-producing γδ T cells that express CD8αß heterodimers and expand in preclinical models of infection and cancer. Optimal CD8αß+ γδ T cell development is directed by low T cell receptor signaling and through provision of interleukin (IL)-4 and IL-7. This population is pathologically relevant as overactive, or constitutive, IL-7R-STAT5B signaling promotes a supraphysiological accumulation of CD8αß+ γδ T cells in the thymus and peripheral lymphoid organs in two mouse models of T cell neoplasia. Likewise, CD8αß+ γδ T cells define a distinct subset of human T cell acute lymphoblastic leukemia pediatric patients. This work characterizes the normal and malignant development of CD8αß+ γδ T cells that are enriched in early life and contribute to innate IFN-γ responses to infection and cancer.
Asunto(s)
Inmunidad Innata , Interferón gamma , Receptores de Antígenos de Linfocitos T gamma-delta , Receptores de Interleucina-7 , Factor de Transcripción STAT5 , Timo , Animales , Interferón gamma/metabolismo , Interferón gamma/inmunología , Ratones , Humanos , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Timo/inmunología , Receptores de Interleucina-7/metabolismo , Factor de Transcripción STAT5/metabolismo , Transducción de Señal/inmunología , Ratones Endogámicos C57BL , Linfocitos T CD8-positivos/inmunología , Ratones Noqueados , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Antígenos CD8/metabolismo , Femenino , Linfocitos Intraepiteliales/inmunología , Linfocitos Intraepiteliales/metabolismo , Interleucina-7/metabolismoRESUMEN
The cytokine IL-7 and its receptor, IL-7R, are critical for T cell and, in the mouse, B cell development, as well as differentiation and survival of naive T cells, and generation and maintenance of memory T cells. They are also required for innate lymphoid cell (ILC) development and maintenance, and consequently for generation of lymphoid structures and barrier defense. Here we discuss the central role of IL-7 and IL-7R in the lymphoid system and highlight the impact of their deregulation, placing a particular emphasis on their 'dark side' as promoters of cancer development. We also explore therapeutic implications and opportunities associated with either positive or negative modulation of the IL-7-IL-7R signaling axis.
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Inmunoterapia/tendencias , Interleucina-7/metabolismo , Neoplasias/inmunología , Receptores de Interleucina-7/metabolismo , Linfocitos T/fisiología , Animales , Diferenciación Celular , Supervivencia Celular , Homeostasis , Humanos , Interleucina-7/inmunología , Receptores de Interleucina-7/inmunologíaRESUMEN
The downstream signaling of the interleukin-7 (IL-7) receptor (IL-7R) plays important physiological and pathological roles, including the differentiation of lymphoid cells and proliferation of acute lymphoblastic leukemia cells. Gain-of-function mutations in the IL-7Rα chain, the specific component of the receptor for IL-7, result in constitutive, IL-7-independent signaling and trigger acute lymphoblastic leukemia. Here, we show that the loss of the phosphoinositide 5-phosphatase INPP5K is associated with increased levels of the INPP5K substrate phosphatidylinositol 4,5-bisphosphate (PtdIns[4,5]P2) and causes an altered dynamic structure of the IL-7 receptor. We discovered that the IL-7Rα chain contains a very conserved positively charged polybasic amino acid sequence in its cytoplasmic juxtamembrane region; this region establish stronger ionic interactions with negatively charged PtdIns(4,5)P2 in the absence of INPP5K, freezing the IL-7Rα chain structure. This dynamic structural alteration causes defects in IL-7R signaling, culminating in decreased expressions of EBF1 and PAX5 transcription factors, in microdomain formation, cytoskeletal reorganization, and bone marrow B-cell differentiation. Similar alterations after the reduced INPP5K expression also affected mutated, constitutively activated IL-7Rα chains that trigger leukemia development, leading to reduced cell proliferation. Altogether, our results indicate that the lipid 5-phosphatase INPP5K hydrolyzes PtdIns(4,5)P2, allowing the requisite conformational changes of the IL-7Rα chain for optimal signaling.
Asunto(s)
Interleucina-7 , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Interleucina-7/genética , Interleucina-7/metabolismo , Fosfatidilinositol 4,5-Difosfato , Receptores de Interleucina-7/genética , Receptores de Interleucina-7/metabolismo , Transducción de Señal/genéticaRESUMEN
Tight regulation of IL-7Rα expression is essential for normal T-cell development. IL-7Rα gain-of-function mutations are known drivers of T-cell acute lymphoblastic leukemia (T-ALL). Although a subset of patients with T-ALL display high IL7R messenger RNA levels and cases with IL7R gains have been reported, the impact of IL-7Rα overexpression, rather than mutational activation, during leukemogenesis remains unclear. In this study, overexpressed IL-7Rα in tetracycline-inducible Il7r transgenic and Rosa26 IL7R knockin mice drove potential thymocyte self-renewal, and thymus hyperplasia related to increased proliferation of T-cell precursors, which subsequently infiltrated lymph nodes, spleen, and bone marrow, ultimately leading to fatal leukemia. The tumors mimicked key features of human T-ALL, including heterogeneity in immunophenotype and genetic subtype between cases, frequent hyperactivation of the PI3K/Akt pathway paralleled by downregulation of p27Kip1 and upregulation of Bcl-2, and gene expression signatures evidencing activation of JAK/STAT, PI3K/Akt/mTOR and Notch signaling. Notably, we also found that established tumors may no longer require high levels of IL-7R expression upon secondary transplantation and progressed in the absence of IL-7, but remain sensitive to inhibitors of IL-7R-mediated signaling ruxolitinib (Jak1), AZD1208 (Pim), dactolisib (PI3K/mTOR), palbociclib (Cdk4/6), and venetoclax (Bcl-2). The relevance of these findings for human disease are highlighted by the fact that samples from patients with T-ALL with high wild-type IL7R expression display a transcriptional signature resembling that of IL-7-stimulated pro-T cells and, critically, of IL7R-mutant cases of T-ALL. Overall, our study demonstrates that high expression of IL-7Rα can promote T-cell tumorigenesis, even in the absence of IL-7Rα mutational activation.
Asunto(s)
Carcinogénesis , Regulación Leucémica de la Expresión Génica , Mutación , Proteínas de Neoplasias , Neoplasias Experimentales , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Receptores de Interleucina-7 , Animales , Carcinogénesis/genética , Carcinogénesis/metabolismo , Humanos , Ratones , Ratones Transgénicos , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Neoplasias Experimentales/genética , Neoplasias Experimentales/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Receptores de Interleucina-7/biosíntesis , Receptores de Interleucina-7/genética , Transducción de Señal , Timocitos/metabolismoRESUMEN
CASZ1 is a conserved transcription factor involved in neural development, blood vessel assembly and heart morphogenesis. CASZ1 has been implicated in cancer, either suppressing or promoting tumor development depending on the tissue. However, the impact of CASZ1 on hematological tumors remains unknown. Here, we show that the T-cell oncogenic transcription factor TAL1 is a direct positive regulator of CASZ1, that T-cell acute lymphoblastic leukemia (T-ALL) samples at diagnosis overexpress CASZ1b isoform, and that CASZ1b expression in patient samples correlates with PI3KAKT- mTOR signaling pathway activation. In agreement, overexpression of CASZ1b in both Ba/F3 and T-ALL cells leads to the activation of PI3K signaling pathway, which is required for CASZ1b-mediated transformation of Ba/F3 cells in vitro and malignant expansion in vivo. We further demonstrate that CASZ1b cooperates with activated NOTCH1 to promote T-ALL development in zebrafish, and that CASZ1b protects human T-ALL cells from serum deprivation and treatment with chemotherapeutic drugs. Taken together, our studies indicate that CASZ1b is a TAL1-regulated gene that promotes T-ALL development and resistance to chemotherapy.
RESUMEN
T-cell acute lymphoblastic leukemia (T-ALL) and T-cell acute lymphoblastic lymphoma (T-LBL) are aggressive hematological malignancies that are currently treated with high-dose chemotherapy. Over the last several years, the search toward novel and less-toxic therapeutic strategies for T-ALL/T-LBL patients has largely focused on the identification of cell-intrinsic properties of the tumor cell. However, non-cell-autonomous activation of specific oncogenic pathways might also offer opportunities that could be exploited at the therapeutic level. In line with this, we here show that endogenous interleukin 7 (IL7) can increase the expression of the oncogenic kinase proviral integration site for Moloney-murine leukemia 1 (PIM1) in CD127+ T-ALL/T-LBL, thereby rendering these tumor cells sensitive to in vivo PIM inhibition. In addition, using different CD127+ T-ALL/T-LBL xenograft models, we also reveal that residual tumor cells, which remain present after short-term in vivo chemotherapy, display consistent upregulation of PIM1 as compared with bulk nontreated tumor cells. Notably, this effect was transient as increased PIM1 levels were not observed in reestablished disease after abrogation of the initial chemotherapy. Furthermore, we uncover that this phenomenon is, at least in part, mediated by the ability of glucocorticoids to cause transcriptional upregulation of IL7RA in T-ALL/T-LBL patient-derived xenograft (PDX) cells, ultimately resulting in non-cell-autonomous PIM1 upregulation by endogenous IL7. Finally, we confirm in vivo that chemotherapy in combination with a pan-PIM inhibitor can improve leukemia survival in a PDX model of CD127+ T-ALL. Altogether, our work reveals that IL7 and glucocorticoids coordinately drive aberrant activation of PIM1 and suggests that IL7-responsive CD127+ T-ALL and T-LBL patients could benefit from PIM inhibition during induction chemotherapy.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Citocinas/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-pim-1/metabolismo , Linfocitos T/inmunología , Animales , Apoptosis , Proliferación Celular , Quimioterapia Combinada , Humanos , Ratones , Leucemia-Linfoma Linfoblástico de Células T Precursoras/inmunología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Linfocitos T/efectos de los fármacos , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Mobile health (mHealth) technologies, such as symptom tracking apps, are crucial for coping with the global pandemic crisis by providing near real-time, in situ information for the medical and governmental response. However, in such a dynamic and diverse environment, methods are still needed to support public health decision-making. This paper uses the lens of strong structuration theory to investigate networks of COVID-19 symptoms in the Belfast metropolitan area. A self-supervised machine learning method measuring information entropy was applied to the Northern Ireland COVIDCare app. The findings reveal: (1) relevant stratifications of disease symptoms, (2) particularities in health-wealth networks, and (3) the predictive potential of artificial intelligence to extract entangled knowledge from data in COVID-related apps. The proposed method proved to be effective for near real-time in-situ analysis of COVID-19 progression and to focus and complement public health decisions. Our contribution is relevant to an understanding of SARS-COV-2 symptom entanglements in localised environments. It can assist decision-makers in designing both reactive and proactive health measures that should be personalised to the heterogeneous needs of different populations. Moreover, near real-time assessment of pandemic symptoms using digital technologies will be critical to create early warning systems of emerging SARS-CoV-2 strains and predict the need for healthcare resources.
Asunto(s)
GTP Fosfohidrolasas , Proteínas de la Membrana , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Humanos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , GTP Fosfohidrolasas/genética , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Subunidad alfa del Receptor de Interleucina-7/genética , Subunidad alfa del Receptor de Interleucina-7/metabolismoAsunto(s)
Interleucina-7 , Quinasas Janus , Fosfatidilinositol 3-Quinasas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Proteínas Proto-Oncogénicas c-akt , Factor de Transcripción STAT5 , Transducción de Señal , Serina-Treonina Quinasas TOR , Adulto , Niño , Humanos , Interleucina-7/metabolismo , Quinasas Janus/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factor de Transcripción STAT5/metabolismo , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3, the most common dominant spinocerebellar ataxia (SCA) worldwide, is caused by over-repetition of a CAG repeat in the ATXN3/MJD1 gene, which translates into a polyglutamine tract within the ataxin-3 protein. There is no treatment for this fatal disorder. Despite evidence of the safety and efficacy of mesenchymal stromal cells (MSCs) in delaying SCA disease progression in exploratory clinical trials, unanticipated regression of patients to the status prior to treatment makes the investigation of causes and solutions urgent and imperative. In the present study, we compared the efficacy of a single intracranial injection with repeated systemic MSC administration in alleviating the MJD phenotype of two strongly severe genetic rodent models. We found that a single MSC transplantation only produces transient effects, whereas periodic administration promotes sustained motor behavior and neuropathology alleviation, suggesting that MSC therapies should be re-designed to get sustained beneficial results in clinical practice. Furthermore, MSC promoted neuroprotection, increased the levels of GABA and glutamate, and decreased the levels of Myo-inositol, which correlated with motor improvements, indicating that these metabolites may serve as valid neurospectroscopic biomarkers of disease and treatment. This study makes important contributions to the design of new clinical approaches for MJD and other SCAs/polyglutamine disorders.
Asunto(s)
Ataxina-3/metabolismo , Enfermedad de Machado-Joseph/metabolismo , Enfermedad de Machado-Joseph/terapia , Animales , Ataxina-3/genética , Ácido Glutámico/metabolismo , Masculino , Trasplante de Células Madre Mesenquimatosas/métodos , Células Madre Mesenquimatosas/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Ácido gamma-Aminobutírico/metabolismoRESUMEN
Despite remarkable progress in polychemotherapy protocols, pediatric B-cell acute lymphoblastic leukemia (B-ALL) remains fatal in around 20% of cases. Hence, novel targeted therapies are needed for patients with poor prognosis. Glucocorticoids (GCs) are drugs commonly administrated for B-ALL treatment. Activation of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin signaling pathway is frequently observed in B-ALL and contributes to GC-resistance. Here, we analyzed for the first time to our knowledge, the therapeutic potential of pan and isoform-selective PI3K p110 inhibitors, alone or combined with dexamethasone (DEX), in B-ALL leukemia cell lines and patient samples. We found that a pan PI3K p110 inhibitor displayed the most powerful cytotoxic effects in B-ALL cells, by inducing cell cycle arrest and apoptosis. Both a pan PI3K p110 inhibitor and a dual γ/δ PI3K p110 inhibitor sensitized B-ALL cells to DEX by restoring nuclear translocation of the GC receptor and counteracted stroma-induced DEX-resistance. Finally, gene expression analysis documented that, on one hand the combination consisting of a pan PI3K p110 inhibitor and DEX strengthened the DEX-induced up- or down-regulation of several genes involved in apoptosis, while on the other, it rescued the effects of genes that might be involved in GC-resistance. Overall, our findings strongly suggest that PI3K p110 inhibition could be a promising strategy for treating B-ALL patients by improving GC therapeutic effects and/or overcoming GC-resistance.
Asunto(s)
Antineoplásicos/farmacología , Fosfatidilinositol 3-Quinasa Clase I/antagonistas & inhibidores , Dexametasona/farmacología , Glucocorticoides/farmacología , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Apoptosis/efectos de los fármacos , Linfocitos B/metabolismo , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Niño , Preescolar , Compuestos Heterocíclicos con 3 Anillos/farmacología , Humanos , Isoquinolinas/farmacología , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Purinas/farmacología , Quinazolinonas/farmacología , Quinoxalinas/farmacología , Tiazolidinedionas/farmacología , Triazinas/farmacologíaRESUMEN
Cancer remains a major cause of morbidity and mortality worldwide. Although progress has been made regarding chemotherapeutic agents, new therapies that combine increased selectivity and efficacy with low resistance are still needed. In the search for new anticancer agents, therapies based on biologically active peptides, in particular, antimicrobial peptides (AMPs), have attracted attention for their decreased resistance development and low cytotoxicity. Many AMPs have proved to be tumoricidal agents against human cancer cells, but their mode of action is still controversial. The existence of common properties shared by the membranes of bacteria and tumor cells points to similar lipid-targeting mechanisms in both cases. On the other hand, anticancer peptides (ACPs) also induce apoptosis and inhibit angiogenesis. Human neutrophil peptide-1 (HNP-1) is an endogenous AMP that has been implicated in different cellular phenomena such as tumor proliferation. The presence of HNP-1 in the serum/plasma of oncologic patients turns this peptide into a potential tumor biomarker. The present work reveals the different effects of HNP-1 on the biophysical and nanomechanical properties of solid and hematological tumor cells. Studies on cellular morphology, cellular stiffness, and membrane ultrastructure and charge using atomic force microscopy (AFM) and zeta potential measurements show a preferential binding of HNP-1 to solid tumor cells from human prostate adenocarcinoma when compared to human leukemia cells. AFM also reveals induction of apoptosis with cellular membrane defects at very low peptide concentrations. Understanding ACPs mode(s) of action will certainly open innovative pathways for drug development in cancer treatment.
Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , alfa-Defensinas/farmacología , Fenómenos Biomecánicos/efectos de los fármacos , Línea Celular Tumoral , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Membrana Celular/ultraestructura , Forma de la Célula/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Módulo de Elasticidad/efectos de los fármacos , Humanos , Masculino , Microscopía de Fuerza Atómica , Neoplasias de la Próstata/patología , Electricidad EstáticaRESUMEN
Phosphatase and tensin homolog (PTEN)-inactivating mutations and/or deletions are an independent risk factor for relapse of T-cell acute lymphoblastic leukemia (T-ALL) patients treated on Dutch Childhood Oncology Group or German Cooperative Study Group for Childhood Acute Lymphoblastic Leukemia protocols. Some monoallelic mutated or PTEN wild-type patients lack PTEN protein, implying that additional PTEN inactivation mechanisms exist. We show that PTEN is inactivated by small deletions affecting a few exons in 8% of pediatric T-ALL patients. These microdeletions were clonal in 3% and subclonal in 5% of patients. Conserved deletion breakpoints are flanked by cryptic recombination signal sequences (cRSSs) and frequently have non-template-derived nucleotides inserted in between breakpoints, pointing to an illegitimate RAG recombination-driven activity. Identified cRSSs drive RAG-dependent recombination in a reporter system as efficiently as bona fide RSSs that flank gene segments of the T-cell receptor locus. Remarkably, equivalent microdeletions were detected in thymocytes of healthy individuals. Microdeletions strongly associate with the TALLMO subtype characterized by TAL1 or LMO2 rearrangements. Primary and secondary xenotransplantation of TAL1-rearranged leukemia allowed development of leukemic subclones with newly acquired PTEN microdeletions. Ongoing RAG activity may therefore actively contribute to the acquisition of preleukemic hits, clonal diversification, and disease progression.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Eliminación de Gen , Proteínas de Homeodominio/genética , Proteínas con Dominio LIM/genética , Fosfohidrolasa PTEN/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Proteínas Proto-Oncogénicas/genética , Recombinación Genética/genética , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Reordenamiento Génico , Humanos , Ratones , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , Proteína 1 de la Leucemia Linfocítica T Aguda , Trasplante HeterólogoRESUMEN
Interleukin-7 and interleukin-7 receptor are essential for normal T-cell development and homeostasis, whereas excessive interleukin-7/interleukin-7 receptor-mediated signaling promotes leukemogenesis. The protein kinase, casein kinase 2, is overexpressed and hyperactivated in cancer, including T-cell acute lymphoblastic leukemia. Herein, we show that while interleukin-7 had a minor but significant positive effect on casein kinase 2 activity in leukemia T-cells, casein kinase 2 activity was mandatory for optimal interleukin-7/interleukin-7 receptor-mediated signaling. Casein kinase 2 pharmacological inhibition impaired signal transducer and activator of transcription 5 and phosphoinositide 3-kinase/v-Akt murine thymoma viral oncogene homolog 1 pathway activation triggered by interleukin-7 or by mutational activation of interleukin-7 receptor. By contrast, forced expression of casein kinase 2 augmented interleukin-7 signaling in human embryonic kidney 293T cells reconstituted with the interleukin-7 receptor machinery. Casein kinase 2 inactivation prevented interleukin-7-induced B-cell lymphoma 2 upregulation, maintenance of mitochondrial homeostasis and viability of T-cell acute lymphoblastic leukemia cell lines and primary leukemia cells collected from patients at diagnosis. Casein kinase 2 inhibition further abrogated interleukin-7-mediated cell growth and upregulation of the transferrin receptor, and blocked cyclin A and E upregulation and cell cycle progression. Notably, casein kinase 2 was also required for the viability of mutant interleukin-7 receptor expressing leukemia T-cells. Overall, our study identifies casein kinase 2 as a major player in the effects of interleukin-7 and interleukin-7 receptor in T-cell acute lymphoblastic leukemia. This further highlights the potential relevance of targeting casein kinase 2 in this malignancy.
Asunto(s)
Quinasa de la Caseína II/fisiología , Subunidad alfa del Receptor de Interleucina-7/fisiología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Transducción de Señal , Quinasa de la Caseína II/antagonistas & inhibidores , Quinasa de la Caseína II/metabolismo , Ciclo Celular , Supervivencia Celular , Células Cultivadas , Células HEK293 , Humanos , Interleucina-7/fisiología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidadRESUMEN
Phosphorylation regulates the conformation, stability, homo- and heterotypic protein interactions, localization, and activity of the tumor suppressor PTEN. From a simple picture, at the beginning of this millennium, recognizing that CK2 phosphorylated PTEN at the C-terminus and thereby impacted on PTEN stability and activity, research has led to a significantly more complex scenario today, where for instance GSK3, Plk3, ATM, ROCK or Src-family kinases are also gaining the spotlight in this evolving play. Here, we review the current knowledge on the kinases that phosphorylate PTEN, and on the impact that specific phosphorylation events have on PTEN function.
Asunto(s)
Fosfohidrolasa PTEN/fisiología , Proteínas Quinasas/fisiología , Proteínas Supresoras de Tumor/fisiología , Secuencia de Aminoácidos , Animales , Humanos , Datos de Secuencia Molecular , Fosforilación/fisiologíaRESUMEN
Lymphotoxin-mediated activation of the lymphotoxin-ß receptor (LTßR; LTBR) has been implicated in cancer, but its role in T-cell acute lymphoblastic leukaemia (T-ALL) has remained elusive. Here we show that the genes encoding lymphotoxin (LT)-α and LTß (LTA, LTB) are expressed in T-ALL patient samples, mostly of the TAL/LMO molecular subtype, and in the TEL-JAK2 transgenic mouse model of cortical/mature T-ALL (Lta, Ltb). In these mice, expression of Lta and Ltb is elevated in early stage T-ALL. Surface LTα1 ß2 protein is expressed in primary mouse T-ALL cells, but only in the absence of microenvironmental LTßR interaction. Indeed, surface LT expression is suppressed in leukaemic cells contacting Ltbr-expressing but not Ltbr-deficient stromal cells, both in vitro and in vivo, thus indicating that dynamic surface LT expression in leukaemic cells depends on interaction with its receptor. Supporting the notion that LT signalling plays a role in T-ALL, inactivation of Ltbr results in a significant delay in TEL-JAK2-induced leukaemia onset. Moreover, young asymptomatic TEL-JAK2;Ltbr(-/-) mice present markedly less leukaemic thymocytes than age-matched TEL-JAK2;Ltbr(+/+) mice and interference with LTßR function at this early stage delayed T-ALL development. We conclude that LT expression by T-ALL cells activates LTßR signalling in thymic stromal cells, thus promoting leukaemogenesis.
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Receptor beta de Linfotoxina/fisiología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Animales , Carcinogénesis/genética , Línea Celular Tumoral , Linaje de la Célula/genética , Expresión Génica/genética , Humanos , Inmunofenotipificación , Janus Quinasa 2/genética , Receptor beta de Linfotoxina/genética , Receptor beta de Linfotoxina/metabolismo , Ratones Noqueados , Ratones Transgénicos , Datos de Secuencia Molecular , Transducción de Señal , Microambiente Tumoral/genéticaRESUMEN
In the current issue of Blood, Yokoyama et al demonstrate that an IL7R mutation similar to those found in patients with acute lymphoblastic leukemia (ALL) can be leukemogenic in vivo when expressed in normal hematopoietic progenitors.
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Regulación Neoplásica de la Expresión Génica , Células Madre Hematopoyéticas/fisiología , Leucemia de Células B/genética , Leucemia de Células T/genética , Receptores de Interleucina-7/genética , Animales , Femenino , EmbarazoRESUMEN
PURPOSE: B-cell survival and differentiation critically depend on the interaction of BAFF-R and TACI with their ligands, BAFF and APRIL. Mature B-cell defects lead to Common Variable Immunodeficiency (CVID), which is associated with elevated serum levels of BAFF and APRIL. Nevertheless, BAFF-R and TACI expression in CVID and their relationship with ligand availability remain poorly understood. METHODS AND RESULTS: We found that BAFF-R expression was dramatically reduced on B cells of CVID patients, relative to controls. BAFF-R levels inversely correlated with serum BAFF concentration both in CVID and healthy subjects. We also found that recombinant BAFF stimulation reduced BAFF-R expression on B cells without decreasing transcript levels. On the other hand, CVID subjects had increased TACI expression on B cells in direct association with serum BAFF but not APRIL levels. Moreover, splenomegaly was associated with higher TACI expression, suggesting that perturbations of TACI function may underlie lymphoproliferation in CVID. CONCLUSIONS: Our results indicate that availability of BAFF determines BAFF-R and TACI expression on B cells, and that BAFF-R expression is controlled by BAFF binding. Identification of the factors governing BAFF-R and TACI is crucial to understanding CVID pathogenesis, and B-cell biology in general, as well as to explore their potential as therapeutic targets.