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Despite the progress in cure rates for pediatric cancers, several challenges remain, such as the management of diseases with poor prognosis. The efficacy of intensified chemotherapies is also accompanied by increased risks of severe acute and chronic toxicities. Thus, therapies specifically targeting tumor cells, or inhibiting oncogenic molecular aberrations, could provide more effective and less toxic treatments for pediatric cancers. Personalization of chemotherapies through pharmacogenetics and precision dosing could also improve the efficacy and toxicity of chemotherapies. In this review, we describe precision medicine strategies implemented or undergoing clinical evaluation in the treatment of pediatric cancers.
Malgré les progrès sur les taux de guérison des cancers pédiatriques, plusieurs défis restent à relever, comme la prise en charge des maladies à mauvais pronostic. L'efficacité des chimiothérapies intensives s'accompagne aussi de risques accrus de toxicités aiguës et chroniques graves. Ainsi, les thérapies ciblant spécifiquement les cellules tumorales, ou inhibant les aberrations moléculaires oncogéniques, pourraient offrir des traitements plus efficaces et moins toxiques pour les cancers pédiatriques. La personnalisation des chimiothérapies grâce à la pharmacogénétique et au dosage de précision pourrait également améliorer l'efficacité et la toxicité des chimiothérapies. Dans cet article de revue, nous décrivons les stratégies de médecine de précision implémentées ou en cours d'évaluation clinique dans le traitement des cancers pédiatriques.
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Neoplasias , Medicina de Precisión , Niño , Humanos , Neoplasias/tratamiento farmacológico , Farmacogenética , Terapia Molecular DirigidaRESUMEN
Coronavirus disease-2019 in children has been linked to various clinical presentation, from paucisymptomatic cutaneous eruptions, to multisystemic inflammatory syndrome. We report the case of an 8-year-old boy who presented with persistent fever and pancytopenia, associated to a skin rash. An extensive etiological workup showed a positive serology for severe acute respiratory syndrome coronavirus 2 and Epstein-Barr virus. A few weeks later, type B acute lymphocytic leukemia was diagnosed. This case underlines the polymorphic appearance of coronavirus disease-2019 and the need for critical appraisal.
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COVID-19/complicaciones , Exantema/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patología , SARS-CoV-2/aislamiento & purificación , COVID-19/transmisión , COVID-19/virología , Niño , Exantema/virología , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras B/virología , PronósticoRESUMEN
Malignant or nonmalignant lymphoproliferative disorders together with repeated ear, nose, and throat infections should strongly motivate immunologic investigations. Indeed, we report a 7-year-old patient with a history of persistent abdominal symptoms along with recurrent ear, nose, and throat infections, who presented with intra-abdominal masses highly suggestive of a diagnostic of lymphoma, and who was diagnosed with activated-PI3K-delta syndrome, a recently described primary immunodeficiency prone to lymphoproliferation.
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Linfoma/diagnóstico , Enfermedades de Inmunodeficiencia Primaria/diagnóstico , Niño , Fosfatidilinositol 3-Quinasa Clase I , Diagnóstico Diferencial , Humanos , Linfoma/patología , Masculino , Enfermedades de Inmunodeficiencia Primaria/patologíaRESUMEN
Non anemic iron deficiency (NAID) is the most common nutritional deficiency. Symptoms more frequently observed in children and adolescents include fatigue, delayed psychomotor development as well as decreased school and athletic performances. Iron treatment is effective in improving symptoms in older children and adolescents. In children under 2 years of age, there is currently no evidence of the efficacy of substitution therapy on development. Preemptive treatment is not justified considering the available evidence beyond premature or small newborns for gestational age and should only be initiated if a diagnosis of iron deficiency is confirmed. Oral iron supplementation is the first-line treatment of NAID.
La carence en fer sans anémie (CF-sA) est le déficit nutritionnel le plus répandu. Les symptômes plus fréquemment observés chez l'enfant et l'adolescent sont une fatigue, un retard de développement psychomoteur et une diminution des performances scolaires et sportives. Une substitution martiale s'avère efficace dans l'amélioration de ces symptômes chez le grand enfant et l'adolescent. Chez l'enfant d'âge inférieur à deux ans, il n'existe actuellement pas d'évidence de l'efficacité d'un traitement substitutif sur le plan du développement. Un traitement préemptif, en dehors de la prématurité ou d'un retard de croissance intra-utérin, n'est à l'heure actuelle pas justifié en considérant l'évidence disponible, et devrait être débuté uniquement suite à un diagnostic formel de carence martiale. Le traitement de première intention de la CF-sA, en l'absence de contre-indications, est le traitement oral.
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Anemia Ferropénica , Anemia , Adolescente , Anemia/diagnóstico , Anemia/terapia , Anemia Ferropénica/diagnóstico , Anemia Ferropénica/terapia , Cuidadores , Niño , Preescolar , Fatiga , Humanos , Recién Nacido , Hierro/uso terapéuticoRESUMEN
Immune thrombocytopenic purpura is a bleeding disorder for which management remains mainly guided by platelet counts. Pediatric hematologists and emergency physicians collaborated to set up a limited intervention strategy, focusing on clinical bleeding severity irrespective of platelet counts, starting in the emergency room. We report how this strategy was safely applied for 106 consecutive children admitted for newly diagnosed immune thrombocytopenic purpura.
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Tratamiento de Urgencia , Púrpura Trombocitopénica Idiopática/terapia , Adolescente , Niño , Preescolar , Protocolos Clínicos , Femenino , Humanos , Lactante , Masculino , Pediatría , Recuento de Plaquetas , Púrpura Trombocitopénica Idiopática/sangre , Púrpura Trombocitopénica Idiopática/diagnóstico , Estudios RetrospectivosRESUMEN
INTRODUCTION: Childhood cancer and its treatment may lead to various health complications. Related impairment in quality of life, excess in deaths and accumulated healthcare costs are relevant. Genetic variations are suggested to contribute to the wide inter-individual variability of complications but have been used only rarely to risk-stratify treatment and follow-up care. This study aims to identify germline genetic variants associated with acute and late complications of childhood cancer. METHODS AND ANALYSIS: The Genetic Risks for Childhood Cancer Complications Switzerland (GECCOS) study is a nationwide cohort study. Eligible are patients and survivors who were diagnosed with childhood cancers or Langerhans cell histiocytosis before age 21 years, were registered in the Swiss Childhood Cancer Registry (SCCR) since 1976 and have consented to the Paediatric Biobank for Research in Haematology and Oncology, Geneva, host of the national Germline DNA Biobank Switzerland for Childhood Cancer and Blood Disorders (BISKIDS).GECCOS uses demographic and clinical data from the SCCR and the associated Swiss Childhood Cancer Survivor Study. Clinical outcome data consists of organ function testing, health conditions diagnosed by physicians, second primary neoplasms and self-reported information from participants. Germline genetic samples and sequencing data are collected in BISKIDS. We will perform association analyses using primarily whole-exome or whole-genome sequencing to identify genetic variants associated with specified health conditions. We will use clustering and machine-learning techniques and assess multiple health conditions in different models. DISCUSSION: GECCOS will improve knowledge of germline genetic variants associated with childhood cancer-associated health conditions and help to further individualise cancer treatment and follow-up care, potentially resulting in improved efficacy and reduced side effects. ETHICS AND DISSEMINATION: The Geneva Cantonal Commission for Research Ethics has approved the GECCOS study.Research findings will be disseminated through national and international conferences, publications in peer-reviewed journals and in lay language online. TRIAL REGISTRATION NUMBER: NCT04702321.
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Neoplasias , Calidad de Vida , Adulto , Niño , Estudios de Cohortes , Estudios Transversales , Células Germinativas , Humanos , Multimorbilidad , Neoplasias/genética , Neoplasias/terapia , Suiza , Adulto JovenRESUMEN
Many somatic genetic abnormalities have been identified in T-cell acute lymphoblastic leukemia (T-ALL) but each individual abnormality accounts for a small proportion of cases; therapeutic stratification consequently still relies on classical clinical markers. NOTCH1 and/or FBXW7 mutations both lead to activation of the NOTCH1 pathway and are among the most frequent mutations in T-ALL. We screened 141 adult diagnostic T-ALL samples from patients treated on either the Lymphoblastic Acute Leukemia in Adults (LALA)-94 (n = 87) or the GRAALL-2003 (n = 54) trials. In 88 cases (62%) there were demonstrated NOTCH1 mutations (42% heterodimerization [HD], 10% HD+proline glutamate serine threonine [PEST], 6% PEST, 2% juxtamembrane mutations, 2% transactivation domain [TAD]) and 34 cases (24%) had FBXW7 mutations (21 cases had both NOTCH1 and FBXW7 mutations); 40 cases (28%) were wild type for both. There was no significant correlation between NOTCH1 and/or FBXW7 mutations and clinico-biologic features. Median event-free survival (EFS) and overall survival (OS) were 36 versus 17 months (P = .01) and not reached versus 32 months (P = .004) in patients with NOTCH1 and/or FBXW7 mutations versus other patients, respectively. Multivariate analysis showed that the presence of NOTCH1/FBXW7 mutations was an independent good prognostic factor for EFS and OS (P = .02 and P = .01, respectively). These data demonstrate that NOTCH1 pathway activation by either NOTCH1 or FBXW7 mutation identifies a large group of patients with a favorable outcome that could justify individual therapeutic stratification for T-ALL.
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Proteínas de Ciclo Celular/genética , Proteínas F-Box/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/clasificación , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Receptor Notch1/genética , Ubiquitina-Proteína Ligasas/genética , Adulto , Proteínas de Ciclo Celular/metabolismo , Proteínas F-Box/metabolismo , Proteína 7 que Contiene Repeticiones F-Box-WD , Genotipo , Humanos , Mutación/genética , Fenotipo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/terapia , Pronóstico , Receptor Notch1/metabolismo , Sociedades Médicas , Tasa de Supervivencia , Factores de Tiempo , Resultado del Tratamiento , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Rituximab (RTX) is an anti-CD20 monoclonal antibody that targets B cells-from the immature pre-B-cell stage in the bone marrow to mature circulating B cells-while preserving stem cells and plasma cells. It is used to treat autoimmune diseases, hematological malignancies, or complications after hematopoietic stem cell transplantation (HSCT). Its safety profile is acceptable; however, a subset of patients can develop persistent hypogammaglobulinemia and associated severe complications, especially in pediatric populations. We report the unrelated cases of two young men aged 17 and 22, presenting with persistent hypogammaglobulinemia more than 7 and 10 years after treatment with RTX, respectively, and administered after HSCT for hemolytic anemia and Epstein-Barr virus reactivation, respectively. Both patients' immunological workups showed low levels of total immunoglobulin, vaccine antibodies, and class switched-memory B cells but an increase in naive B cells, which can also be observed in primary immunodeficiencies such as those making up common variable immunodeficiency. Whole exome sequencing for one of the patients failed to detect a pathogenic variant causing a Mendelian immunological disorder. Annual assessments involving interruption of immunoglobulin replacement therapy each summer failed to demonstrate the recovery of endogenous immunoglobulin production or normal numbers of class switched-memory B cells 7 and 10 years after the patients' respective treatments with RTX. Although the factors that may lead to prolonged hypogammaglobulinemia after rituximab treatment (if necessary) remain unclear, a comprehensive immunological workup before treatment and long-term follow-up are mandatory to assess long-term complications, especially in children.
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Agammaglobulinemia/diagnóstico , Infecciones por Virus de Epstein-Barr/tratamiento farmacológico , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Rituximab/efectos adversos , Adolescente , Agammaglobulinemia/sangre , Agammaglobulinemia/inducido químicamente , Anemia Aplásica/inmunología , Anemia Aplásica/terapia , Infecciones por Virus de Epstein-Barr/inmunología , Enfermedad Injerto contra Huésped/inmunología , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras B/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Factores de Tiempo , Adulto JovenRESUMEN
Most children with a SARS-CoV-2 infection are asymptomatic or exhibit mild symptoms. However, a small number of children develop features of substantial inflammation temporarily related to the COVID-19 also called multisystem inflammatory syndrome in children (MIS-C) or pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS), clinically similar to Kawasaki disease, toxic shock syndrome and hemophagocytic lymphohistiocytosis (HLH). It is well-known that genetic pre-disposition plays an important role in virally-triggered diseases such as Epstein-Barr virus (EBV)-associated HLH, while this has not yet been established for patients with MIS-C. Here we describe a male patient fulfilling the diagnostic criteria of MIS-C, who was initially treated according to current consensus guidelines. Presence of hypofibrinogenemia, normal lymphocyte counts and C-reactive protein, but substantial hyperferritinemia distinguish this patient from others with MIS-C. The clinical course following initial presentation with acute respiratory distress syndrome was marked by fatal liver failure in the context of EBV-associated HLH despite treatment with steroids, intravenous immunoglobulins, interleukin (IL)-1 receptor blockade and eventually HLH-directed treatment. X-linked lymphoproliferative disease type 1 (XLP1), a subtype of primary HLH was diagnosed in this patient post-mortem. This case report highlights the importance of including HLH in the differential diagnosis in MIS-C with severe disease course to allow specific, risk-adapted treatment and genetic counseling.
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Many primary immunodeficiencies (PIDs) are recognised as being associated with malignancies, particularly lymphoid malignancies, which represent the highest proportion of cancers occurring in conjunction with this underlying condition. When patients present with genetic errors of immunity, clinicians must often reflect on whether to manage antitumoral treatment conventionally or to take a more personalised approach, considering possible existing comorbidities and the underlying status of immunodeficiency. Recent advances in antitumoral immunotherapies, such as monoclonal antibodies, antigen-specific adoptive cell therapies or compounds with targeted effects, potentially offer significant opportunities for optimising treatment for those patients, especially with lymphoid malignancies. In cases involving PIDs, variable oncogenic mechanisms exist, and opportunities for antitumoral immunotherapies can be considered accordingly. In cases involving a DNA repair defect or genetic instability, monoclonal antibodies can be proposed instead of chemotherapy to avoid severe toxicity. Malignancies secondary to uncontrolled virus-driven proliferation or the loss of antitumoral immunosurveillance may benefit from antivirus cell therapies or allogeneic stem cell transplantation in order to restore the immune antitumoral caretaker function. A subset of PIDs is caused by gene defects affecting targetable signalling pathways directly involved in the oncogenic process, such as the constitutive activation of phosphoinositol 3-kinase/protein kinase B (PI3K/AKT) in activated phosphoinositide 3-kinase delta syndrome (APDS), which can be settled with PI3K/AKT inhibitors. Therefore, immunotherapy provides clinicians with interesting antitumoral therapeutic weapons to treat malignancies when there is an underlying PID.
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Inmunoterapia/métodos , Neoplasias/complicaciones , Neoplasias/terapia , Enfermedades de Inmunodeficiencia Primaria/complicaciones , Enfermedades de Inmunodeficiencia Primaria/terapia , Animales , Anticuerpos Monoclonales Humanizados/uso terapéutico , Niño , Reparación del ADN , Inestabilidad Genómica , Humanos , Factores Inmunológicos/uso terapéutico , Neoplasias/genética , Neoplasias/inmunología , Enfermedades de Inmunodeficiencia Primaria/genética , Enfermedades de Inmunodeficiencia Primaria/inmunologíaRESUMEN
PURPOSE: T lymphoblastic lymphomas (T-LBL) are rare disorders of immature T cells which predominantly involve the mediastinum. Their oncogenic pathways and prognostic variables are not clear. EXPERIMENTAL DESIGN: We undertook a retrospective study of 41 cytoplasmic CD3+ T-LBL (nine cases aged <16 years) by assessing stage of maturation arrest based on T cell receptor (TCR) immunogenotyping, immunohistochemistry, and quantification of the oncogenes thought to be important in immature T cell malignancies. RESULTS: Application of a TCR-based immunogenetic classification allowed the identification of three subcategories: 11 immature IM0/D-LBL showed no TCR or only incomplete TCRD DJ rearrangement and corresponded to cytoplasmic CD3+ precursors of uncertain lineage. Sixteen mature TCRD(del)-LBL showed biallelic TCRD deletion and both TCRG and TCRB rearrangement, consistent with TCRalphabeta lineage restriction. Fourteen intermediate LBL (Int-LBL) showed complete TCRD VDJ and TCRG VJ rearrangement, with TCRB VDJ rearrangement in the majority. All Int-LBL expressed HOX11/TLX1 or HOXA9 transcripts and a proportion of the latter were associated with CALM-AF10 or NUP214-ABL fusion transcripts. IM0/D-LBL were restricted to adults with extrathymic disease and bone marrow involvement, whereas Int-LBL and TCRD(del)-LBL were found in children and adults with predominantly thymic disease. In adults, the Int-LBL subgroup was associated with a significantly superior clinical outcome. This subgroup can be identified either by TCR immunogenotyping or HOXA9/TLX1 transcript quantification. CONCLUSION: Application of this molecular classification will allow the prospective evaluation of prognostic effects within pediatric and adult protocols.
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Proteínas de Homeodominio/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteínas Proto-Oncogénicas/genética , Receptores de Antígenos de Linfocitos T/genética , Adolescente , Adulto , Anciano , Biopsia , Niño , Preescolar , ADN de Neoplasias/genética , Femenino , Genotipo , Humanos , Ganglios Linfáticos/patología , Masculino , Persona de Mediana Edad , Derrame Pleural/genética , Reacción en Cadena de la Polimerasa , Leucemia-Linfoma Linfoblástico de Células Precursoras/clasificación , Receptor Notch1/genética , Estudios RetrospectivosRESUMEN
Short-term intensive chemotherapy regimens have substantially improved the prognosis of pediatric patients with Burkitt lymphoma (BL), which now has an excellent overall outcome. However, central nervous system (CNS) involvement at diagnosis remains a poor prognostic factor, and progressive or relapsed disease in the CNS is associated with even worse outcomes. We report 3 boys aged 4, 7, and 12 years treated under the French Société Française d'Oncologie Pédiatrique LMB 89/96 protocols who presented, respectively, with CNS-/bone marrow+ stage-IV BL; CNS+ stage-IV BL; and stage-I BL. Each experienced an isolated CNS relapse, which was treated with CNS-directed salvage chemotherapy. All 3 are alive after 11 years of median follow-up, indicating that this chemotherapy regimen can be curative in pediatric BL with isolated CNS relapse.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma de Burkitt/tratamiento farmacológico , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Terapia Recuperativa , Linfoma de Burkitt/patología , Neoplasias del Sistema Nervioso Central/patología , Niño , Preescolar , Ciclofosfamida/uso terapéutico , Citarabina/uso terapéutico , Humanos , Imagen por Resonancia Magnética , Masculino , Metotrexato/uso terapéutico , Recurrencia Local de Neoplasia/patología , Inducción de Remisión , Resultado del TratamientoRESUMEN
T-cell acute lymphoblastic leukemia (T-ALL) expands in various bone marrow (BM) sites of the body. We investigated whether different BM sites could differently modulate T-ALL propagation using in vivo animal models. We observed that mouse and human T-ALL develop slowly in the BM of tail vertebrae compared with the BM from thorax vertebrae. T-ALL recovered from tail BM displays lower cell-surface marker expression and decreased metabolism and cell-cycle progression, demonstrating a dormancy phenotype. Functionally, tail-derived T-ALL exhibit a deficient short-term ex vivo growth and a delayed in vivo propagation. These features are noncell-autonomous because T-ALL from tail and thorax shares identical genomic abnormalities and functional disparities disappear in vivo and in prolonged in vitro assays. Importantly tail-derived T-ALL displays higher intrinsic resistance to cell-cycle-related drugs (ie, vincristine sulfate and cytarabine). Of note, T-ALL recovered from gonadal adipose tissues or from cocultures with adipocytes shares metabolic, cell-cycle, and phenotypic or chemoresistance features, with tail-derived T-ALL suggesting adipocytes may participate in the tail BM imprints on T-ALL. Altogether these results demonstrate that BM sites differentially orchestrate T-ALL propagation stamping specific features to leukemic cells such as quiescence and decreased response to cell-cycle-dependent chemotherapy.
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Development of novel therapies is critical for T-cell acute leukaemia (T-ALL). Here, we investigated the effect of inhibiting the MAPK/MEK/ERK pathway on T-ALL cell growth. Unexpectedly, MEK inhibitors (MEKi) enhanced growth of 70% of human T-ALL cell samples cultured on stromal cells independently of NOTCH activation and maintained their ability to propagate in vivo. Similar results were obtained when T-ALL cells were cultured with ERK1/2-knockdown stromal cells or with conditioned medium from MEKi-treated stromal cells. Microarray analysis identified interleukin 18 (IL-18) as transcriptionally up-regulated in MEKi-treated MS5 cells. Recombinant IL-18 promoted T-ALL growth in vitro, whereas the loss of function of IL-18 receptor in T-ALL blast cells decreased blast proliferation in vitro and in NSG mice. The NFKB pathway that is downstream to IL-18R was activated by IL-18 in blast cells. IL-18 circulating levels were increased in T-ALL-xenografted mice and also in T-ALL patients in comparison with controls. This study uncovers a novel role of the pro-inflammatory cytokine IL-18 and outlines the microenvironment involvement in human T-ALL development.
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Interleucina-18/inmunología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/inmunología , Células del Estroma/inmunología , Animales , Células de la Médula Ósea/citología , Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/patología , Línea Celular , Línea Celular Tumoral , Proliferación Celular , Regulación Leucémica de la Expresión Génica , Silenciador del Gen , Humanos , Interleucina-18/sangre , Interleucina-18/genética , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Ratones , Ratones Endogámicos NOD , Leucemia-Linfoma Linfoblástico de Células T Precursoras/sangre , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Células del Estroma/citología , Células del Estroma/metabolismo , Células del Estroma/patología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Linfocitos T/patologíaRESUMEN
T cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer that is frequently associated with activating mutations in NOTCH1 and dysregulation of MYC. Here, we performed 2 complementary screens to identify FDA-approved drugs and drug-like small molecules with activity against T-ALL. We developed a zebrafish system to screen small molecules for toxic activity toward MYC-overexpressing thymocytes and used a human T-ALL cell line to screen for small molecules that synergize with Notch inhibitors. We identified the antipsychotic drug perphenazine in both screens due to its ability to induce apoptosis in fish, mouse, and human T-ALL cells. Using ligand-affinity chromatography coupled with mass spectrometry, we identified protein phosphatase 2A (PP2A) as a perphenazine target. T-ALL cell lines treated with perphenazine exhibited rapid dephosphorylation of multiple PP2A substrates and subsequent apoptosis. Moreover, shRNA knockdown of specific PP2A subunits attenuated perphenazine activity, indicating that PP2A mediates the drug's antileukemic activity. Finally, human T-ALLs treated with perphenazine exhibited suppressed cell growth and dephosphorylation of PP2A targets in vitro and in vivo. Our findings provide a mechanistic explanation for the recurring identification of phenothiazines as a class of drugs with anticancer effects. Furthermore, these data suggest that pharmacologic PP2A activation in T-ALL and other cancers driven by hyperphosphorylated PP2A substrates has therapeutic potential.
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Apoptosis , Fenotiazinas/química , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Proteína Fosfatasa 2/metabolismo , Animales , Animales Modificados Genéticamente , Línea Celular Tumoral , Supervivencia Celular , Cromatografía de Afinidad , Modelos Animales de Enfermedad , Antagonistas de Dopamina/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Espectrometría de Masas , Ratones , Perfenazina/química , Fosforilación , Pigmentación , Proteómica , Receptores Notch/metabolismo , Factores de Tiempo , Pez CebraRESUMEN
Neuropilins and semaphorins are known as modulators of axon guidance, angiogenesis, and organogenesis in the developing nervous system, but have been recently evidenced as also playing a role in the immune system. Here we describe the expression and role of semaphorin 3F (SEMA3F) and its receptor neuropilin-2 (NRP2) in human T cell precursors. NRP2 and SEMA3F are expressed in the human thymus, in both lymphoid and non-lymphoid compartments. SEMA3F have a repulsive effect on thymocyte migration and inhibited CXCL12- and sphingosine-1-phosphate (S1P)-induced thymocyte migration by inhibiting cytoskeleton reorganization prior to stimuli. Moreover, NRP2 and SEMA3F are expressed in human T-cell acute lymphoblastic leukemia/lymphoma primary cells. In these tumor cells, SEMA3F also blocks their migration induced by CXCL12 and S1P. Our data show that SEMA3F and NRP2 are further regulators of human thymocyte migration in physiological and pathological conditions.
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Movimiento Celular/genética , Proteínas de la Membrana/genética , Proteínas del Tejido Nervioso/genética , Neuropilina-2/genética , Células Precursoras de Linfocitos T/metabolismo , Anticuerpos Bloqueadores/inmunología , Anticuerpos Bloqueadores/farmacología , Movimiento Celular/efectos de los fármacos , Células Cultivadas , Quimiocina CXCL12/farmacología , Niño , Preescolar , Expresión Génica , Humanos , Lactante , Recién Nacido , Lisofosfolípidos/farmacología , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/farmacología , Microscopía Confocal , Proteínas del Tejido Nervioso/metabolismo , Proteínas del Tejido Nervioso/farmacología , Neuropilina-2/inmunología , Neuropilina-2/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Esfingosina/análogos & derivados , Esfingosina/farmacología , Timocitos/metabolismo , Timo/citología , Timo/metabolismoRESUMEN
PURPOSE: Pediatric T-cell lymphoblastic lymphomas (T-LBL) are commonly treated on T-cell acute lymphoblastic leukemia (T-ALL) -derived protocols. Therapeutic stratification based on response to the prephase treatment and on minimal residual disease assessment is well established in T-ALL but is not easy to extrapolate to T-LBL. The identification of molecular prognostic markers at diagnosis in T-LBL could provide an alternative for early therapeutic stratification. Our study determines the frequency and prognostic value of NOTCH1/FBXW7 mutations (N/F(mut)), FLASH deletion at chromosome 6q, and TCR rearrangements in a prospective cohort of pediatric T-LBL. PATIENTS AND METHODS: Pathologic samples were obtained at diagnosis for 54 patients treated according to the EuroLB02 protocol in France. N/F(mut) were identified by direct sequencing and allelic dosage was used to detect FLASH and TCRγ deletions, which were interpreted in conjunction with TCRγ, TCRß, and TCRδ rearrangements. RESULTS: N/F(mut) were found in 55% of T-LBL patients, in whom they were associated with improved event-free survival (P < .01) and overall survival (P < .01). FLASH monoallelic deletions were observed in 18% of patients; they were predominantly N/F wild-type (six of nine) and tended to be of inferior prognosis (P = .09). Absence of biallelic TCRγ deletion (ABD) was seen in 7%, all of which were N/F(mut) and identified a poor prognosis group (P = .02). On multivariate analysis of N/F(mut), TCRγ ABD, and FLASH deletion, only N/F(mut) was an independent factor for good prognosis. CONCLUSION: Mutational status of NOTCH1/FBXW7 represents a promising marker for early therapeutic stratification in pediatric T-LBL.
Asunto(s)
Proteínas Reguladoras de la Apoptosis/genética , Proteínas de Unión al Calcio/genética , Proteínas de Ciclo Celular/genética , Proteínas F-Box/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Receptores de Antígenos de Linfocitos T/genética , Ubiquitina-Proteína Ligasas/genética , Adolescente , Niño , Preescolar , Proteína 7 que Contiene Repeticiones F-Box-WD , Femenino , Humanos , Lactante , Masculino , Mutación , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológico , Pronóstico , Receptor Notch1/genética , Eliminación de SecuenciaRESUMEN
Cytogenetic, molecular and phenotyping features of malignant hematologic diseases succeeded in improving their management by a more accurate stratification of patients according to several groups of risk and by providing a rational for targeted therapy. Three major types of treatment (excluding cellular therapy) are currently available in onco-hematology: conventional chemotherapy, small molecules for targeted therapy and monoclonal antibodies. Conventional chemotherapy with optimization of doses and multidrug-based regimens allowed to substantially improve survival of patients and keeps a place of choice in treatment of these diseases. Targeted treatments came from the cytogenetic and molecular characterization of hemopathies. Thus, the kinase Bcr-Abl, as a result of the translocation t(9;22)(q34;q11), has been successfully targeted by tyrosine kinase inhibitors (TKI) in chronic myeloid leukemia and Ph+âacute lymphoblastic leukemia. Molecular abnormalities like internal-tandem duplication/point activating mutations in FLT3 in some acute myeloblastic leukemia or epigenetic dysregulations in some blood malignancies can also be targeted by small molecules. Hematopoietic malignant cells are phenotypically characterized by expression of cluster of differentiation (CD) on their surface. These CD are detected by flow cytometry using specific antibodies. Monoclonal antibodies targeting different CD have been developed for treatment. Rituximab, an anti-CD20 antibody, was the first monoclonal antibody successfully developed for treatment of malignant hematologic diseases. Since rituximab, many other monoclonal antibodies are being developed. Trends in malignant hematologic diseases presented here will include treatments, which have at least entered phase I/II clinical trials in adult or childhood leukemia. They include some novel drugs of conventional chemotherapy like second-generation nucleoside analogues. We will give an overview of the small molecules targeting the different cellular pathways and we will highlight those appearing as the most promising like novel TKIs. The large field of monoclonal antibodies will be also approached focusing on antibodies developed in leukemias.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias Hematológicas/tratamiento farmacológico , Terapia Molecular Dirigida/métodos , Nucleótidos de Adenina/uso terapéutico , Antineoplásicos/química , Arabinonucleósidos/uso terapéutico , Química Farmacéutica , Clofarabina , Humanos , Nucleósidos de Purina/uso terapéutico , Pirimidinonas/uso terapéuticoRESUMEN
BACKGROUND: Notch receptors normally play a key role in guiding a variety of cell fate decisions during development and differentiation of metazoan organisms. On the other hand, dysregulation of Notch1 signaling is associated with many different types of cancer as well as tumor angiogenesis, making Notch1 a potential therapeutic target. PRINCIPAL FINDINGS: Here we report the in vitro activities of inhibitory Notch1 monoclonal antibodies derived from cell-based and solid-phase screening of a phage display library. Two classes of antibodies were found, one directed against the EGF-repeat region that encompasses the ligand-binding domain (LBD), and the second directed against the activation switch of the receptor, the Notch negative regulatory region (NRR). The antibodies are selective for Notch1, inhibiting Jag2-dependent signaling by Notch1 but not by Notch 2 and 3 in reporter gene assays, with EC(50) values as low as 5+/-3 nM and 0.13+/-0.09 nM for the LBD and NRR antibodies, respectively, and fail to recognize Notch4. While more potent, NRR antibodies are incomplete antagonists of Notch1 signaling. The antagonistic activity of LBD, but not NRR, antibodies is strongly dependent on the activating ligand. Both LBD and NRR antibodies bind to Notch1 on human tumor cell lines and inhibit the expression of sentinel Notch target genes, including HES1, HES5, and DTX1. NRR antibodies also strongly inhibit ligand-independent signaling in heterologous cells transiently expressing Notch1 receptors with diverse NRR "class I" point mutations, the most common type of mutation found in human T-cell acute lymphoblastic leukemia (T-ALL). In contrast, NRR antibodies failed to antagonize Notch1 receptors bearing rare "class II" or "class III" mutations, in which amino acid insertions generate a duplicated or constitutively sensitive metalloprotease cleavage site. Signaling in T-ALL cell lines bearing class I mutations is partially refractory to inhibitory antibodies as compared to cell-penetrating gamma-secretase inhibitors. CONCLUSIONS/SIGNIFICANCE: Antibodies that compete with Notch1 ligand binding or that bind to the negative regulatory region can act as potent inhibitors of Notch1 signaling. These antibodies may have clinical utility for conditions in which inhibition of signaling by wild-type Notch1 is desired, but are likely to be of limited value for treatment of T-ALLs associated with aberrant Notch1 activation.