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INTRODUCTION: About 15% of people with a myeloproliferative neoplasm (MPN) are identified as MPN, unclassifiable using the 2016 WHO classification. METHODS: We tested whether persons with platelet concentration ≥450 × 10E+9/L, bone marrow megakaryocyte morphology typical of prefibrotic/early myelofibrosis (pre-MF), and no minor criteria of pre-MF should be classified as a distinct MPN subtype, clonal megakaryocyte dysplasia with isolated thrombocytosis (CMD-IT). RESULTS: 139 subjects meet these criteria who we compared with primary myelofibrosis (PMF) including 402 with pre-MF and 521 with overt myelofibrosis. CMD-IT subjects were more likely female and younger. They had lower frequencies of JAK2V617F compared with persons with PMF (55% vs. 70%; p < 0.001) and higher frequencies of CALR mutations (37% vs. 17%; p < 0.001). They also had lower frequency of variations associated with JAK2V617F susceptibility, JAK2 46/1 (35% vs. 47%; p = 0.021), and VEGFA rs3025039 (12% vs. 17%; p = 0.030). Subjects with CMD-IT had lower incidences of thrombotic events compared with those with pre-MF (9.7% vs. 26%; p < 0.001) and longer survival (median, not reached vs. 23 years; HR = 0.34 (0.10, 0.30); p < 0.001). CONCLUSION: Our data indicate CMD-IT is a distinct MPN subtype and should be included in the classification of myeloid neoplasms.
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Trastornos Mieloproliferativos , Neoplasias , Mielofibrosis Primaria , Trombocitemia Esencial , Trombocitosis , Femenino , Humanos , Mielofibrosis Primaria/diagnóstico , Mielofibrosis Primaria/genética , Megacariocitos , Trombocitemia Esencial/diagnóstico , Trombocitemia Esencial/genética , Mutación , Trastornos Mieloproliferativos/diagnóstico , Trastornos Mieloproliferativos/genética , Trombocitosis/genética , Fenotipo , Janus Quinasa 2/genética , Calreticulina/genéticaRESUMEN
Inhibitors of poly(ADP-ribose) polymerase (PARPi) are increasingly employed as salvage therapy in epithelial ovarian cancer (EOC), but cytotoxic drug exposure along with PARP inhibition may favor development of hematological disorders. In our study, of 182 women with EOC treated with PARPi, 16 (8.7%) developed therapy-related myeloid neoplasms (t-MNs), with 12 cases of myelodysplasia and 4 of acute myeloid leukemia. All experienced persistent cytopenia after PARPi discontinuation. Seven patients had del(5q)/-5 and/or del(7q)/-7, nine had a complex karyotype and TP53 mutations, recently reported as risk factor for t-MNs in EOC post-PARPi, were found in 12 out of 13 tested patients. Four patients had a rapid and fatal outcome, one had stable disease, eleven underwent induction therapy, followed by allogeneic hematopoietic cell transplantation in seven. Three of these 11 patients experienced refractory disease, and 8 had complete remission. During a 6.8 months (range 2.3-49) median observation time, 3 out of 16 patients were alive, with one surviving patient free of both solid and hematological tumors. Ten patients died because of leukemia, two because of transplant-related events, one from heart failure. Five more patients experienced persistent cell blood count abnormalities following PARPi discontinuation, without reaching MDS diagnostic criteria. A customized Myelo-panel showed clonal hematopoiesis in all five patients. These findings confirm the actual risk of t-MNs in EOC patients after chemotherapy and prolonged PARPi therapy. The management of these patients is complex and outcomes are extremely poor. Careful diagnostic procedures are strongly recommended whenever unusual cytopenias develop in patients receiving PARPi therapy.
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Neoplasias Primarias Secundarias , Neoplasias Ováricas , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Análisis Citogenético , Femenino , Humanos , Neoplasias Primarias Secundarias/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Terapia RecuperativaRESUMEN
INTRODUCTION: In 1991, we reported 18 persons with a clinical-pathologic entity and termed atypical myeloproliferative disorder because they did not meet the contemporary diagnostic criteria for a myeloproliferative neoplasm. We sought to gain further knowledge on this disease entity. METHODS: This retrospective cohort study included consecutive subjects registered in the database of the Center for the Study of Myelofibrosis in Pavia, Italy, from 1998 to 2020 (June), and diagnosed with atypical myeloproliferative disorder according to our adjudicated criteria. We studied clinical, histological, cytogenetic, and molecular covariates and risks of thrombosis, disease progression, and death. Data were compared with those of concurrent subjects with prefibrotic myelofibrosis. RESULTS: Fifteen new subjects with atypical myeloproliferative disorder were identified. Seven were male. Median age was 50 years (IQR, 41-54 years). Thirteen were diagnosed with a synchronous symptomatic or incidentally detected thrombotic event. The bone marrow showed megakaryocyte hyperplasia with dysplasia. JAK2V617F was present in 10 subjects and CALR mutation in one. No other somatic mutations were identified in next generation sequencing. After a median follow-up of 101 months (IQR, 40-160 months), no subject had disease progression or blast transformation. Incidence of post-diagnosis or recurrent thrombosis was 3.9 events (95% confidence interval, 3.5-4.0) and 5.0 events (4.6-5.6) per 100 person-years. Features of subjects with atypical myeloproliferative disorder differed markedly from those of 546 subjects with prefibrotic myelofibrosis. CONCLUSION: Our data indicate that these 15 persons have a distinct myeloproliferative neoplasm. We propose naming this new disorder clonal megakaryocyte dysplasia with normal blood values.
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Calreticulina , Neoplasias Hematológicas , Janus Quinasa 2 , Megacariocitos , Mutación Missense , Trastornos Mieloproliferativos , Adulto , Sustitución de Aminoácidos , Médula Ósea/metabolismo , Médula Ósea/patología , Calreticulina/genética , Calreticulina/metabolismo , Femenino , Neoplasias Hematológicas/sangre , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patología , Humanos , Janus Quinasa 2/genética , Janus Quinasa 2/metabolismo , Masculino , Megacariocitos/metabolismo , Megacariocitos/patología , Persona de Mediana Edad , Trastornos Mieloproliferativos/sangre , Trastornos Mieloproliferativos/genética , Trastornos Mieloproliferativos/patología , Estudios Retrospectivos , TrombosisRESUMEN
We investigated the occurrence and management of therapy-related hematological disorders (tr-HDs) in women with epithelial ovarian cancer (EOC) exposed to poly-ADP-ribose polymerase inhibitors (PARPi), after previous chemotherapy. We analyzed 130 consecutive EOC patients treated with PARPi at the European Institute of Oncology, Milan. In line with the literature, overall survival of the entire population was 37% at 5.5 years (89% were advanced stages). Cell blood counts were collected prior to start PARPi, at each new cycle and at monthly intervals. Patients displaying persistent and/or marked hematological abnormalities underwent bone marrow evaluation, with cytogenetic and molecular analysis. Nine patients (6,9%) developed tr-HDs, after a median 22.8 months of PARPi exposure. Two patients died early and could not be treated. Two patients have no indication for active treatment and are presently under close hematological monitoring. Five patients underwent chemotherapy followed, in three cases, by allogeneic hematopoietic transplantation: three patients are in complete remission of their hematological and gynecological malignancies at 13, 19, and 25 months; the remaining two patients died due to progression of their hematological disease. We show the potential risk of hematological disorders in EOC patients treated with chemotherapy and prolonged PARPi therapy. In our series, tr-HDs incidence was higher compared to recent reports in large series. Our observations suggest careful monitoring in order to conclusively define, on large series and prolonged follow-up, the actual risk of tr-HDs in patients under PARPi. Notably, prompt diagnosis of hematological abnormalities and appropriate management allow achievement of remission from severe hematological complications, at least in most patients.
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Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Enfermedades Hematológicas/diagnóstico , Neoplasias Ováricas/tratamiento farmacológico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversos , Adulto , Anciano , Recuento de Células Sanguíneas , Médula Ósea/patología , Carcinoma Epitelial de Ovario/mortalidad , Femenino , Enfermedades Hematológicas/inducido químicamente , Enfermedades Hematológicas/epidemiología , Enfermedades Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas , Humanos , Incidencia , Persona de Mediana Edad , Neoplasias Ováricas/mortalidad , Estudios Retrospectivos , Trasplante HomólogoAsunto(s)
Infecciones por Coronavirus/terapia , Eritrocitos/inmunología , Inmunoglobulina G/inmunología , Neumonía Viral/terapia , Anciano , Anciano de 80 o más Años , Anemia/complicaciones , Anemia/inmunología , Anemia/terapia , Autoanticuerpos/análisis , Autoanticuerpos/inmunología , Betacoronavirus/inmunología , Betacoronavirus/aislamiento & purificación , Transfusión Sanguínea , COVID-19 , Prueba de Coombs , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/inmunología , Femenino , Humanos , Inmunoglobulina G/análisis , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/complicaciones , Neumonía Viral/inmunología , SARS-CoV-2RESUMEN
The human white adipose tissue (WAT) contains progenitors with cooperative roles in breast cancer (BC) angiogenesis, local and metastatic progression. The biguanide Metformin (Met), commonly used for Type 2 diabetes, might have activity against BC and was found to inhibit angiogenesis in vivo. We studied Met and another biguanide, phenformin (Phe), in vitro and in vivo in BC models. In vitro, biguanides activated AMPK, inhibited Complex 1 of the respiratory chain and induced apoptosis of BC and WAT endothelial cells. In coculture, biguanides inhibited the production of several angiogenic proteins. In vivo, biguanides inhibited local and metastatic growth of triple negative and HER2+ BC in immune-competent and immune-deficient mice orthotopically injected with BC. Biguanides inhibited local and metastatic BC growth in a genetically engineered murine model model of HER2+ BC. In vivo, biguanides increased pimonidazole binding (but not HIF-1 expression) of WAT progenitors, reduced tumor microvessel density and altered the vascular pericyte/endothelial cell ratio, so that cancer vessels displayed a dysplastic phenotype. Phe was significantly more active than Met both in vitro and in vivo. Considering their safety profile, biguanides deserve to be further investigated for BC prevention in high-risk subjects, in combination with chemo and/or targeted therapy and/or as post-therapy consolidation or maintenance therapy for the prevention of BC recurrence.
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Neoplasias de la Mama/tratamiento farmacológico , Metformina/farmacología , Neovascularización Patológica/prevención & control , Fenformina/farmacología , Microambiente Tumoral , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/irrigación sanguínea , Neoplasias de la Mama/patología , Línea Celular Tumoral , Complejo I de Transporte de Electrón/antagonistas & inhibidores , Femenino , Humanos , Ratones , Metástasis de la Neoplasia , Fosforilación , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
BACKGROUND: Myeloid neoplasms, including acute myeloid leukemia, have been traditionally among the less investigated cancer types concerning germline predisposition. Indeed, myeloid neoplasms with germline predisposition are challenging to identify because often display similar clinical and morphological characteristics of sporadic cases and have similar age at diagnosis. However, a misidentifications of familiarity in myeloid neoplasms have a critical impact on clinical management both for the carriers and their relatives. AIMS: We conducted a family segregation study, in order to identify novel cancer predisposing genes in myeloid neoplasms and classify novel identified variants. METHODS AND RESULTS: We performed a thorough genomic analysis using a large custom gene panel (256 genes), the Myelo-Panel, targeted on cancer predisposing genes. In particular, we assessed both germline and somatic variants in four families, each with two siblings, who developed hematological neoplasms: seven acute myeloid leukemia and one Philadelphia-positive chronic myeloid leukemia. In each family, we identified at least one novel potentially predisposing variant, affecting also genes not included in the current European LeukemiaNet guidelines for AML management. Moreover, we suggest reclassification of two germline variants as pathogenic: likely pathogenic p.S21Tfs*139 in CEPBA and VUS p.K392Afs*66 in DDX41. CONCLUSION: We believe that predisposition to hematological neoplasms is still underestimated and particularly difficult to diagnosed. Considering that misidentification of familiarity in myeloid neoplasms have a critical impact on the clinical management both for the carriers and their relatives, our study highlights the importance of revision, in this clinical context, of clinical practices that should include thorough reconstruction of family history and in-depth genetic testing.
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Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Leucemia Mieloide Aguda , Linaje , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/diagnóstico , Femenino , Masculino , Persona de Mediana Edad , Adulto , ARN Helicasas DEAD-box/genética , AncianoRESUMEN
Background: The management of locally advanced rectal cancer (LARC) relies on a multimodal approach. Neither instrumental work-up nor molecular biomarkers are currently available to identify a risk-adapted strategy. Objectives: We aim to investigate the role of circulating tumor DNA (ctDNA) and its clearance at different timepoints during chemo-radiotherapy (CRT) and correlate them with clinical outcomes. Design: Between November 2014 and November 2019, we conducted a monocentric prospective observational study enrolling consecutive patients with LARC managed with neoadjuvant standard CRT (capecitabine and concomitant pelvic long-course radiotherapy), followed by consolidation capecitabine in selected cases and surgery. Methods: Blood samples for ctDNA were obtained at pre-planned timepoints. We evaluated the correlation of baseline variant allele frequency (VAF) with pathologic complete response (pCR) down-staging, node regression (pN0), event-free survival (EFS), and overall survival (OS). Results: Among 112 screened patients, 61 were enrolled. In all, 38 (62%) had a positive ctDNA at baseline with VAF > 0 and 23 had negative ctDNA (VAF = 0). Among patients with negative ctDNA, 30% had a complete response, while only 13% of positive ctDNA patients had pCR [odds ratio (OR) 0.35 (95% confidence interval (CI): 0.10-1.26), p = 0.11]. Similarly, 96% and 74% of pN0 were observed among negative and positive ctDNA patients, respectively [OR 0.13 (95% CI: 0.02-1.07), p = 0.058]. The presence of a baseline VAF > 0 was associated with a trend toward a lower EFS compared with VAF = 0 patients [hazard ratio (HR) = 2.30, 95% CI: 0.63-8.36, p = 0.21]. Within the limitations of small sample size, no difference in OS was observed according to the baseline ctDNA status (HR = 1.18, 95% CI: 0.35-4.06, p = 0.79). Conclusion: Within the limitations of a reduced number of patients, patients with baseline negative ctDNA seem to show a higher probability of pN0 status and a trend toward improved EFS. Prospective translational studies are required to define the role of ctDNA analysis in the multimodal treatment of LARC.
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We herein characterize the immunopathological features of two Italian COVID-19 patients who underwent bilateral lung transplantation (bLTx). Removed lungs underwent histopathological evaluation. Gene expression profiling (GEP) for immune-related signatures was performed on lung specimens and SARS-CoV-2-stimulated peripheral blood mononuclear cells (PBMCs). Cytokine levels were measured on lungs, bronchoalveolar lavage fluids and in culture supernatants. Pathological assessment showed extensive lung damage with the pattern of proliferative to fibrotic phases, with diffuse alveolar damage mimicking usual interstitial pneumonia (UIP). Lungs' GEP revealed overexpression of pathogen recognition receptors, effector cytokines and chemokines, immune activation receptors and of the inflammasome components. Multiplex cytokine analysis confirmed a proinflammatory state, with high levels of monocyte/macrophage chemotactic and activating factors and of IL-6 and TNF-α. A similar profile was observed in SARS-CoV-2-stimulated PBMCs collected 7 days after transplant. The pattern of tissue damage observed in the lungs suggests that this may represent the output of protracted disease, resembling a diffuse UIP-like picture. The molecular immune profiling supports the paradigm of a persistent proinflammatory state and sustained humoral immunity, conditions that are maintained despite the iatrogenic immunosuppression.
Asunto(s)
COVID-19/cirugía , Quimiocinas/metabolismo , Citocinas/metabolismo , Leucocitos Mononucleares/metabolismo , Trasplante de Pulmón , Pulmón/patología , Síndrome de Dificultad Respiratoria/cirugía , Adolescente , Líquido del Lavado Bronquioalveolar/citología , Líquido del Lavado Bronquioalveolar/virología , COVID-19/sangre , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/inmunología , Genotipo , Humanos , Inflamasomas/metabolismo , Interleucina-6/metabolismo , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/virología , Ganglios Linfáticos/patología , Ganglios Linfáticos/virología , Masculino , Persona de Mediana Edad , Plasma/virología , Polimorfismo de Nucleótido Simple , Síndrome de Dificultad Respiratoria/inmunología , Síndrome de Dificultad Respiratoria/patología , Síndrome de Dificultad Respiratoria/virología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
BACKGROUND: During the course of COVID-19, the disease caused by the new coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), thrombotic phenomena and/or diffuse vascular damage are frequent, and viral elements have been observed within endothelial cells. OBJECTIVES: CD146 + circulating endothelial cells (CD146 + CECs) and their progenitors (CEPs) are increased in cardiovascular, thrombotic, infectious, and cancer diseases. The present study was designed to investigate their kinetics in novel coronavirus (COVID-19) patients. METHODS: We used a validated flow cytometry procedure to enumerate viable and apoptotic CD146 + CECs and CEPs in COVID-19 patients during the course of the disease and in patients who recovered. RESULTS: Viable CEPs per milliliter were significantly increased in COVID-19 patients compared with healthy controls. This increase was observed in patients with mild symptoms and not further augmented in patients with severe symptoms. In patients who recovered, CEPs decreased, but were in a range still significantly higher than normal controls. Regarding mature CD146 + CECs, in COVID-19 patients, their absolute number was similar to those observed in healthy controls, but the viable/apoptotic CD146 + CEC ratio was significantly different. Both mild and severe COVID-19 patients had significantly less apoptotic CD146 + CECs compared with healthy controls. Patients who recovered had significantly less CD146 + CECs per milliliter when compared with controls as well as to mild and severe COVID-19 patients. A positive correlation was found between the copies of SARS-CoV-2 RNA in the cellular fraction and apoptotic CEPs per milliliter in severe COVID-19 patients. CONCLUSIONS: CD146 + CECs and CEPs might be investigated as candidate biomarkers of endothelial damage in COVID-19 patients.
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Apoptosis , Prueba de Ácido Nucleico para COVID-19 , COVID-19/diagnóstico , Células Progenitoras Endoteliales/patología , Citometría de Flujo , Reacción en Cadena de la Polimerasa , ARN Viral/sangre , SARS-CoV-2/genética , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Antígeno CD146/sangre , COVID-19/sangre , COVID-19/patología , COVID-19/virología , Estudios de Casos y Controles , Células Progenitoras Endoteliales/metabolismo , Femenino , Interacciones Huésped-Patógeno , Humanos , Cinética , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Índice de Severidad de la Enfermedad , Carga ViralRESUMEN
Dysfunctions in mitochondrial dynamics and metabolism are common pathological processes associated with Parkinson's disease (PD). It was recently shown that an inherited form of PD and dementia is caused by mutations in the OPA1 gene, which encodes for a key player in mitochondrial fusion and structure. iPSC-derived neural cells from these patients exhibited severe mitochondrial fragmentation, respiration impairment, ATP deficits, and heightened oxidative stress. Reconstitution of normal levels of OPA1 in PD-derived neural cells normalized mitochondria morphology and function. OPA1-mutated neuronal cultures showed reduced survival in vitro. Intriguingly, selective inhibition of necroptosis effectively rescued this survival deficit. Additionally, dampening necroptosis in MPTP-treated mice protected from DA neuronal cell loss. This human iPSC-based model captures both early pathological events in OPA1 mutant neural cells and the beneficial effects of blocking necroptosis, highlighting this cell death process as a potential therapeutic target for PD.
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Apoptosis/efectos de los fármacos , Neuronas Dopaminérgicas/patología , Fármacos Neuroprotectores/farmacología , Enfermedad de Parkinson/patología , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Animales , Diferenciación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/efectos de los fármacos , GTP Fosfohidrolasas/genética , Células Madre Pluripotentes Inducidas/efectos de los fármacos , Células Madre Pluripotentes Inducidas/metabolismo , Lisosomas/efectos de los fármacos , Lisosomas/metabolismo , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones Endogámicos C57BL , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Mutación/genética , Necrosis , Células-Madre Neurales/efectos de los fármacos , Células-Madre Neurales/metabolismo , Estrés Oxidativo/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/farmacologíaRESUMEN
Metformin can induce breast cancer (BC) cell apoptosis and reduce BC local and metastatic growth in preclinical models. Since Metformin is frequently used along with Aspirin or beta-blockers, we investigated the effect of Metformin, Aspirin and the beta-blocker Atenolol in several BC models. In vitro, Aspirin synergized with Metformin in inducing apoptosis of triple negative and endocrine-sensitive BC cells, and in activating AMPK in BC and in white adipose tissue (WAT) progenitors known to cooperate to BC progression. Both Aspirin and Atenolol added to the inhibitory effect of Metformin against complex I of the respiratory chain. In both immune-deficient and immune-competent preclinical models, Atenolol increased Metformin activity against angiogenesis, local and metastatic growth of HER2+ and triple negative BC. Aspirin increased the activity of Metformin only in immune-competent HER2+ BC models. Both Aspirin and Atenolol, when added to Metformin, significantly reduced the endothelial cell component of tumor vessels, whereas pericytes were reduced by the addition of Atenolol but not by the addition of Aspirin. Our data indicate that the addition of Aspirin or of Atenolol to Metformin might be beneficial for BC control, and that this activity is likely due to effects on both BC and microenvironment cells.
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Antineoplásicos/farmacología , Aspirina/farmacología , Atenolol/farmacología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Metformina/farmacología , Microambiente Tumoral/efectos de los fármacos , Proteínas Quinasas Activadas por AMP/metabolismo , Tejido Adiposo Blanco/efectos de los fármacos , Tejido Adiposo Blanco/metabolismo , Animales , Apoptosis/efectos de los fármacos , Biomarcadores de Tumor , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Complejo I de Transporte de Electrón/metabolismo , Femenino , Humanos , NAD/metabolismo , Metástasis de la Neoplasia , Células Madre/efectos de los fármacos , Células Madre/metabolismo , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patología , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Potocki-Shaffer syndrome (PSS) is a contiguous gene deletion syndrome that results from haploinsufficiency of at least two genes within the short arm of chromosome 11[del(11)(p11.2p12)]. The clinical features of PSS can include developmental delay, mental retardation, multiple exostoses, parietal foramina, enlarged anterior fontanel, minor craniofacial anomalies, ophthalmologic anomalies, and genital abnormalities in males. We constructed a natural panel of 11p11.2-p13 deletions using cell lines from 10 affected individuals, fluorescence in situ hybridization (FISH), microsatellite analyses, and array-based comparative genomic hybridization (array CGH). We then compared the deletion sizes and clinical features between affected individuals. The full spectrum of PSS manifests when deletions are at least 2.1 Mb in size, spanning from D11S1393 to D11S1385/D11S1319 (44.6-46.7 Mb from the 11p terminus) and encompassing EXT2, responsible for multiple exostoses, and ALX4, causing parietal foramina. Yet one subject with parietal foramina whose deletion does not include ALX4 indicates that ALX4 in this subject may be rendered functionally haploinsufficient by a position effect. Based on comparative deletion mapping of eight individuals with the full PSS syndrome including mental retardation and two PSS families with no mental retardation, at least one gene related to mental retardation is likely located between D11S554 and D11S1385/D11S1319, 45.6-46.7 Mb from the 11p terminus.
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Anomalías Múltiples/genética , Cromosomas Humanos Par 11/genética , Exostosis Múltiple Hereditaria/genética , Eliminación de Gen , Discapacidad Intelectual/genética , Línea Celular , Niño , Preescolar , Disostosis Craneofacial/genética , Femenino , Genotipo , Humanos , Hibridación Fluorescente in Situ , Masculino , Repeticiones de Microsatélite , Hueso Parietal/anomalías , Fenotipo , Mapeo Físico de Cromosoma , SíndromeRESUMEN
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm underlain by the formation of BCR-ABL1 - an aberrant tyrosine kinase - in the leukaemic blasts. Long-term survival rates in CML prior to the advent of tyrosine kinase inhibitors (TKIs) were dismal, albeit the incidence of secondary malignancies was higher than that of age-matched population. Current figures confirm the safety of TKIs with conflicting data concerning the increased risk of secondary tumours. We postulate that care has to be taken when distinguishing between coexisting, secondary-to-treatment and second in sequence, but independent tumourigenic events, in order to achieve an unbiased picture of the adverse effects of novel treatments. To illustrate this point, we present a case of a patient in which CML and peripheral T-cell lymphoma (PTCL) coexisted, although the clinical presentation of the latter followed the achievement of major molecular response of CML to TKIs.
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Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Linfoma de Células T Periférico/patología , Antineoplásicos/uso terapéutico , Proteínas de Fusión bcr-abl/sangre , Proteínas de Fusión bcr-abl/genética , Humanos , Mesilato de Imatinib/uso terapéutico , Hibridación Fluorescente in Situ , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Linfoma de Células T Periférico/genética , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
The best-known situation indissolubly linked to mosaicism is the uniparental disomy where a trisomic or monosomic zygote develops at least one cell line with 46 chromosomes. The mosaicism normal/abnormal cell lines may remain confined to placenta or persist in the embryo. Here, we describe a second situation that might also be indissolubly linked to a mosaic condition or at least to a confined placental mosaicism. We analysed the case of a mosaicism del(8p)/inv dup(8p) found in prenatal diagnosis. We had already demonstrated that the first product of the abnormal meiotic recombination at the basis of the inv dup rearrangements is a dicentric chromosome. Its breakage leads to the formation of a deleted and an inv dup chromosome. Although we had previously assumed that the dicentric underwent a breakage at meiosis II so that the zygote inherited the inv dup chromosome, our findings and those of others indeed indicate that the dicentric may be inherited in the zygote and that it might persist as such in early postzygotic stages, then undergoing different breakages in different cells leading to different abnormal chromosomes, either deleted or duplicated. Selection versus the most viable cell line(s) results either in a confined placental mosaicism with the inv dup cell line as the only one present in the embryo or in children with both the deleted and the inv dup cell lines. Phenotype/karyotype relationships in inv dup rearrangements must also take into account the influence of the other abnormal cell line during embryogenesis.
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Deleción Cromosómica , Inversión Cromosómica/genética , Cromosomas Humanos Par 8/genética , Mosaicismo , Feto Abortado , Muestra de la Vellosidad Coriónica , Bandeo Cromosómico , Marcadores Genéticos , Cardiopatías Congénitas/genética , Humanos , Hibridación Fluorescente in SituRESUMEN
A girl with oral, facial, and digital anomalies presented at birth with a large cleft palate filled by a nasopharyngeal mass and was found later to have several vertebral anomalies and mental retardation. A similar phenotype has been previously reported in a sporadic male patient [Gabrielli et al., 1994: Am J Med Genet 53:290-293], suggesting a new variant form of oral-facial-digital syndrome.
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Anomalías Múltiples/genética , Trastornos Psicomotores/genética , Anomalías Múltiples/fisiopatología , Encéfalo/patología , Femenino , Humanos , Lactante , Recién Nacido , Cuello/patología , Trastornos Psicomotores/fisiopatología , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: The endothelium is not a homogeneous organ. Endothelial cell heterogeneity has been described at the level of cell morphology, function, gene expression, and antigen composition. As a consequence of the genetic, transcriptome and surrounding environment diversity, endothelial cells from different vascular beds have differentiated functions and phenotype. Detection of circulating endothelial cells (CECs) by flow cytometry is an approach widely used in cancer patients, and their number, viability and kinetic is a promising tool to stratify patient receiving anti-angiogenic treatment. METHODOLOGY/PRINCIPAL FINDINGS: Currently CECs are identified as positive for a nuclear binding antigen (DNA+), negative for the pan leukocyte marker CD45, and positive for CD31 and CD146. Following an approach recently validated in our laboratory, we investigated the expression of CD109 on CECs from the peripheral blood of healthy subject and cancer patients. The endothelial nature of these cells was validated by RT-PCR for the presence of m-RNA level of CDH5 (Ve-Cadherin) and CLDN5 (Claudin5), two endothelial specific transcripts. Before treatment, significantly higher levels of CD109+ CECs and viable CD109+CECs were found in breast cancer patients and glioblastoma patients compared to healthy controls, and their number significantly decreased after treatment. Higher levels of endothelial specific transcripts expressed in developing endothelial cells CLEC14a, TMEM204, ARHGEF15, GPR116, were observed in sorted CD109+CECs when compared to sorted CD146+CECs, suggesting that these genes can play an important role not only during embryogenesis but also in adult angiogenesis. Interestingly, mRNA levels of TEM8 (identified as Antrax Toxin Receptor1, Antrax1) were expressed in CD109+CECs+ but not in CD146+CECs. CONCLUSION: Taken together our results suggest that CD109 represent a rare population of circulating tumor endothelial cells, that play a potentially useful prognostic role in patients with glioblastoma. The role of CD109 expression in cancer vessel-specific endothelial cells deserves to be further investigated by gene expression studies.
Asunto(s)
Antígenos CD/análisis , Células Endoteliales/patología , Proteínas de Neoplasias/análisis , Neoplasias/sangre , Neoplasias/patología , Células Neoplásicas Circulantes/patología , Adulto , Anciano , Antígenos CD/sangre , Antígenos CD/genética , Neoplasias de la Mama/sangre , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Antígeno CD146/análisis , Antígeno CD146/sangre , Antígeno CD146/genética , Células Endoteliales/metabolismo , Femenino , Proteínas Ligadas a GPI/análisis , Proteínas Ligadas a GPI/sangre , Proteínas Ligadas a GPI/genética , Regulación Neoplásica de la Expresión Génica , Glioblastoma/sangre , Glioblastoma/genética , Glioblastoma/patología , Humanos , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/sangre , Proteínas de Neoplasias/genética , Neoplasias/genética , Células Neoplásicas Circulantes/metabolismoRESUMEN
Obesity is associated with an increased frequency, morbidity, and mortality of several types of neoplastic diseases, including postmenopausal breast cancer. We found that human adipose tissue contains two populations of progenitors with cooperative roles in breast cancer. CD45(-)CD34(+)CD31(+)CD13(-)CCRL2(+) endothelial cells can generate mature endothelial cells and capillaries. Their cancer-promoting effect in the breast was limited in the absence of CD45(-)CD34(+)CD31(-)CD13(+)CD140b(+) mesenchymal progenitors/adipose stromal cells (ASC), which generated pericytes and were more efficient than endothelial cells in promoting local tumor growth. Both endothelial cells and ASCs induced epithelial-to-mesenchymal transition (EMT) gene expression in luminal breast cancer cells. Endothelial cells (but not ASCs) migrated to lymph nodes and to contralateral nascent breast cancer lesions where they generated new vessels. In vitro and in vivo, endothelial cells were more efficient than ASCs in promoting tumor migration and in inducing metastases. Granulocyte colony-stimulating factor (G-CSF) effectively mobilized endothelial cells (but not ASCs), and the addition of chemotherapy and/or of CXCR4 inhibitors did not increase endothelial cell or ASC blood mobilization. Our findings suggest that adipose tissue progenitor cells cooperate in driving progression and metastatic spread of breast cancer.
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Adipocitos/patología , Tejido Adiposo Blanco/patología , Antígenos CD34/metabolismo , Neoplasias de la Mama/patología , Neoplasias Pulmonares/secundario , Neovascularización Patológica/patología , Células Madre/patología , Adipocitos/metabolismo , Tejido Adiposo Blanco/metabolismo , Animales , Apoptosis , Western Blotting , Neoplasias de la Mama/irrigación sanguínea , Neoplasias de la Mama/metabolismo , Diferenciación Celular , Movimiento Celular , Proliferación Celular , Femenino , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Factor Estimulante de Colonias de Granulocitos/genética , Factor Estimulante de Colonias de Granulocitos/metabolismo , Humanos , Neoplasias Pulmonares/irrigación sanguínea , Neoplasias Pulmonares/metabolismo , Metástasis Linfática , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/patología , Ratones , Ratones Endogámicos NOD , Ratones SCID , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores CXCR4 , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células Madre/metabolismo , Células Tumorales CultivadasRESUMEN
Cell fusion plays a well-recognized physiological role during development, while its function during progression is still unclear. Here, we show that acute myeloid leukemia (AML) cells spontaneously fused with murine host cells in vivo. AML cells fused in most cases with mouse macrophages. Other targets of AML cell fusion were dendritic and endothelial cells. Cytogenetic and molecular analysis revealed that successive recipients conserved detectable amounts of parental DNA. Moreover, in a mouse AML1-ETO model where female AML1-ETO-leukemic cells, expressing CD45.2, were injected in congenic CD45.1 male mice AML cells, we found hybrid cells expressing both allelic types of CD45 and XXY set of sexual chromosomes. More importantly, the fusion protein AML1-ETO was transferred in the hybrid cells. When sorted hybrid cells were reinjected in a secondary recipient, they gave rise to leukemia with 100% penetrance and similar time of onset of leukemic cells. Our data indicate that in vivo fusion of cancer cells with host cells may be a mechanism of gene transfer for cancer dissemination and suggest that fused cells may be used to identify still unrecognized leukemogenic genes that are conserved in hybrid cells and able to perpetuate leukemia in vivo.
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Leucemia Mieloide Aguda/metabolismo , Macrófagos/metabolismo , Fusión de Membrana , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacología , Antígenos CD34/metabolismo , Antígeno CD47/inmunología , Línea Celular Tumoral , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , Células Dendríticas/metabolismo , Modelos Animales de Enfermedad , Células Endoteliales/metabolismo , Femenino , Células Madre Hematopoyéticas/metabolismo , Humanos , Receptores de Hialuranos/inmunología , Células Híbridas/metabolismo , Leucemia Linfoide/genética , Leucemia Linfoide/metabolismo , Leucemia Mieloide Aguda/genética , Masculino , Fusión de Membrana/efectos de los fármacos , Ratones , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteína 1 Compañera de Translocación de RUNX1 , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Trasplante HeterólogoRESUMEN
Previous studies have suggested a "catalytic role" in neoplastic angiogenesis and cancer progression for bone marrow-derived endothelial progenitor cells (EPC). However, preclinical and clinical studies have shown that the quantitative role of marrow-derived EPCs in cancer vascularization is extremely variable. We have found that human and murine white adipose tissue (WAT) is a very rich reservoir of CD45-CD34(+) EPCs with endothelial differentiation potential, containing a mean of 263 times more CD45-CD34(+) cells/mL than bone marrow. Compared with marrow-derived CD34(+) cells mobilized in blood by granulocyte colony-stimulating factor, purified WAT-CD34(+) cells expressed similar levels of stemness-related genes, significantly increased levels of angiogenesis-related genes, and increased levels of FAP-α, a crucial suppressor of antitumor immunity. In vitro, WAT-CD34(+) cells generated mature endothelial cells and capillary tubes as efficiently as mature mesenchymal cells. The coinjection of human WAT-CD34(+) cells from lipotransfer procedures contributed to tumor vascularization and significantly increased tumor growth and metastases in several orthotopic models of human breast cancer in immunodeficient mice. Endothelial cells derived from human WAT-CD34(+) cells lined the lumen of cancer vessels. These data indicate that CD34(+) WAT cells can promote cancer progression and metastases. Our results highlight the importance of gaining a better understanding of the role of different WAT-derived cells used in lipotransfer for breast reconstruction in patients with breast cancer.