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Alleviating symptom burden in patients with myeloproliferative neoplasms (MPNs) is imperative to achieving optimal management. Research remains to elucidate the relationship between the JAK2V617F (Janus kinase 2) mutation present in many MPN patients, and the symptomatology they experience. This retrospective study analysed data collected from MPN patients included in the Myeloproliferative Neoplasms: An In-depth Case-Control (MOSAICC) pilot study. The MPN Symptom Assessment Form was administered, and median symptom scores were compared between JAK2V617F-positive and JAK2V617F-negative groups. Multivariate logistic regression analysis adjusted for confounding variables. Overall, 106 MPN patients participated: 65.1% were JAK2V617F positive, 30.2% were JAK2V617F negative and 4.7% had an unknown status. Multivariate analysis revealed a low symptom burden for early satiety (p < 0.01), dizziness (p < 0.05), cough (p < 0.05) and bone pain (p < 0.01) in those receiving venesection alone. Interferon alpha was significantly associated (p < 0.05) with severe burden for 16 of the 27 symptoms. JAK2V617F-positive females experienced a greater symptom burden than JAK2V617F-positive males. There was no discernible relationship between the JAK2V617F mutation and symptom burden in MPN patients, unlike the therapeutic agents investigated. Larger studies are required to validate these results and identify mechanisms of symptom development and control in MPN patients.
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BACKGROUND: The success of early dexamethasone therapy for hospitalised COVID-19 cases in treatment of Sars-CoV-2 infection may predominantly reflect its anti-inflammatory action against a hyperinflammation (HI) response. It is likely that there is substantial heterogeneity in HI responses in COVID-19. METHODS: Blood CRP, ferritin, neutrophil, lymphocyte and platelet counts were scored to assess HI (HI5) and combined with a validated measure of generalised medical deterioration (NEWS2) before day 2. Our primary outcome was 28 day mortality from early treatment with dexamethasone stratified by HI5-NEWS2 status. FINDINGS: Of 1265 patients, high risk of HI (high HI5-NEWS2) (n = 367, 29.0%) conferred a strikingly increased mortality (36.0% vs 7.8%; Age adjusted hazard ratio (aHR) 5.9; 95% CI 3.6-9.8, p<0.001) compared to the low risk group (n = 455, 36.0%). An intermediate risk group (n = 443, 35.0%) also showed significantly higher mortality than the low risk group (17.6% vs 7.8%), aHR 2.2, p = 0.005). Early dexamethasone treatment conferred a 50.0% reduction in mortality in the high risk group (36.0% to 18.0%, aHR 0.56, p = 0.007). The intermediate risk group showed a trend to reduction in mortality (17.8% to 10.3%, aHR 0.82, p = 0.46) which was not observed in the low risk group (7.8% to 9.2%, aHR 1.4, p = 0.31). INTERPRETATION: Higher HI5-NEWS2 scores measured at COVID-19 diagnosis, strongly associate with increased mortality at 28 days. Significant reduction in mortality with early dexamethasone treatment was only observed in the high risk group. Therefore, the HI5-NEWS2 score could be utilised to stratify randomised clinical trials to test whether intensified anti-inflammatory therapy would further benefit high risk patients and whether alternative approaches would benefit low risk groups. Considering its recognised morbidity, we suggest that early dexamethasone should not be routinely prescribed for HI5-NEWS2 low risk individuals with COVID-19 and clinicians should cautiously assess the risk benefit of this intervention in all cases.
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COVID-19 , Humanos , SARS-CoV-2 , Prueba de COVID-19 , Tratamiento Farmacológico de COVID-19 , Antiinflamatorios/uso terapéutico , Dexametasona/uso terapéuticoRESUMEN
It is well recognized that B-cell clonal disorders such as Waldenstrom's macroglobulinaemia may affect the central nervous system by direct infiltration of malignant B cells (Bing-Neel syndrome). However, there is no recognition in the current literature of a clear link between paraproteinaemia and primary brain tumours such as glioma. We present 3 cases of classical IgM paraproteinaemic neuropathy who developed glioblastoma in the course of their illness following treatment with chemoimmunotherapy (CIT). Due to the progressive symptomatic nature of their neuropathy, all 3 patients were treated with CIT. The patients presented with glioblastoma, IDH-wildtype at 9 months, 5 years, and 6 years following treatment completion. None of the patients had unequivocal evidence of known predisposing factors for glioblastoma. Both disorders are exceedingly rare and the chance of random association is less than one in a million. Potential common pathogenic mechanisms include the influence of paraproteins and circulating lymphoplasmacytic cells on blood-brain permeability and CNS immune micro-environment as well as raised circulating angiogenic cytokines such as vascular endothelial growth factor. In cases with anti-myelin-associated glycoprotein (MAG) antibodies, surface MAG on glial cells may act as a target releasing cells from growth inhibition. We suggest that all glioblastoma cases be screened at diagnosis for serum paraproteins and that such cases be reported to central registries to establish the frequency of the association more accurately.
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A significant proportion of COVID-19 patients show evidence of hyperinflammation (HI), of which secondary haemophagocytic lymphohistiocytosis (sHLH) is the most severe manifestation and diagnosed with HScore. Using a COVID-relevant modification of the HScore (%HScore), we set out to determine the prevalence of sHLH in 567 COVID-19 inpatient cases.The overall incidence of individuals with an 80% probability of sHLH in our COVID-19 cohort was 1.59% on admission and only rose to 4.05% if calculated at any time during admission. This small cohort as defined by %HScore showed no excess mortality compared with the whole cohort. Overall, %HScores were lower in older patients (p<0.0001) and did not reliably predict outcome at any cut-off value (AUROC 0.533, p=0.211, odds ratio 0.99).Our study demonstrates that a modified version (%HScore) of the conventional sHLH scoring system (HScore) does not enable risk stratification in people hospitalised with COVID. We propose further work is needed to develop novel approaches to predict HI and improve trial stratification for HI directed therapy in people with COVID-19.
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COVID-19 , Linfohistiocitosis Hemofagocítica , Anciano , Estudios de Cohortes , Humanos , Incidencia , Linfohistiocitosis Hemofagocítica/epidemiología , SARS-CoV-2Asunto(s)
Ciclofosfamida , Enfermedades del Sistema Nervioso Periférico , Prednisolona , Rituximab , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ciclofosfamida/uso terapéutico , Humanos , Inmunoglobulina M , Inmunoterapia , Enfermedades del Sistema Nervioso Periférico/terapia , Prednisolona/uso terapéutico , Rituximab/uso terapéutico , Resultado del TratamientoRESUMEN
Despite the identification of acquired genetic mutations associated with Myeloproliferative Neoplasms (MPNs) there is a paucity of information relating to modifiable risk factors that may lead to these mutations. The MOSAICC Study was an exploratory case-control study of polycythemia vera (PV), essential thrombocythemia (ET), and Myelofibrosis (MF). MPN patients and population controls (identified by General Practitioners) and non-blood relative/friend controls were recruited from 2 large UK centers. Participants completed a telephone-based questionnaire analyzed by unconditional logistic regression analysis adjusting for potential confounders. Risk factors for MPNs identified included increasing childhood household density [odds ratio (OR) 2.55, 95% confidence interval (CI) 1.16-5.62], low childhood socioeconomic status (OR 2.30, 95%CI 1.02-5.18) and high pack years smoking (OR 2.19, 95%CI 1.03-4.66) and current smoking restricted to JAK2 positive PV cases (OR 3.73, 95%CI 1.06-13.15). Obesity was linked with ET (OR 2.59, 95%CI 1.02-6.58) confirming results in previous cohort studies. Receipt of multiple CT scans was associated with a strongly increased risk of MPN although with wide confidence intervals (OR 5.38, 95%CI 1.67-17.3). Alcohol intake was inversely associated with risk of PV (OR 0.41, 95%CI 0.19-0.92) and ET (OR 0.48, 95%CI 0.24-0.98). The associations with childhood household density, high pack years smoking and alcohol were also seen in multivariate analysis. This is the largest case control study in MPNs to date and confirms the previously reported associations with obesity and cigarette smoking from cohort studies in addition to novel associations. In particular, the role of smoking and JAK2 mutation cases merits further evaluation.
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Determining the underlying cause of persistent eosinophilia is important for effective clinical management but remains a diagnostic challenge in many cases. We identified STAT5B N642H, an established oncogenic mutation, in 27/1715 (1.6%) cases referred for investigation of eosinophilia. Of the 27 mutated cases, a working diagnosis of hypereosinophilic syndrome (HES; n = 7) or a myeloid neoplasm with eosinophilia (n = 20) had been made prior to the detection of STAT5B N642H. Myeloid panel analysis identified a median of 2 additional mutated genes (range 0-4) with 4 cases having STAT5B N642H as a sole abnormality. STAT5B N642H was absent in cultured T cells of 4/4 positive cases. Individuals with SF3B1 mutations (9/27; 33%) or STAT5B N642H as a sole abnormality had a markedly better overall survival compared to cases with other additional mutations (median 65 months vs. 14 months; hazard ratio = 8.1; P < 0.001). The overall survival of STAT5B-mutated HES cases was only 30 months, suggesting that these cases should be reclassified as chronic eosinophilic leukemia, not otherwise specified (CEL-NOS). The finding of STAT5B N642H as a recurrent mutation in myeloid neoplasia with eosinophilia provides a new diagnostic and prognostic marker as well as a potential target for therapy.
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Biomarcadores de Tumor/genética , Eosinofilia/genética , Mutación , Trastornos Mieloproliferativos/genética , Factor de Transcripción STAT5/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Eosinofilia/patología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Trastornos Mieloproliferativos/patología , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Adulto JovenRESUMEN
Biallelic variants in the ERCC excision repair 6 like 2 gene (ERCC6L2) are known to cause bone marrow failure (BMF) due to defects in DNA repair and mitochondrial function. Here, we report on eight cases of BMF from five families harboring biallelic variants in ERCC6L2, two of whom present with myelodysplasia. We confirm that ERCC6L2 patients' lymphoblastoid cell lines (LCLs) are hypersensitive to DNA-damaging agents that specifically activate the transcription coupled nucleotide excision repair (TCNER) pathway. Interestingly, patients' LCLs are also hypersensitive to transcription inhibitors that interfere with RNA polymerase II (RNA Pol II) and display an abnormal delay in transcription recovery. Using affinity-based mass spectrometry we found that ERCC6L2 interacts with DNA-dependent protein kinase (DNA-PK), a regulatory component of the RNA Pol II transcription complex. Chromatin immunoprecipitation PCR studies revealed ERCC6L2 occupancy on gene bodies along with RNA Pol II and DNA-PK. Patients' LCLs fail to terminate transcript elongation accurately upon DNA damage and display a significant increase in nuclear DNA-RNA hybrids (R loops). Collectively, we conclude that ERCC6L2 is involved in regulating RNA Pol II-mediated transcription via its interaction with DNA-PK to resolve R loops and minimize transcription-associated genome instability. The inherited BMF syndrome caused by biallelic variants in ERCC6L2 can be considered as a primary transcription deficiency rather than a DNA repair defect.
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Alelos , Enfermedades de la Médula Ósea/metabolismo , ADN Helicasas/metabolismo , Reparación del ADN , Enfermedades Genéticas Congénitas/metabolismo , Inestabilidad Genómica , Transcripción Genética , Células A549 , Enfermedades de la Médula Ósea/genética , Enfermedades de la Médula Ósea/patología , ADN Helicasas/genética , Proteína Quinasa Activada por ADN/genética , Proteína Quinasa Activada por ADN/metabolismo , Femenino , Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Congénitas/patología , Células HeLa , Humanos , Masculino , ARN Polimerasa II/genética , ARN Polimerasa II/metabolismo , SíndromeRESUMEN
Biological sample collection is becoming more common in epidemiology research to obtain DNA for genetic analysis. There are many different DNA collection methods but little evidence on their relative effectiveness. Therefore, we took the opportunity of a prospective case-control study in myeloproliferative neoplasms (MPNs) to compare DNA yield from 8.5 mL PAXgene tubes for whole blood collection versus 2 mL Oragene OG-500 saliva collection kits. MPNs include polycythaemia vera, essential thrombocythaemia, and primary myelofibrosis. These are rare diseases and our exploratory case-control study (MOSAICC) sought to improve knowledge regarding their aetiology and to determine optimal methodology for a larger UK-wide study. Overall, 233 participants were recruited to the MOSIACC study, and we collected 187 blood and 214 saliva samples. The mean DNA yield from blood was 659.18 ng/µL, significantly higher than the mean DNA yield from saliva samples (275.79 ng/µL). The higher provision of saliva samples might reflect its non-invasive and more convenient nature, compared to blood sample provision. The differences in mean DNA yields might reflect differences in clinical assistance, adherence to instructions, and health status of individuals. In conclusion, both sample collection techniques are simple, effective, and suitable for DNA collection for genetic analysis in future epidemiological research studies but OG-500 kits offer a less invasive alternative for those who refuse to provide blood.
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ADN/sangre , ADN/aislamiento & purificación , Saliva/química , Manejo de Especímenes , Estudios de Casos y Controles , Análisis Costo-Beneficio , Estudios de Factibilidad , Humanos , Trastornos Mieloproliferativos/diagnóstico , Trastornos Mieloproliferativos/genética , Estudios Prospectivos , Manejo de Especímenes/economíaRESUMEN
The myeloproliferative neoplasms (MPN) including polycythaemia vera (PV), essential thrombocythaemia and primary myelofibrosis (PMF) are rare diseases contributing to significant morbidity. Symptom management is a prime treatment objective but current symptom assessment tools have not been validated compared to the general population. The MPN-symptom assessment form (MPN-SAF), a reliable and validated clinical tool to assess MPN symptom burden, was administered to MPN patients (n = 106) and, for the first time, population controls (n = 124) as part of a UK case-control study. Mean symptom scores were compared between patients and controls adjusting for potential confounders. Mean patient scores were compared to data collected by the Mayo Clinic, USA on 1,446 international MPN patients to determine patient group representativeness. MPN patients had significantly higher mean scores than controls for 25 of the 26 symptoms measured (P < 0.05); fatigue was the most common symptom (92.4% and 78.1%, respectively). Female MPN patients suffered worse symptom burden than male patients (P < 0.001) and substantially worse burden than female controls (P < 0.001). Compared to the Mayo clinic patients, MPN-UK patients reported similar symptom burden but lower satiety (P = 0.046). Patients with PMF reported the worst symptom burden (88.3%); significantly higher than PV patients (P < 0.001). For the first time we report quality of life was worse in MPN-UK patients compared with controls (P < 0.001).
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Trastornos Mieloproliferativos/terapia , Calidad de Vida , Costo de Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Clonal proliferation in myeloproliferative neoplasms (MPN) is driven by somatic mutations in JAK2, CALR or MPL, but the contribution of inherited factors is poorly characterized. Using a three-stage genome-wide association study of 3,437 MPN cases and 10,083 controls, we identify two SNPs with genome-wide significance in JAK2(V617F)-negative MPN: rs12339666 (JAK2; meta-analysis P=1.27 × 10(-10)) and rs2201862 (MECOM; meta-analysis P=1.96 × 10(-9)). Two additional SNPs, rs2736100 (TERT) and rs9376092 (HBS1L/MYB), achieve genome-wide significance when including JAK2(V617F)-positive cases. rs9376092 has a stronger effect in JAK2(V617F)-negative cases with CALR and/or MPL mutations (Breslow-Day P=4.5 × 10(-7)), whereas in JAK2(V617F)-positive cases rs9376092 associates with essential thrombocythemia (ET) rather than polycythemia vera (allelic χ(2) P=7.3 × 10(-7)). Reduced MYB expression, previously linked to development of an ET-like disease in model systems, associates with rs9376092 in normal myeloid cells. These findings demonstrate that multiple germline variants predispose to MPN and link constitutional differences in MYB expression to disease phenotype.
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Policitemia Vera/genética , Trombocitemia Esencial/genética , Adulto , Anciano , Alelos , Calreticulina/genética , Estudios de Casos y Controles , Estudios de Cohortes , Proteínas de Unión al ADN/genética , Femenino , Proteínas de Unión al GTP/genética , Frecuencia de los Genes , Genes myb/genética , Predisposición Genética a la Enfermedad , Variación Genética , Genotipo , Proteínas HSP70 de Choque Térmico/genética , Humanos , Janus Quinasa 2/genética , Proteína del Locus del Complejo MDS1 y EV11 , Masculino , Persona de Mediana Edad , Mutación , Trastornos Mieloproliferativos/genética , Factores de Elongación de Péptidos/genética , Polimorfismo de Nucleótido Simple , Proto-Oncogenes/genética , Receptores de Trombopoyetina/genética , Telomerasa/genética , Factores de Transcripción/genéticaRESUMEN
BACKGROUND: Myeloproliferative neoplasms (MPNs) including the classic entities; polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis are rare diseases with unknown aetiology. The MOSAICC study, is an exploratory case-control study in which information was collected through telephone questionnaires and medical records. METHODS: As part of the study, 106 patients with MPN were asked about their perceived diagnosis and replies correlated with their haematologist's diagnosis. For the first time, a patient perspective on their MPN diagnosis and classification was obtained. Logistic regression analyses were utilised to evaluate the role of variables in whether or not a patient reported their diagnosis during interview with co-adjustment for these variables. Chi square tests were used to investigate the association between MPN subtype and patient reported categorisation of MPN. RESULTS: Overall, 77.4 % of patients reported a diagnosis of MPN. Of those, 39.6 % recognised MPN as a 'blood condition', 23.6 % recognised MPN as a 'cancer' and 13.2 % acknowledged MPN as an 'other medical condition'. There was minimal overlap between the categories. Patients with PV were more likely than those with ET to report their disease as a 'blood condition'. ET patients were significantly more likely than PV patients not to report their condition at all. Patients from a single centre were more likely to report their diagnosis as MPN while age, educational status, and WHO re-classification had no effect. CONCLUSIONS: The discrepancy between concepts of MPN in patients could result from differing patient interest in their condition, varying information conveyed by treating hematologists, concealment due to denial or financial concerns. Explanations for the differences in patient perception of the nature of their disease, requires further, larger scale investigation.
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B-cell receptor (BCR) signaling plays a key role in the behavior of chronic lymphocytic leukemia (CLL). However, cellular consequences of signaling are incompletely defined. Here we explored possible links between BCR signaling and the unfolded protein response (UPR), a stress response pathway that can promote survival of normal and malignant cells. Compared with normal B cells, circulating CLL cells expressed increased, but variable, levels of UPR components. Higher expression of CHOP and XBP1 RNAs was associated with more aggressive disease. UPR activation appeared due to prior tissue-based antigenic stimulation because elevated expression of UPR components was detected within lymph node proliferation centers. Basal UPR activation also correlated closely with surface immunoglobulin M (sIgM) signaling capacity in vitro in both IGHV unmutated CLL and within mutated CLL. sIgM signaling increased UPR activation in vitro with responders showing increased expression of CHOP and XBP1 RNAs, and PERK and BIP proteins, but not XBP1 splicing. Inhibitors of BCR-associated kinases effectively prevented sIgM-induced UPR activation. Overall, this study demonstrates that sIgM signaling results in activation of some components the UPR in CLL cells. Modulation of the UPR may contribute to variable clinical behavior, and its inhibition may contribute to clinical responses to BCR-associated kinase inhibitors.
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Linfocitos B/inmunología , Inmunoglobulina M/inmunología , Péptidos y Proteínas de Señalización Intracelular/inmunología , Leucemia Linfocítica Crónica de Células B/inmunología , Proteínas Tirosina Quinasas/inmunología , Receptores de Antígenos de Linfocitos B/inmunología , Respuesta de Proteína Desplegada , Agammaglobulinemia Tirosina Quinasa , Linfocitos B/patología , Humanos , Leucemia Linfocítica Crónica de Células B/patología , Transducción de Señal , Quinasa SykRESUMEN
Myeloproliferative neoplasms (MPNs) are a heterogeneous group of diseases including polycythemia vera (PV), essential thrombocythemia (ET), and primary(idiopathic) myelofibrosis (PMF). In this systematic review, we provide a comprehensive report on the incidence and prevalence of MPNs across the globe. Electronic databases (PubMed, EMBASE, MEDLINE, and Web of Science) were searched from their inception to August 2012 for articles reporting MPN incidence or prevalence rates. A random effects meta-analysis was undertaken to produce combined incidence rates for PV, ET, and PMF. Both heterogeneity and small study bias were assessed. Thirty-four studies were included. Reported annual incidence rates ranged from 0.01 to 2.61, 0.21 to 2.27, and 0.22 to 0.99 per 100,000 for PV, ET, and PMF, respectively. The combined annual incidence rates for PV, ET, and PMF were 0.84, 1.03, and 0.47 per 100,000. There was high heterogeneity across disease entities (I(2) 97.1-99.8%) and evidence of publication bias for ET and PMF (Egger test, P = 50.007 and P ≤ 0.001, respectively).The pooled incidence reflects the rarity of MPNs. The calculated pooled incidence rates do not reflect MPN incidence across the globe due to the high unexplained heterogeneity. Improved, widespread registration of MPNs would provide better information for global comparison of the incidence and prevalence of MPNs.
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Trastornos Mieloproliferativos/epidemiología , Policitemia Vera/epidemiología , Mielofibrosis Primaria/epidemiología , Trombocitemia Esencial/epidemiología , Humanos , IncidenciaAsunto(s)
Janus Quinasa 1/antagonistas & inhibidores , Janus Quinasa 2/antagonistas & inhibidores , Mielofibrosis Primaria/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazoles/uso terapéutico , Anemia/inducido químicamente , Humanos , Dosis Máxima Tolerada , Nitrilos , Mielofibrosis Primaria/complicaciones , Mielofibrosis Primaria/enzimología , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Pirazoles/efectos adversos , Pirimidinas , Recurrencia , Esplenomegalia/tratamiento farmacológico , Esplenomegalia/etiología , Evaluación de Síntomas , Trombocitopenia/inducido químicamenteRESUMEN
Myeloproliferative neoplasms (MPNs) are characterized by overproduction of mature functional blood cells and are often associated with an acquired genetic mutation of Janus Kinase 2(V617F). The etiology of MPNs remains unknown. The aim of this article was to review and collate all known published data investigating environmental and lifestyle factors associated with MPNs. Medline, Embase, PubMed, Cochrane, and Web of Science were systematically searched using terms for MPNs and observational study designs to identify studies investigating the risk factors for MPNs published before March 2010. Of 9,156 articles identified, 19 met the selection criteria. Although the studies exhibited heterogeneity, in case definitions, study design, and risk factors investigated, several themes emerged. A strong association was found with Jewish descent, and with a family history of MPNs. Autoimmune conditions, specifically Crohn's disease, were more common in patients with MPNs. Certain occupational groups were significantly associated with MPNs including occupations with potential exposure to benzene and/or petroleum. Blood donation was associated with an increased risk of polycythemia vera specifically. The vast heterogeneity in studies identified as part of this review suggests that large scale systematic assessment of etiological factors associated with MPNs is warranted.
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Contaminantes Ambientales/toxicidad , Neoplasias Hematológicas/etnología , Neoplasias Hematológicas/etiología , Estilo de Vida , Trastornos Mieloproliferativos/etnología , Trastornos Mieloproliferativos/etiología , Autoinmunidad , Donantes de Sangre , Etnicidad , Femenino , Interacción Gen-Ambiente , Predisposición Genética a la Enfermedad , Neoplasias Hematológicas/genética , Humanos , Janus Quinasa 2/genética , Masculino , Mutación , Trastornos Mieloproliferativos/genética , Factores de RiesgoRESUMEN
B-cell receptor and microenvironment-derived signals promote accumulation of chronic lymphocytic leukemia (CLL) cells through increased proliferation and/or decreased apoptosis. In this study, we investigated the regulation of BIM, a proapoptotic BCL2-related protein, which is tightly regulated by phosphorylation. Surface IgM stimulation increased phosphorylation of 2 BIM isoforms, BIM(EL) and BIM(L), in a subset of CLL samples. In contrast, in normal B cells, anti-IgM triggered selective phosphorylation of BIM(EL) only. In CLL, anti-IgM-induced BIM phosphorylation correlated with unmutated IGHV gene status and with progressive disease. Strikingly, it was also associated with progressive disease within the mutated IGHV gene subset. BIM phosphorylation was dependent on MEK1/2 kinase activity, and we identified BIM(EL) serine 69, previously linked to pro-survival responses, as the major site of phosphorylation in CLL and in Ramos cells. BIM(EL)/BIM(L) phosphorylation was associated with release of the pro-survival protein MCL1. Coculture of CLL cells with HK cells, a model of the CLL microenvironment, promoted CLL cell survival and was associated with MEK1/2 activation and BIM(EL) phosphorylation. Hence, BIM phosphorylation appears to play a key role in apoptosis regulation in CLL cells, potentially coordinating antigen and microenvironment-derived survival signals. Antigen-mediated effects on BIM may be an important determinant of clinical behavior.
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Proteínas Reguladoras de la Apoptosis/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Anticuerpos Antiidiotipos/farmacología , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/fisiología , Proteína 11 Similar a Bcl2 , Biomarcadores de Tumor/metabolismo , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Activación Enzimática , Humanos , Proteínas de la Membrana/genética , Proteínas de la Membrana/fisiología , Proteínas Mutantes/química , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Fosforilación/efectos de los fármacos , Pronóstico , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteolisis/efectos de los fármacos , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/fisiología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiologíaRESUMEN
PURPOSE: To determine the origin and relationship of the rare IgG+ variant of chronic lymphocytic leukemia (CLL) to the two common IgM+IgD+ subsets that are distinguished by expression of unmutated or mutated V(H) genes, with the former having a worse prognosis. EXPERIMENTAL DESIGN: IgG+ CLL cells were characterized using phenotypic, functional, and immunogenetic analyses. RESULTS: IgG+ CLL was phenotypically similar to mutated IgM+IgD+ CLL (M-CLL) and variably expressed CD38 (4 of 14). ZAP-70, a tyrosine kinase preferentially expressed in unmutated CLL, was found in only 2 of 14 cases. The ability to signal via surface IgM (sIgM) varies between the main subsets of CLL and is associated with expression of ZAP-70. In IgG(+) CLL, 9 of 14 responded to engagement of sIgG with no apparent requirement for expression of CD38 or ZAP-70. However, signal capacity correlated with intensity of sIgG expression. Most switched immunoglobulin variable region genes were somatically mutated without intraclonal variation, and no case expressed activation-induced cytidine deaminase. Derivation from a postgerminal center B cell is, therefore, likely, and a relationship with M-CLL is suggested. This is supported by a shared biased usage of the V4-34 gene. Similar bias in normal B cells developed with age, providing an expanded population for transforming events. However, conserved sequences detected in the CDR3 of V4-34-encoded gamma chains were not found M-CLL, indicating no direct path of isotype switch from M-CLL. CONCLUSION: IgG+ CLL is likely to arise from an age-related expanded pool of B cells, on a path parallel to M-CLL, and perhaps with a similar clinical course.