RESUMEN
ABSTRACT: SETBP1 mutations are found in various clonal myeloid disorders. However, it is unclear whether they can initiate leukemia, because SETBP1 mutations typically appear as later events during oncogenesis. To answer this question, we generated a mouse model expressing mutated SETBP1 in hematopoietic tissue: this model showed profound alterations in the differentiation program of hematopoietic progenitors and developed a myeloid neoplasm with megakaryocytic dysplasia, splenomegaly, and bone marrow fibrosis, prompting us to investigate SETBP1 mutations in a cohort of 36 triple-negative primary myelofibrosis (TN-PMF) cases. We identified 2 distinct subgroups, one carrying SETBP1 mutations and the other completely devoid of somatic variants. Clinically, a striking difference in disease aggressiveness was noted, with patients with SETBP1 mutation showing a much worse clinical course. In contrast to myelodysplastic/myeloproliferative neoplasms, in which SETBP1 mutations are mostly found as a late clonal event, single-cell clonal hierarchy reconstruction in 3 patients with TN-PMF from our cohort revealed SETBP1 to be a very early event, suggesting that the phenotype of the different SETBP1+ disorders may be shaped by the opposite hierarchy of the same clonal SETBP1 variants.
Asunto(s)
Sistema Hematopoyético , Enfermedades Mielodisplásicas-Mieloproliferativas , Trastornos Mieloproliferativos , Mielofibrosis Primaria , Animales , Ratones , Humanos , Mielofibrosis Primaria/genética , Trastornos Mieloproliferativos/genética , Mutación , Proteínas Portadoras/genética , Proteínas Nucleares/genéticaRESUMEN
Evans syndrome (ES) is rare and mostly treated on a "case-by-case" basis and no guidelines are available. With the aim of assessing disease awareness and current management of adult ES, a structured survey was administered to 64 clinicians from 50 Italian participating centers. Clinicians had to be involved in the management of autoimmune cytopenias and were enrolled into the ITP-NET initiative. The survey included domains on epidemiology, diagnosis, and therapy of ES and was designed to capture current practice and suggested work-up and management. Thirty clinicians who had followed a median of 5 patients (1-45)/15 years responded. The combination of AIHA plus ITP was more common than the ITP/AIHA with neutropenia (p < .001) and 25% of patients had an associated condition, including lymphoproliferative syndromes, autoimmune diseases, or primary immunodeficiencies. The agreement of clinicians for each diagnostic test is depicted (i.e., 100% for blood count and DAT; only 40% for anti-platelets and anti-neutrophils; 77% for bone marrow evaluation). Most clinicians reported that ES requires a specific approach compared to isolated autoimmune cytopenias, due to either a more complex pathogenesis and a higher risk of relapse and thrombotic and infectious complications. The heterogeneity of treatment choices among different physicians suggests the need for broader harmonization.
RESUMEN
Little is known of the course of COVID-19 and the antibody response to infection or vaccination in patients with hairy-cell leukaemia (HCL). Among a total of 58 HCL cases we studied in these regards, 37 unvaccinated patients, mostly enjoying a relatively long period free from anti-leukaemic treatment, developed COVID-19 between March 2020 and December 2021 with a usually favourable outcome (fatality rate: 5/37, 14%); however, active leukaemia, older age and more comorbidities were associated with a worse course. Postinfection (n = 11 cases) and postvaccination (n = 28) seroconversion consistently developed, except after recent anti-CD20 or venetoclax therapy, correlating with perivaccine B-cell count. Vaccination appeared to protect from severe COVID-19 in 11 patients with breakthrough infection.
Asunto(s)
COVID-19 , Leucemia de Células Pilosas , Leucemia , Humanos , COVID-19/prevención & control , SARS-CoV-2 , Vacunación , Anticuerpos AntiviralesRESUMEN
Antiphospholipid syndrome (APS) is a chronic systemic autoimmune disease characterized by venous, arterial, and microvascular thromboses and/or recurrent pregnancy morbidity, that occur in the persistent presence of antiphospholipid antibodies (aPL). APS can present with a wide range of clinical manifestations often reffered as "extra-criteria". These features, although apparently less common, can severely impact patients' outcome. Here, we report the case of a patient with a newly diagnosed APS. He previously experienced a recurrence of venous thrombosis after discontinuation of anticoagulant therapy in association with cutaneous ulcerations as presenting symptoms. Interestingly, skin lesions did not improve with full anticoagulant treatment. Due to concomitant presence of thrombotic and microvascular involvement, immunomodulatory therapy with steroid pulses followed by intravenous injections of belimumab was started, with progressive and significant amelioration, leading to complete recovery. Following the presentation of the current case report, we highlight the importance of suspecting APS in young patients experiencing unprovoked thrombosis. We also emphasized the critical issue of testing aPL during anticoagulant treatment and focused on the need of aPL retesting in patients with positivity at high titers. We also highlight the double nature of aPL-mediated clinical manifestations. While most patients presented with pure thrombotic complications, one should always remember that APS is an autoimmune-mediated disease, which can benefit from alternative therapeutic approaches beyond anticoagulation.
Asunto(s)
Síndrome Antifosfolípido , Lupus Eritematoso Sistémico , Trombosis , Masculino , Femenino , Embarazo , Humanos , Síndrome Antifosfolípido/complicaciones , Síndrome Antifosfolípido/diagnóstico , Síndrome Antifosfolípido/tratamiento farmacológico , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/tratamiento farmacológico , Anticuerpos Antifosfolípidos , Anticoagulantes/uso terapéutico , Trombosis/tratamiento farmacológico , Trombosis/etiologíaRESUMEN
Splanchnic vein thrombosis is a rare but potentially life-threatening manifestation of venous thromboembolism, with challenging implications both at the pathological and therapeutic level. It is frequently associated with liver cirrhosis, but it could also be provoked by myeloproliferative disorders, cancer of various gastroenterological origin, abdominal infections and thrombophilia. A portion of splanchnic vein thrombosis is still classified as idiopathic. Here, we review the mechanisms of splanchnic vein thrombosis, including new insights on the role of clonal hematopoiesis in idiopathic SVT pathogenesis, with important implications from the therapeutic standpoint.
Asunto(s)
Trastornos Mieloproliferativos , Tromboembolia Venosa , Trombosis de la Vena , Humanos , Trombosis de la Vena/complicaciones , Trastornos Mieloproliferativos/complicacionesRESUMEN
Essential thrombocythemia (ET) is a myeloproliferative neoplasm variant characterized by excessive production of platelets. Since the most common cause of mortality and morbidity in ET patients is thrombosis, the excessive production of platelets may cause thrombotic events. However, little is known about the function of platelets in ET. We report a female patient who presented as asymptomatic, without a remarkable medical history, and ET was diagnosed after an incidental finding of moderate thrombocytosis. Notably, together with thrombocytosis, an abnormal platelet phenotype was found for the presence of a massive, rapid and spontaneous formation of aggregates and platelet hypersensitivity to subthreshold concentrations of aggregating agonists. Bone marrow histopathological examination and genetic analysis with the JAK2 (V617F) gene mutation findings confirmed the initial suspicion of ET. Although the ET patient was placed on aspirin, the persistence of the platelet hyperactivation and hyperaggregability prompted a switch in antiplatelet medication from entero-coated (EC) to plain aspirin. As result, platelet hypersensitivity to agonists and spontaneous aggregation were no longer found. Collectively, our study demonstrates that platelet function analysis could be a reliable predictor of ET and that plain aspirin should be preferred over EC aspirin to attenuate platelet hyperreactivity.
Asunto(s)
Hipersensibilidad , Trombocitemia Esencial , Trombocitosis , Humanos , Femenino , Trombocitemia Esencial/diagnóstico , Trombocitemia Esencial/tratamiento farmacológico , Agregación Plaquetaria , Plaquetas , Trombocitosis/tratamiento farmacológico , Aspirina/farmacología , Aspirina/uso terapéuticoRESUMEN
The impact of secondary infections (SI) on COVID-19 outcome in patients with hematological malignancies (HM) is scarcely documented. To evaluate incidence, clinical characteristics, and outcome of SI, we analyzed the microbiologically documented SI in a large multicenter cohort of adult HM patients with COVID-19. Among 1741 HM patients with COVID-19, 134 (7.7%) had 185 SI, with a 1-month cumulative incidence of 5%. Median time between COVID-19 diagnosis and SI was 16 days (IQR: 5-36). Acute myeloid leukemia (AML) and lymphoma/plasma cell neoplasms (PCN) were more frequent diagnoses in SI patients compared to patients without SI (AML: 14.9% vs. 7.1%; lymphoma/PCN 71.7% vs. 65.3%). Patients with SI were older (median age 70 vs. 66 years, p = 0.002), with more comorbidities (median Charlson Comorbidity Index 5 vs. 4, p < 0.001), higher frequency of critical COVID-19 (19.5% vs. 11.5%, p = 0.046), and more frequently not in complete remission (75% vs. 64.7% p = 0.024). Blood and bronchoalveolar lavage were the main sites of isolation for SI. Etiology of infections was bacterial in 80% (n = 148) of cases, mycotic in 9.7% (n = 18) and viral in 10.3% (n = 19); polymicrobial infections were observed in 24 patients (18%). Escherichia coli represented most of Gram-negative isolates (18.9%), while coagulase-negative Staphylococci were the most frequent among Gram-positive (14.2%). The 30-day mortality of patients with SI was higher when compared to patients without SI (69% vs. 15%, p < 0.001). The occurrence of SI worsened COVID-19 outcome in HM patients. Timely diagnosis and adequate management should be considered to improve their prognosis.
Asunto(s)
COVID-19 , Coinfección , Neoplasias Hematológicas , Linfoma , Humanos , Anciano , COVID-19/complicaciones , Prueba de COVID-19 , Neoplasias Hematológicas/complicacionesRESUMEN
The imbalance between reactive oxygen species (ROS) synthesis and their scavenging by anti-oxidant defences is the common soil of many disorders, including hypercholesterolemia. Platelets, the smallest blood cells, are deeply involved in the pathophysiology of occlusive arterial thrombi associated with myocardial infarction and stroke. A great deal of evidence shows that both increased intraplatelet ROS synthesis and impaired ROS neutralization are implicated in the thrombotic process. Hypercholesterolemia is recognized as cause of atherosclerosis, cerebro- and cardiovascular disease, and, closely related to this, is the widespread acceptance that it strongly contributes to platelet hyperreactivity via direct oxidized LDL (oxLDL)-platelet membrane interaction via scavenger receptors such as CD36 and signaling pathways including Src family kinases (SFK), mitogen-activated protein kinases (MAPK), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. In turn, activated platelets contribute to oxLDL generation, which ends up propagating platelet activation and thrombus formation through a mechanism mediated by oxidative stress. When evaluating the effect of lipid-lowering therapies on thrombogenesis, a large body of evidence shows that the effects of statins and proprotein convertase subtilisin/kexin type 9 inhibitors are not limited to the reduction of LDL-C but also to the down-regulation of platelet reactivity mainly by mechanisms sensitive to intracellular redox balance. In this review, we will focus on the role of oxidative stress-related mechanisms as a cause of platelet hyperreactivity and the pathophysiological link of the pleiotropism of lipid-lowering agents to the beneficial effects on platelet function.
Asunto(s)
Inhibidores de Hidroximetilglutaril-CoA Reductasas , Hipercolesterolemia , Hiperlipidemias , Trombosis , Antioxidantes/metabolismo , Antígenos CD36/metabolismo , LDL-Colesterol/metabolismo , Humanos , Proteínas Quinasas Activadas por Mitógenos/metabolismo , NADP/metabolismo , NADPH Oxidasas/metabolismo , Oxidación-Reducción , Proproteína Convertasas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Suelo , Subtilisinas/metabolismo , Familia-src Quinasas/metabolismoRESUMEN
The onco-suppressor p53 is a transcription factor that regulates a wide spectrum of genes involved in various cellular functions including apoptosis, cell cycle arrest, senescence, autophagy, DNA repair and angiogenesis. p53 and NF-κB generally have opposing effects in cancer cells. While p53 activity is associated with apoptosis induction, the stimulation of NF-κB has been demonstrated to promote resistance to programmed cell death. Although the transcription factor NF-κB family is considered as the master regulator of cancer development and maintenance, it has been mainly studied in relation to its ability to regulate p53. This has revealed the importance of the crosstalk between NF-κB, p53 and other crucial cell signaling pathways. This review analyzes the various mechanisms by which NF-κB regulates the activity of p53 and the role of p53 on NF-κB activity.
Asunto(s)
FN-kappa B/genética , Proteína p53 Supresora de Tumor/genética , Animales , Regulación de la Expresión Génica/genética , Humanos , Transducción de Señal/genéticaRESUMEN
It is now about 20 years since the first case of a gain-of-function mutation involving the as-yet-unknown actor in cholesterol homeostasis, proprotein convertase subtilisin/kexin type 9 (PCSK9), was described. It was soon clear that this protein would have been of huge scientific and clinical value as a therapeutic strategy for dyslipidemia and atherosclerosis-associated cardiovascular disease (CVD) management. Indeed, PCSK9 is a serine protease belonging to the proprotein convertase family, mainly produced by the liver, and essential for metabolism of LDL particles by inhibiting LDL receptor (LDLR) recirculation to the cell surface with the consequent upregulation of LDLR-dependent LDL-C levels. Beyond its effects on LDL metabolism, several studies revealed the existence of additional roles of PCSK9 in different stages of atherosclerosis, also for its ability to target other members of the LDLR family. PCSK9 from plasma and vascular cells can contribute to the development of atherosclerotic plaque and thrombosis by promoting platelet activation, leukocyte recruitment and clot formation, also through mechanisms not related to systemic lipid changes. These results further supported the value for the potential cardiovascular benefits of therapies based on PCSK9 inhibition. Actually, the passive immunization with anti-PCSK9 antibodies, evolocumab and alirocumab, is shown to be effective in dramatically reducing the LDL-C levels and attenuating CVD. While monoclonal antibodies sequester circulating PCSK9, inclisiran, a small interfering RNA, is a new drug that inhibits PCSK9 synthesis with the important advantage, compared with PCSK9 mAbs, to preserve its pharmacodynamic effects when administrated every 6 months. Here, we will focus on the major understandings related to PCSK9, from its discovery to its role in lipoprotein metabolism, involvement in atherothrombosis and a brief excursus on approved current therapies used to inhibit its action.
Asunto(s)
Aterosclerosis/genética , LDL-Colesterol/metabolismo , Dislipidemias/genética , Placa Aterosclerótica/genética , Proproteína Convertasa 9/genética , Trombosis/genética , Anticuerpos Monoclonales Humanizados/uso terapéutico , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/enzimología , Aterosclerosis/patología , Plaquetas/efectos de los fármacos , Plaquetas/enzimología , Plaquetas/patología , LDL-Colesterol/antagonistas & inhibidores , Dislipidemias/tratamiento farmacológico , Dislipidemias/enzimología , Dislipidemias/patología , Fibrinolíticos/uso terapéutico , Regulación de la Expresión Génica , Humanos , Hipolipemiantes/uso terapéutico , Metabolismo de los Lípidos/efectos de los fármacos , Metabolismo de los Lípidos/genética , Inhibidores de PCSK9 , Placa Aterosclerótica/tratamiento farmacológico , Placa Aterosclerótica/enzimología , Placa Aterosclerótica/patología , Activación Plaquetaria/efectos de los fármacos , Proproteína Convertasa 9/biosíntesis , ARN Interferente Pequeño/uso terapéutico , Receptores de LDL/genética , Receptores de LDL/metabolismo , Transducción de Señal , Trombosis/enzimología , Trombosis/patología , Trombosis/prevención & controlRESUMEN
COVID-19 infection is associated with a broad spectrum of presentations, but alveolar capillary microthrombi have been described as a common finding in COVID-19 patients, appearing as a consequence of a severe endothelial injury with endothelial cell membrane disruption. These observations clearly point to the identification of a COVID-19-associated coagulopathy, which may contribute to thrombosis, multi-organ damage, and cause of severity and fatality. One significant finding that emerges in prothrombotic abnormalities observed in COVID-19 patients is that the coagulation alterations are mainly mediated by the activation of platelets and intrinsically related to viral-mediated endothelial inflammation. Beyond the well-known role in hemostasis, the ability of platelets to also release various potent cytokines and chemokines has elevated these small cells from simple cell fragments to crucial modulators in the blood, including their inflammatory functions, that have a large influence on the immune response during infectious disease. Indeed, platelets are involved in the pathogenesis of acute lung injury also by promoting NET formation and affecting vascular permeability. Specifically, the deposition by activated platelets of the chemokine platelet factor 4 at sites of inflammation promotes adhesion of neutrophils on endothelial cells and thrombogenesis, and it seems deeply involved in the phenomenon of vaccine-induced thrombocytopenia and thrombosis. Importantly, the hyperactivated platelet phenotype along with evidence of cytokine storm, high levels of P-selectin, D-dimer, and, on the other hand, decreased levels of fibrinogen, von Willebrand factor, and thrombocytopenia may be considered suitable biomarkers that distinguish the late stage of COVID-19 progression in critically ill patients.
Asunto(s)
Plaquetas/fisiología , COVID-19/sangre , Trombosis/patología , Coagulación Sanguínea , Trastornos de la Coagulación Sanguínea/etiología , Plaquetas/metabolismo , Plaquetas/virología , COVID-19/metabolismo , Síndrome de Liberación de Citoquinas , Células Endoteliales/patología , Productos de Degradación de Fibrina-Fibrinógeno , Hemostasis , Humanos , Inflamación , Fenotipo , Activación Plaquetaria/fisiología , SARS-CoV-2/metabolismo , SARS-CoV-2/patogenicidad , Trombocitopenia/metabolismo , Trombosis/metabolismo , Trombosis/virologíaRESUMEN
The development of drugs able to target BTK, PI3k-delta and BCL2 has dramatically improved chronic lymphocytic leukaemia (CLL) therapies. However, drug resistance to these therapies has already been reported due to non-recurrent changes in oncogenic pathways and genes expression signatures. In this study, we investigated the cooperative role of the BCL2 inhibitor venetoclax and the BRD4 inhibitor JQ1. In particular, we found that JQ1 shows additional activity with venetoclax, in CLL cell lines and in ex vivo isolated primary CD19+ lymphocytes, arguing in favour of combination strategies. Lastly, JQ1 is also effective in venetoclax-resistant CLL cell lines. Together, our findings indicated that the BET inhibitor JQ1 could be a promising therapy in CLL, both as first-line therapy in combination with venetoclax and as second-line therapy, after the emergence of venetoclax-resistant clones.
Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Sulfonamidas/uso terapéutico , Factores de Transcripción/antagonistas & inhibidores , Azepinas/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Sinergismo Farmacológico , Humanos , Sulfonamidas/farmacología , Factores de Transcripción/metabolismo , Triazoles/farmacologíaRESUMEN
BACKGROUND AND AIMS: In the association between hypercholesterolemia (HC) and thrombotic risk platelet hyper-reactivity plays an important role. The inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) to reduce plasma LDL-cholesterol merges as effective therapeutic strategy to prevent cardiovascular (CV) events. Aim of this study was to verify whether a treatment up to 12 months with the monoclonal antibodies (mAbs) anti-PCSK9 influences platelet function in primary HC. METHODS AND RESULTS: In patients affected by primary HC (n = 24), all on background of statin and 17 on acetyl salicylic acid (ASA), platelet function parameters were evaluated at baseline up to 12 months of treatment with the mAb anti-PCSK9 alirocumab or evolocumab. From baseline, the treatment with anti-PCSK9 mAbs: i) in ASA HC patients, significantly decreased platelet aggregation detected in platelet-rich plasma by light transmission aggregometry and in whole blood Platelet Function Analyzer-100 assay; ii) in all HC patients, significantly decreased platelet membrane expression of CD62P and plasma levels of the in vivo platelet activation markers soluble CD40 Ligand, Platelet Factor-4, and soluble P-Selectin. Furthermore, CD62P expression, and sP-Selectin, PF-4, sCD40L levels significantly correlated with serum PCSK9. CONCLUSION: Besides markedly lowering LDL-c levels, our results suggest that HC patients benefit from anti-PCSK9 mAb treatment also for reducing platelet reactivity and increasing platelet sensitivity to the inhibitory effects of aspirin. These effects on platelets could play a role in the reduction of CV event incidence in patients treated with PCSK9 inhibitors.
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticolesterolemiantes/uso terapéutico , Plaquetas/efectos de los fármacos , Hipercolesterolemia/tratamiento farmacológico , Inhibidores de PCSK9 , Inhibidores de Agregación Plaquetaria/uso terapéutico , Agregación Plaquetaria/efectos de los fármacos , Inhibidores de Serina Proteinasa/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticolesterolemiantes/efectos adversos , Biomarcadores/sangre , Plaquetas/metabolismo , Ligando de CD40/sangre , LDL-Colesterol/sangre , Femenino , Humanos , Hipercolesterolemia/sangre , Hipercolesterolemia/diagnóstico , Hipercolesterolemia/enzimología , Italia , Masculino , Persona de Mediana Edad , Selectina-P/sangre , Inhibidores de Agregación Plaquetaria/efectos adversos , Factor Plaquetario 4/sangre , Proproteína Convertasa 9/sangre , Estudios Prospectivos , Inhibidores de Serina Proteinasa/efectos adversos , Factores de Tiempo , Resultado del TratamientoRESUMEN
Platelet hyperactivation is involved in the established prothrombotic condition of metabolic diseases such as Type 2 Diabetes Mellitus (T2DM) and familial hypercholesterolemia (HC), justifying the therapy with aspirin, a suppressor of thromboxane synthesis through the irreversible inhibition of cyclooxygenase-1 (COX-1), to prevent cardiovascular diseases. However, some patients on aspirin show a higher than expected platelet reactivity due, at least in part, to a pro-oxidant milieu. The aim of this study was to investigate platelet reactivity in T2DM (n = 103) or HC (n = 61) patients (aspirin, 100 mg/day) and its correlation with biomarkers of redox function including the superoxide anion scavenger superoxide dismutase (SOD) and the in vivo marker of oxidative stress urinary 8-iso-prostaglandin F2α. As results, in T2DM and HC subjects the prevalence of high on-aspirin platelet reactivity was comparable when both non-COX-1-dependent and COX-1-dependent assays were performed, and platelet reactivity is associated with a lower SOD activity that in a stepwise linear regression appears as the only predictor of platelet reactivity. To conclude, in T2DM and HC, similarly, the impairment of redox equilibrium associated with a decrease of SOD activity could contribute to a suboptimal response to aspirin.
Asunto(s)
Aspirina/uso terapéutico , Diabetes Mellitus Tipo 2/complicaciones , Hipercolesterolemia/complicaciones , Inhibidores de Agregación Plaquetaria/uso terapéutico , Superóxido Dismutasa/metabolismo , Trombosis/prevención & control , Anciano , Aspirina/administración & dosificación , Plaquetas/efectos de los fármacos , Inhibidores de la Ciclooxigenasa/administración & dosificación , Inhibidores de la Ciclooxigenasa/uso terapéutico , Diabetes Mellitus Tipo 2/metabolismo , Femenino , Humanos , Hipercolesterolemia/metabolismo , Masculino , Persona de Mediana Edad , Estrés Oxidativo/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/administración & dosificación , Trombosis/etiología , Trombosis/metabolismo , Tromboxanos/metabolismoRESUMEN
Despite the advent of tyrosine kinase inhibitors, a proportion of chronic myeloid leukemia patients in chronic phase fail to respond to imatinib or to second-generation inhibitors and progress to blast crisis. Until now, improvements in the understanding of the molecular mechanisms responsible for chronic myeloid leukemia transformation from chronic phase to the aggressive blast crisis remain limited. Here we present a large parallel sequencing analysis of 10 blast crisis samples and of the corresponding autologous chronic phase controls that reveals, for the first time, recurrent mutations affecting the ubiquitin-conjugating enzyme E2A gene (UBE2A, formerly RAD6A). Additional analyses on a cohort of 24 blast crisis, 41 chronic phase as well as 40 acute myeloid leukemia and 38 atypical chronic myeloid leukemia patients at onset confirmed that UBE2A mutations are specifically acquired during chronic myeloid leukemia progression, with a frequency of 16.7% in advanced phases. In vitro studies show that the mutations here described cause a decrease in UBE2A activity, leading to an impairment of myeloid differentiation in chronic myeloid leukemia cells.
Asunto(s)
Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mieloide Aguda/genética , Mutación , Enzimas Ubiquitina-Conjugadoras/genética , Crisis Blástica/genética , Diferenciación Celular , Progresión de la Enfermedad , Resistencia a Antineoplásicos/genética , Femenino , Células HEK293 , Humanos , Mesilato de Imatinib/uso terapéutico , Células K562 , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Leucemia Mieloide Aguda/patología , Masculino , Inhibidores de Proteínas Quinasas/farmacología , Análisis de Secuencia de ADN , Secuenciación del ExomaRESUMEN
Atypical Chronic Myeloid Leukemia (aCML) is a myeloproliferative neoplasm characterized by neutrophilic leukocytosis and dysgranulopoiesis. From a genetic point of view, aCML shows a heterogeneous mutational landscape with mutations affecting signal transduction proteins but also broad genetic modifiers and chromatin remodelers, making difficult to understand the molecular mechanisms causing the onset of the disease. The JAK-STAT, MAPK and ROCK pathways are known to be responsible for myeloproliferation in physiological conditions and to be aberrantly activated in myeloproliferative diseases. Furthermore, experimental evidences suggest the efficacy of inhibitors targeting these pathways in repressing myeloproliferation, opening the way to deep clinical investigations. However, the activation status of these pathways is rarely analyzed when genetic mutations do not occur in a component of the signaling cascade. Given that mutations in functionally unrelated genes give rise to the same pathology, it is tempting to speculate that alteration in the few signaling pathways mentioned above might be a common feature of pathological myeloproliferation. If so, targeted therapy would be an option to be considered for aCML patients.
Asunto(s)
Quinasas Janus/metabolismo , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/tratamiento farmacológico , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/metabolismo , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Transducción de Señal/efectos de los fármacos , Quinasas Asociadas a rho/metabolismo , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinesulfonil)-2-Metilpiperazina/uso terapéutico , Animales , Humanos , Quinasas Janus/genética , Proteínas Quinasas Activadas por Mitógenos/genética , Mutación/genética , Nitrilos , Pirazoles/uso terapéutico , Piridonas/uso terapéutico , Pirimidinas , Pirimidinonas/uso terapéutico , Transducción de Señal/genética , Quinasas Asociadas a rho/genéticaRESUMEN
We recently described morgana as an essential protein able to regulate centrosome duplication and genomic stability, by inhibiting ROCK. Here we show that morgana (+/-) mice spontaneously develop a lethal myeloproliferative disease resembling human atypical chronic myeloid leukemia (aCML), preceded by ROCK hyperactivation, centrosome amplification, and cytogenetic abnormalities in the bone marrow (BM). Moreover, we found that morgana is underexpressed in the BM of patients affected by atypical CML, a disorder of poorly understood molecular basis, characterized by nonrecurrent cytogenetic abnormalities. Morgana is also underexpressed in the BM of a portion of patients affected by Philadelphia-positive CML (Ph(+) CML) caused by the BCR-ABL oncogene, and in this condition, morgana underexpression predicts a worse response to imatinib, the standard treatment for Ph(+) CML. Thus, morgana acts as an oncosuppressor with different modalities: (1) Morgana underexpression induces centrosome amplification and cytogenetic abnormalities, and (2) in Ph(+) CML, it synergizes with BCR-ABL signaling, reducing the efficacy of imatinib treatment. Importantly, ROCK inhibition in the BM of patients underexpressing morgana restored the efficacy of imatinib to induce apoptosis, suggesting that ROCK inhibitors, combined with imatinib treatment, can overcome suboptimal responses in patients in which morgana is underexpressed.
Asunto(s)
Benzamidas/farmacología , Proteínas Portadoras/fisiología , Resistencia a Antineoplásicos/genética , Proteínas de Fusión bcr-abl/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Cromosoma Filadelfia , Piperazinas/farmacología , Pirimidinas/farmacología , Quinasas Asociadas a rho/antagonistas & inhibidores , Animales , Apoptosis , Western Blotting , Médula Ósea/metabolismo , Médula Ósea/patología , Proliferación Celular , Citometría de Flujo , Proteínas de Fusión bcr-abl/genética , Humanos , Mesilato de Imatinib , Técnicas para Inmunoenzimas , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Chaperonas Moleculares , Inhibidores de Proteínas Quinasas/farmacología , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células Tumorales Cultivadas , Quinasas Asociadas a rho/genética , Quinasas Asociadas a rho/metabolismoRESUMEN
Despite the recent identification of recurrent SETBP1 mutations in atypical chronic myeloid leukemia (aCML), a complete description of the somatic lesions responsible for the onset of this disorder is still lacking. To find additional somatic abnormalities in aCML, we performed whole-exome sequencing on 15 aCML cases. In 2 cases (13.3%), we identified somatic missense mutations in the ETNK1 gene. Targeted resequencing on 515 hematological clonal disorders revealed the presence of ETNK1 variants in 6 (8.8%) of 68 aCML and 2 (2.6%) of 77 chronic myelomonocytic leukemia samples. These mutations clustered in a small region of the kinase domain, encoding for H243Y and N244S (1/8 H243Y; 7/8 N244S). They were all heterozygous and present in the dominant clone. The intracellular phosphoethanolamine/phosphocholine ratio was, on average, 5.2-fold lower in ETNK1-mutated samples (P < .05). Similar results were obtained using myeloid TF1 cells transduced with ETNK1 wild type, ETNK1-N244S, and ETNK1-H243Y, where the intracellular phosphoethanolamine/phosphocholine ratio was significantly lower in ETNK1-N244S (0.76 ± 0.07) and ETNK1-H243Y (0.37 ± 0.02) than in ETNK1-WT (1.37 ± 0.32; P = .01 and P = .0008, respectively), suggesting that ETNK1 mutations may inhibit the catalytic activity of the enzyme. In summary, our study shows for the first time the evidence of recurrent somatic ETNK1 mutations in the context of myeloproliferative/myelodysplastic disorders.
Asunto(s)
Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielomonocítica Crónica/genética , Mutación/genética , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Secuencia de Aminoácidos , Estudios de Casos y Controles , Estudios de Seguimiento , Humanos , Datos de Secuencia Molecular , Pronóstico , Homología de Secuencia de AminoácidoRESUMEN
BACKGROUND: Chronic Myeloid Leukemia was always referred as a unique cancer due to the apparent independence from tumor suppressors' deletions/mutations in the early stages of the disease. However, it is now well documented that even genetically wild-type tumor suppressors can be involved in tumorigenesis, when functionally inactivated. In particular, tumor suppressors' functions can be impaired by subtle variations of protein levels, changes in cellular compartmentalization and post-transcriptional/post-translational modifications, such as phosphorylation, acetylation, ubiquitination and sumoylation. Notably, tumor suppressors inactivation offers challenging therapeutic opportunities. The reactivation of an inactive and genetically wild-type tumor suppressor could indeed promote selective apoptosis of cancer cells without affecting normal cells. MAIN BODY: Chronic Myeloid Leukemia (CML) could be considered as the paradigm for non-genomic loss of function of tumor suppressors due to the ability of BCR-ABL to directly promote functionally inactivation of several tumor suppressors. SHORT CONCLUSION: In this review we will describe new insights on the role of FoxO, PP2A, p27, BLK, PTEN and other tumor suppressors in CML pathogenesis. Finally, we will describe strategies to promote tumor suppressors reactivation in CML.