RESUMEN
8p11 myeloproliferative syndrome is a rare hematological malignancy caused by the translocation of FGFR1. Patients present with a myeloproliferative neoplasm that frequently transforms into acute myeloid leukemia or T-lymphoblastic lymphoma/leukemia. Here, we report a molecular study of a patient with 8p11 myeloproliferative syndrome who developed acute B-lymphoblastic leukemia and then transformed to mixed-phenotype acute leukemia. A 67-year-old woman was diagnosed with a myeloproliferative neoplasm with t(6;8)(q27;p12) and was monitored for polycythemia vera. Four years later, she developed acute B-lymphoblastic leukemia with an additional chromosomal abnormality of - 7. Despite two induction regimens, she failed to achieve complete remission, and leukemia transformed into mixed-phenotype leukemia. Targeted sequencing of serial bone marrow samples identified the RUNX1 L144R mutation upon transformation to B-cell leukemia. After those two induction regimens, some RUNX1 mutation-positive leukemic cells obtained the JAK2 V617F mutation, which was associated with the emergence of myeloid markers, including myeloperoxidase.
Asunto(s)
Leucemia Mieloide Aguda , Trastornos Mieloproliferativos , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Femenino , Humanos , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Trastornos Mieloproliferativos/genética , Trastornos Mieloproliferativos/patología , Leucemia Mieloide Aguda/genética , Translocación GenéticaRESUMEN
A 65-year-old man with nonsevere aplastic anemia received rabbit anti-thymocyte globulin and cyclosporine and partially responded. Six months after the initiation of treatment, he was diagnosed with stage IV angioimmunoblastic T-cell lymphoma and received chemotherapy. PET/CT scan analysis indicated a complete response. However, he showed sustained myelosuppression and was diagnosed with relapse of aplastic anemia. He did not respond to cyclosporine, eltrombopag or methenolone. Fifteen months after eltrombopag administration, he developed MDS with t(3;21)(q26.2;q22). Patients should be monitored carefully for the emergence of not only -7/del(7q) but also 3q26 abnormalities, including t(3;21)(q26.2;q22), during and after eltrombopag treatment.
RESUMEN
Tyrosine kinase inhibitors (TKIs) are standard therapies for chronic myeloid leukemia (CML) that can eradicate Ph-positive leukemic cells. However, disease control is not achievable in a minority of cases, most commonly due to evolution of TKI-resistant clones. There have also been rare cases of emergence of Ph-negative clones with other cytogenetic abnormalities, and, less commonly, development of Ph-negative acute myeloid leukemia (AML), whose molecular pathogenesis is largely unknown. Here we report molecular features of a patient with Ph + CML who developed Ph-negative AML after showing a major molecular response to dasatinib. A 55-year-old man was diagnosed with CML. He achieved a complete cytogenetic response three months after dasatinib therapy but developed AML with normal karyotype 1 year later. After receiving induction and consolidation chemotherapy for AML, the patient achieved complete remission with no evidence of CML under maintenance with bosutinib. Targeted sequencing of serial bone marrow samples identified mutations in IDH2 and NPM1 in the Ph-negative AML cells, which had not been detected in CML cells. These results suggest that Ph-negative AML in this patient originated from a preleukemic population, which might have expanded during or after the successful elimination of CML clones with TKI therapy.
Asunto(s)
Compuestos de Anilina/administración & dosificación , Dasatinib/administración & dosificación , Isocitrato Deshidrogenasa , Mutación , Proteínas de Neoplasias , Nitrilos/administración & dosificación , Proteínas Nucleares , Inhibidores de Proteínas Quinasas/administración & dosificación , Quinolinas/administración & dosificación , Humanos , Isocitrato Deshidrogenasa/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Nucleofosmina , Cromosoma FiladelfiaAsunto(s)
Enfermedad de Hodgkin , Linfoma no Hodgkin , Antraciclinas/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Enfermedad de Hodgkin/tratamiento farmacológico , Humanos , Linfoma no Hodgkin/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Terapia Recuperativa , Resultado del TratamientoRESUMEN
A 70-year-old woman experienced pain in both gastrocnemius muscles, numbness in the toes, and muscle weakness in both the legs that lasted for two months. After getting admitted to our hospital, the muscle weakness extended to both her arms, and nerve conduction studies revealed decreased nerve conduction velocity, which was more prominent in the elbow and the axilla than in the wrist. A magnetic resonance imaging revealed a tumor in the right femoral neck, which was histologically diagnosed as plasmacytoma. Laboratory findings revealed IgA lambda type M protein and an elevated VEGF level of 2,320 pg/ml; edema was present in both the legs. After a diagnosis of POEMS syndrome, lenalidomide and dexamethasone treatment were initiated simultaneously, along with irradiation. The treatment improved polyneuropathy, along with a decrease in the VEGF level. Increased vascular permeability due to elevated VEGF led to the development of neuropathy of POEMS syndrome, and treatment against proliferating monoclonal plasma cells is effective. In the present case, we believe that a prompt control of the plasmacytoma with novel therapeutic agents for myeloma with irradiation resulted in the improvement of the neurological symptoms.
Asunto(s)
Dexametasona/uso terapéutico , Lenalidomida/uso terapéutico , Síndrome POEMS , Plasmacitoma , Anciano , Femenino , Humanos , Síndrome POEMS/tratamiento farmacológico , Factor A de Crecimiento Endotelial VascularRESUMEN
A 56-year-old man who sustained a right waist injury 1 month ago, reported to our department complaining of pain in the right waist and femur for 1 day. In a computed tomography examination, hematoma of the right iliopsoas muscle was revealed, and arterial embolization was immediately performed but was not effective. Laboratory findings showed hemoglobin levels as 5.4 g/dl, platelet of 20.2×104/µl, prothrombine time of 13.1 s, partial thromboplastin time (APTT) of 81.1 s, and a convex upward curve of the APTT cross-mixing test. The activity of the coagulation factor VIII was <1.0%, but its amount was 120%, and the level of factor VIII inhibitor was 130 Bethesda Unit/ml. Disseminated intravascular coagulation was not noted. Under the diagnosis of acquired hemophilia A, treatment with prednisolone and recombinant activated factor VII was initiated. However, APTT remained prolonged, and intubation and mechanical ventilation were required because of right hemothorax. After steroid pulse therapy and plasma exchange, APTT returned to its normal range, and the inhibitor disappeared. Thus, we finally succeeded in extubation. This case indicated that intensive care may be necessary in the early phase treatment for acquired hemophilia A.
Asunto(s)
Hemofilia A/terapia , Intercambio Plasmático , Respiración Artificial , Factor VIII , Humanos , Masculino , Persona de Mediana Edad , Tiempo de Tromboplastina ParcialRESUMEN
A 59-year-old woman with anaplastic large cell lymphoma (ALCL), ALK-negative, was treated with brentuximab vedotin (BV) against relapse after 6 regimens of systemic chemotherapy and radiation. Despite achieving an initial response, skin lesions worsened after 11 courses. A skin biopsy after the development of resistance to BV confirmed loss of CD30 expression by the tumor cells, suggesting a possible cause of resistance. This case shows that down-regulation of CD30 does occur during BV treatment, resulting in resistance to this drug. Because of this possibility, in the future, expression of CD30 should be carefully monitored with extended use of BV against ALCL.
Asunto(s)
Inmunoconjugados/uso terapéutico , Antígeno Ki-1/inmunología , Linfoma Anaplásico de Células Grandes/tratamiento farmacológico , Quinasa de Linfoma Anaplásico , Brentuximab Vedotina , Femenino , Humanos , Antígeno Ki-1/análisis , Linfoma Anaplásico de Células Grandes/química , Linfoma Anaplásico de Células Grandes/metabolismo , Persona de Mediana Edad , Proteínas Tirosina Quinasas Receptoras/análisis , Resultado del TratamientoRESUMEN
We experienced two patients with mixed phenotype acute leukemia with t(9;22)(q34;q11.2); BCR-ABL1 according to the WHO classification 2008. The type of BCR/ABL1 was major in both patients, and the chimeric gene was also detected in neutrophils from peripheral blood by the fluorescence in situ hybridization technique. Patient 1 was a 59-year-old Japanese woman, and patient 2 a 45-year-old Japanese man. They had both developed leukemia suddenly. Their leukemic blasts expressed B cell and myeloid cell antigens, but concomitantly in patient 1 (biphenotypic) and separately in patient 2 (biclonal). Percentages of BCR-ABL1-positive neutrophils were 98% and 89%, respectively. Both patients received an imatinib (600 mg/day)-combined Hyper-CVAD regimen as induction therapy, followed by treatment with dasatinib (140 mg/day). MEC therapy was also applied between these two treatments in patient 2. At present, patient 1 has obtained complete molecular remission quantitatively and qualitatively, and patient 2 only quantitatively. Considering their acute onsets with no prior history of chronic myelocytic leukemia (CML), they were both diagnosed as having acute leukemia with Ph1, but not blastic crisis of CML. In this tyrosine kinase inhibitor era, it has become more difficult to differentiate these two types of Ph1-positive leukemia development.
Asunto(s)
Proteínas de Fusión bcr-abl/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mieloide Aguda/diagnóstico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Benzamidas/uso terapéutico , Dasatinib , Diagnóstico Diferencial , Femenino , Humanos , Mesilato de Imatinib , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Masculino , Persona de Mediana Edad , Neutrófilos/metabolismo , Fenotipo , Piperazinas/uso terapéutico , Pirimidinas/uso terapéutico , Tiazoles/uso terapéuticoRESUMEN
We report a 40-year-old woman diagnosed as having acute myeloid leukemia with CBFB-MYH11. Before and after stem cell transplantation in the phase of molecular remission of the marrow, CBFB-MYH11-positive cells were detected by RT-PCR analysis in skin lesions. The former was pathologically diagnosed as leukemic infiltration, while the latter was considered to be graft-versus-host disease. We can speculate that a low level of leukemic stem cells not detectable by RT-PCR analysis remained in the bone marrow, at least prior to transplantation. This case may suggest interesting biological features of inv(16)-type acute myeloid leukemia.
Asunto(s)
Médula Ósea/patología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Leucemia Mieloide Aguda/patología , Piel/patología , Adulto , Femenino , Enfermedad Injerto contra Huésped/genética , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Proteínas de Fusión Oncogénica/metabolismo , RecurrenciaRESUMEN
We report a 69-year-old male with CD3-positive peripheral T-cell lymphoma, not otherwise specified (PTCL-nos). Interestingly, tumor cells slightly expressed CD20 as well. Southern analyses of the tumor cells showed rearrangement for only the T cell receptor gene but not the immunoglobulin genes. This patient achieved partial remission with a treatment regimen of THP-COP excluding prednisolone, but died of pneumonia. Although CD20-positive PTCL is rare, a review of the reported cases suggests that CD20-positive PTCL has a poor prognosis and that bone marrow infiltration of tumor cells results in a poorer prognosis in CD20-positive PTCL than in usual PTCL. By accumulating cases of this rare entity of lymphoma, we need to clarify the biological nature of the tumor cells and usefulness of rituximab combined with standard chemotherapy.
Asunto(s)
Antígenos CD20 , Linfoma de Células T Periférico/diagnóstico , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ciclofosfamida/administración & dosificación , Doxorrubicina/administración & dosificación , Doxorrubicina/análogos & derivados , Resultado Fatal , Citometría de Flujo , Reordenamiento Génico , Pruebas Genéticas , Humanos , Linfoma de Células T Periférico/tratamiento farmacológico , Linfoma de Células T Periférico/genética , Masculino , Persona de Mediana Edad , Prednisolona/administración & dosificación , Receptores de Antígenos de Linfocitos T/genética , Rituximab , Vincristina/administración & dosificaciónRESUMEN
We previously tested a less toxic CAG regimen consisting of low-dose cytarabine, aclarubicin and granulocyte-colony stimulating factor for the treatment of patients with relapsed or refractory myeloid malignancies or elderly patients with untreated ones, obtaining a satisfactory complete remission rate of 62%. Gemtuzumab ozogamicin, an anti-CD33 monoclonal antibody conjugated to calicheamicin, has recently been approved as a single agent in Japan for the treatment of relapsed/refractory CD33-positive acute myelogenous leukemia (9 mg/m(2) on days1 and 15). Complete remission rate was reported as 30% in a phase 2 trial in Japan. In this study, effectiveness and safety of combining dose-attenuated gemtuzumab ozogamicin (3 mg/m(2) on day5) and original CAG regimen were assessed in nine patients with relapsed/refractory CD33-positive acute myelogenous leukemia and a median age of 70 years. Rate of complete remission with or without platelet recovery was 44% (4/9). The median duration of complete remission and overall survival were 5.5 and 16 months, respectively. Reversible myelosuppression and liver toxicity were the main adverse events, but no regimen-related death was recorded. Although only a small number of cases were included in this preliminary study, this CAG-GO regimen was found to be feasible and useful even in high-risk relapsed or refractory patients.
Asunto(s)
Aminoglicósidos/administración & dosificación , Anticuerpos Monoclonales Humanizados/administración & dosificación , Antígenos CD , Antígenos de Diferenciación Mielomonocítica , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Aclarubicina/administración & dosificación , Aclarubicina/efectos adversos , Anciano , Aminoglicósidos/efectos adversos , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Citarabina/administración & dosificación , Citarabina/efectos adversos , Femenino , Gemtuzumab , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Factor Estimulante de Colonias de Granulocitos/efectos adversos , Humanos , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Recurrencia , Inducción de Remisión , Lectina 3 Similar a Ig de Unión al Ácido Siálico , Tasa de SupervivenciaRESUMEN
It is well known that patients with rheumatoid arthritis (RA) have a higher risk of developing malignant lymphoma (ML) than the general population. Most of these lymphomas occur in patients receiving immunosuppressive (IS) agents such as methotrexate (MTX). Spontaneous regression of tumors is often observed after the discontinuation of IS drugs, especially in patients with Epstein-Barr virus-positive lymphoma. Here we encountered an RA patient who developed extranodal NK/T-cell lymphoma, nasal type during treatment of RA with MTX and etanercept. Despite the discontinuation of MTX and etanercept, the tumor did not show any regression. Complete response was achieved after treatment with concurrent chemoradiotherapy. ML of NK-cell origin is extremely rare, while the majority of ML cases associated with RA are of B-cell origin. This report describes extranodal NK/T-cell lymphoma, nasal type case associated with RA. Such cases should be accumulated to evaluate the mechanism of onset and clinical characteristics of NK/T-cell lymphoma associated with RA.
Asunto(s)
Artritis Reumatoide/complicaciones , Células Asesinas Naturales , Linfoma de Células T/etiología , Neoplasias Nasales/etiología , Anciano , Artritis Reumatoide/tratamiento farmacológico , Etanercept , Humanos , Inmunoglobulina G/efectos adversos , Inmunoglobulina G/uso terapéutico , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico , Masculino , Metotrexato/efectos adversos , Metotrexato/uso terapéutico , Receptores del Factor de Necrosis Tumoral/uso terapéuticoRESUMEN
Malignant lymphoma (ML) is frequently associated with several forms of collagen diseases such as Sjören syndrome, systemic lupus erythematodes, and rheumatoid arthritis. However, the occurrence of ML in systemic sclerosis (SSc) patients has rarely been reported. Here we report an SSc patient who developed mediastinal (thymic) large B-cell lymphoma (MLBCL). A 31-year-old woman was diagnosed as having SSc in August 2007. The patient was treated with low-dose prednisolone (10 mg/day) without any effect. One year after the diagnosis, chest computed tomography-scan demonstrated thymic tumor in the anterior mediastinum. Thymectomy was performed, and a pathohistological diagnosis of MLBCL was established. Immunohistochemical analysis demonstrated that the tumor cells were positive for CD45 and CD20, but negative for CD30 and EBV-encoded RNA. The patient was treated with 6 courses of CHOP regimen, resulting in complete remission of lymphoma. This report describes the first SSc patient associated with MLBCL. SSc patients occasionally develop ML after a relatively short interval. Our case suggests that intensive monitoring for the development of ML is needed in newly diagnosed SSc patients.
Asunto(s)
Linfoma de Células B Grandes Difuso/etiología , Esclerodermia Sistémica/complicaciones , Neoplasias del Timo/etiología , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ciclofosfamida/administración & dosificación , Doxorrubicina/administración & dosificación , Femenino , Humanos , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/patología , Linfoma de Células B Grandes Difuso/terapia , Tomografía de Emisión de Positrones , Prednisolona/administración & dosificación , Inducción de Remisión , Timectomía , Neoplasias del Timo/diagnóstico , Neoplasias del Timo/patología , Neoplasias del Timo/terapia , Tomografía Computarizada por Rayos X , Vincristina/administración & dosificaciónRESUMEN
A transcriptional repressor TEL belongs to the ETS family transcription factors and acts as a tumor suppressor. We identified five alternatively spliced TEL isoforms generated possibly through exon skipping mechanisms, by using reverse transcriptase-polymerase chain reaction analysis. Among them, we examined molecular and biological functions of a DeltaETS-TEL isoform (TEL-f). This isoform abrogated specific DNA-binding capacity to and trans-repressional ability through the ETS-binding site. Regardless, it showed dominant-negative effects over wild-type-TEL (TEL-a)-mediated transcriptional repression partly through sequestration of TEL-a from nucleus to cytoplasm. Moreover, TEL-f dominantly interfered with TEL-a-mediated erythroid differentiation in MEL cells and growth suppression in NIH3T3 cells. Interestingly, TEL isoforms without the entire (Delta exons 6+7-TEL) or a part (Delta exon 7-TEL) of ETS domain were expressed more frequently in myelodysplastic syndrome-derived leukemia than in myelodysplastic syndrome before transformation. This observation suggests that accumulation of the dominant-negative DeltaETS-TEL molecules could be a related phenomenon to leukemic progression of myelodysplastic syndrome.
Asunto(s)
Proteínas de Unión al ADN/fisiología , Proteínas Represoras/fisiología , Empalme Alternativo , Animales , Células COS , Diferenciación Celular , Línea Celular Tumoral , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Proteínas de Unión al ADN/biosíntesis , Proteínas de Unión al ADN/química , Proteínas de Unión al ADN/genética , Dimerización , Eritrocitos/citología , Eritrocitos/metabolismo , Genes Dominantes , Células HeLa , Humanos , Leucocitos Mononucleares/metabolismo , Ratones , Células 3T3 NIH , Isoformas de Proteínas , Estructura Terciaria de Proteína , Proteínas Proto-Oncogénicas c-ets , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteínas Represoras/biosíntesis , Proteínas Represoras/química , Proteínas Represoras/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteínas Supresoras de Tumor/química , Proteínas Supresoras de Tumor/fisiología , Proteína ETS de Variante de Translocación 6RESUMEN
TEL is an ETS family transcription factor that possesses multiple putative mitogen-activated protein kinase phosphorylation sites. We here describe the functional regulation of TEL via ERK pathways. Overexpressed TEL becomes phosphorylated in vivo by activated ERK. TEL is also directly phosphorylated in vitro by ERK. The inducible phosphorylation sites are Ser(213) and Ser(257). TEL binds to a common docking domain in ERK. In vivo ERK-dependent phosphorylation reduces trans-repressional and DNA-binding abilities of TEL for ETS-binding sites. A mutant carrying substituted glutamates on both Ser(213) and Ser(257) functionally mimics hyperphosphorylated TEL and also shows a dominant-negative effect on TEL-induced transcriptional suppression. Losing DNA-binding affinity through phosphorylation but heterodimerizing with unmodified TEL could be an underlying mechanism. Moreover, the glutamate mutant dominantly interferes with TEL-induced erythroid differentiation in MEL cells and growth suppression in NIH 3T3 cells. Finally, endogenous TEL is dephosphorylated in parallel with ERK inactivation in differentiating MEL cells and is phosphorylated through ERK activation in Ras-transformed NIH 3T3 cells. These data indicate that TEL is a constituent downstream of ERK in signal transduction systems and is physiologically regulated by ERK in molecular and biological features.
Asunto(s)
Proteínas de Unión al ADN/metabolismo , Regulación de la Expresión Génica , Sistema de Señalización de MAP Quinasas/fisiología , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Proteínas Represoras/metabolismo , Animales , Diferenciación Celular/fisiología , Línea Celular , Proteínas de Unión al ADN/genética , Células Eritroides/citología , Células Eritroides/metabolismo , Humanos , Ratones , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Fosforilación , Proteínas Proto-Oncogénicas c-ets , Proteínas Recombinantes de Fusión/metabolismo , Proteínas Represoras/genética , Serina/metabolismo , Proteína ETS de Variante de Translocación 6RESUMEN
A 26-year-old woman was diagnosed as having autoimmune hemolytic anemia in September 2002. Her eosinophil count was already high (2,190/microliter) at that time. She received prednisolone therapy with a good response and was released from the treatment in April 2003. Eosinophil numbers were within the normal range under the prednisolone administration. However, they began to increase after its completion. No underlying causes for the eosinophilia were evident. When the eosinophil count reached 5,474/microliter, the patient developed massive pleural effusion as well as palpebral swelling and myalgia, leading to a diagnosis of hypereosinophilic syndrome. Re-administration of prednisolone resulted in the disappearance of these symptoms and eosinophilia. Her eosinophils seemed to have reactivated after cessation of the prednisolone therapy and infiltrated into her organs.
Asunto(s)
Anemia Hemolítica Autoinmune/tratamiento farmacológico , Síndrome Hipereosinofílico/etiología , Prednisolona/uso terapéutico , Síndrome de Abstinencia a Sustancias , Adulto , Femenino , HumanosRESUMEN
TEL belongs to a member of the ETS family transcription factors that represses transcription of target genes such as FLI-1. Although TEL is essential for establishing hematopoiesis in neonatal bone marrow, its role in erythroid lineage is not understood. To investigate a role for TEL in erythroid differentiation, we introduced TEL into mouse erythroleukemia (MEL) cells. Overexpressing wild-type-TEL in MEL cells enhanced differentiation induced by hexamethylene bisacetamide or dimethylsulfoxide, as judged by the increased levels of erythroid-specific delta-aminolevulinate synthase and beta-globin mRNAs. TEL bound to a corepressor mSin3A through the helix-loop-helix domain. A TEL mutant lacking this domain still bound to the ETS binding site, but lost its transrepressional effect. This mutant completely blocked erythroid differentiation in MEL cells. Moreover, it showed dominant-negative effects over TEL-mediated transcriptional repression and acceleration of erythroid differentiation. Endogenous TEL mRNA was found to increase during the first 3 days in differentiating MEL cells and drastically decrease thereafter. All these data suggest that TEL might play some role in erythroid cell differentiation.
Asunto(s)
Diferenciación Celular/fisiología , Proteínas de Unión al ADN/fisiología , Virus de la Leucemia Murina de Friend/aislamiento & purificación , Leucemia Eritroblástica Aguda/patología , Proteínas Represoras/fisiología , 5-Aminolevulinato Sintetasa/genética , Animales , Secuencia de Bases , Cartilla de ADN , Ensayo de Cambio de Movilidad Electroforética , Globinas/genética , Células HeLa , Humanos , Leucemia Eritroblástica Aguda/genética , Leucemia Eritroblástica Aguda/virología , Ratones , Proteínas Proto-Oncogénicas c-ets , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células Tumorales Cultivadas , Proteína ETS de Variante de Translocación 6Asunto(s)
Crisis Blástica/terapia , Trasplante de Médula Ósea/métodos , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Adulto , Trasplante de Médula Ósea/inmunología , Recuento de Células , Femenino , Supervivencia de Injerto , Células Madre Hematopoyéticas , Humanos , Inducción de Remisión , Trasplante Homólogo , Trasplante IsogénicoRESUMEN
Ten patients with acute myelogenous leukemia or high risk myelodysplastic syndrome who had achieved complete remission following treatment with the CAG regimen were monitored for peripheral blood WT1 expression mRNA levels. Induction therapy with the CAG regimen did not seem to be enough to lower WT1 expression levels to the normal range. In comparison with patients who received intensive chemotherapy for post-remission therapy, those who received only CAG therapy showed higher levels of WT1 expression and more easily relapsed. These data suggest that CAG therapy alone might not be sufficient to maintain complete remission and WT1 monitoring could be useful in the choice of appropriate post-remission therapy after achieving remission with the CAG regimen.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Mieloide Aguda/metabolismo , Síndromes Mielodisplásicos/metabolismo , Proteínas WT1/genética , Aclarubicina/administración & dosificación , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Citarabina/administración & dosificación , Esquema de Medicación , Femenino , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/tratamiento farmacológico , Inducción de RemisiónRESUMEN
TEL is a nuclear phosphoprotein that belongs to a member of the ETS family transcription factors. TEL acts as a tumor suppressor and is essential for establishing hematopoiesis in neonatal bone marrow. Because TEL possesses multiple putative mitogen-activated protein (MAP) kinase phosphorylation sites, we here investigated functional regulation of TEL via stress signaling pathways. We showed that TEL becomes phosphorylated in vivo by activated p38 but not by JNK1. The constitutive and inducible phosphorylation sites were found to be Ser(22) and Ser(257), respectively. TEL bound to p38 and was directly phosphorylated in vitro by p38. In vivo p38-dependent phosphorylation reduced trans-repressional abilities of TEL through ETS-binding consensus site. These data indicate that TEL's functions are potentially regulated by p38 which is activated by various kinds of stresses. TEL could be a constituent downstream of the specific MAP kinase in the signal transduction system.