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1.
Int J Mol Sci ; 22(15)2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34360557

RESUMO

Among the eight human glutathione peroxidase isoforms, glutathione peroxidase 4 (GPX4) is the only enzyme capable of reducing complex lipid peroxides to the corresponding alcohols. In mice, corruption of the Gpx4 gene leads to embryonic lethality and more detailed expression silencing studies have implicated the enzyme in several physiological processes (e.g., embryonal cerebrogenesis, neuronal function, male fertility). Experiments with conditional knockout mice, in which expression of the Gpx4 gene was silenced in erythroid precursors, indicated a role of Gpx4 in erythropoiesis. To test this hypothesis in a cellular in vitro model we transfected mouse erythroleukemia cells with a Gpx4 siRNA construct and followed the expression kinetics of erythropoietic gene products. Our data indicate that Gpx4 is expressed at high levels in mouse erythroleukemia cells and that expression silencing of the Gpx4 gene delays in vitro erythropoiesis. However, heterozygous expression of a catalytically inactive Gpx4 mutant (Gpx4+/Sec46Ala) did not induce a defective erythropoietic phenotype in different in vivo and ex vivo models. These data suggest that Gpx4 plays a role in erythroid differentiation of mouse erythroleukemia cells but that heterozygous expression of a catalytically inactive Gpx4 is not sufficient to compromise in vivo and ex vivo erythropoiesis.


Assuntos
Eritropoese , Leucemia Eritroblástica Aguda/patologia , Mitocôndrias/patologia , Estresse Oxidativo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/antagonistas & inibidores , RNA Interferente Pequeno/genética , Animais , Leucemia Eritroblástica Aguda/etiologia , Leucemia Eritroblástica Aguda/metabolismo , Masculino , Camundongos , Camundongos Knockout , Mitocôndrias/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo
2.
Medicine (Baltimore) ; 100(15): e25528, 2021 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-33847676

RESUMO

RATIONALE: Pure erythroid leukemia is a rare subcategory of acute myeloid leukemia characterized by predominant immature erythroid population. Its occurrence subsequent to acute myelomonocytic leukemia has not been reported before. We reported this rare case to call attention because it may pose a diagnostic challenge. PATIENTS CONCERNS: A 54-year-old female patient presented to our hospital in March 2018 with symptoms of easy fatigability. DIAGNOSIS: Bone marrow aspiration was hypercellular showing 67.2% blasts mainly including moderate myeloblasts and monoblasts. There was mild dysplasia with some cells having round, oval, or bizarre nuclei which containing 1 to 3 nucleolus. Erythroid lineage was hypoplasia and mature erythrocytes were generally normal. Conventional cytogenetics of bone marrow cells revealed complex karyotype (44, XX, del (5) (q14q34) del (5) (q14q34), del (14) t (11;14) (q10; q10), -16, del (17), -18[10]). INTERVENTIONS: The patient was treated with second line chemotherapy but did not respond. QUTCOMES: She died of cardiopulmonary failure 19days after starting of therapy. LESSONS: This unexpected and relatively uncommon occurrence was associated with a universally rapid and fatal clinical course with survival measured in <2 months despite intensive chemotherapy. We call attention to this rare phenomenon because it may pose a diagnostic challenge.


Assuntos
Leucemia Eritroblástica Aguda/diagnóstico , Leucemia Mielomonocítica Aguda/diagnóstico , Células da Medula Óssea/patologia , Análise Citogenética , Diagnóstico Diferencial , Células Precursoras Eritroides/patologia , Evolução Fatal , Feminino , Humanos , Cariotipagem , Leucemia Eritroblástica Aguda/etiologia , Leucemia Mielomonocítica Aguda/complicações , Ilustração Médica , Pessoa de Meia-Idade
3.
Leuk Res ; 70: 13-19, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29729583

RESUMO

The 2016 revision of the World Health Organization (WHO) classification of tumours of haematopoietic and lymphoid tissues was published. According to 2016 WHO criteria, diagnostic criteria of acute erythroid leukemia was revised. We reassessed 34 de novo acute erythroid leukemia (AEL) diagnosed by 2008 WHO criteria, according to 2016 WHO criteria. A total of 623 patients (excluding M3) with acute myeloid leukemia including 34 patients with AEL were enrolled. Among 34 patients diagnosed with AEL, diagnosis was shifted to MDS-EB in 28 patients (28/34, 82.3%) and MDS-U in 2 patients (2/34, 5.9%), while remained as AEL in 4 patients (4/34, 11.8%) according to 2016 WHO criteria. Interphase FISH for cytogenetic changes of MDS (-5/del(5q), -7/del(7q), del(20q), +8) revealed cytogenetic aberrations in 50.0% (17/34) of AEL 2008 group. AEL 2008 group showed higher frequency of complex cytogenetic abnormalities and higher MDS related cytogenetic abnormalities than AML excluding AEL group. Transformation to another AML subtype was noted in 10% in AEL shifted to MDS. Majority (88.2%) of AEL by 2008 WHO criteria was reclassified to MDS by 2016 WHO criteria. Clinical characteristics of shifted AEL were similar to those of MDS rather than de novo AML.


Assuntos
Leucemia Eritroblástica Aguda/diagnóstico , Síndromes Mielodisplásicas/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Medula Óssea/metabolismo , Medula Óssea/patologia , Aberrações Cromossômicas , Bandeamento Cromossômico , Diagnóstico Diferencial , Suscetibilidade a Doenças , Feminino , Duplicação Gênica , Humanos , Hibridização in Situ Fluorescente , Leucemia Eritroblástica Aguda/etiologia , Leucemia Eritroblástica Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação , Síndromes Mielodisplásicas/etiologia , Síndromes Mielodisplásicas/mortalidade , Guias de Prática Clínica como Assunto , Organização Mundial da Saúde , Adulto Jovem , Tirosina Quinase 3 Semelhante a fms/genética
4.
Blood Rev ; 32(2): 96-105, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28965757

RESUMO

Acute erythroleukemia is a rare form of acute myeloid leukemia recognized by its distinct phenotypic attribute of erythroblastic proliferation. After a century of its descriptive history, many diagnostic, prognostic, and therapeutic implications relating to this unique leukemia subset remain uncertain. The rarity of the disease and the simultaneous involvement of its associated myeloid compartment have complicated in vitro studies of human erythroleukemia cell lines. Although murine and cell line erythroleukemia models have provided valuable insights into pathophysiology, translation of these concepts into treatment are not forthcoming. Integration of knowledge gained through a careful study of these models with more recent data emerging from molecular characterization will help elucidate key mechanistic pathways and provide a much needed framework that accounts for erythroid lineage-specific attributes. In this article, we discuss the evolving diagnostic concept of erythroleukemia, translational aspects of its pathophysiology, and promising therapeutic targets through an appraisal of the current literature.


Assuntos
Medula Óssea/patologia , Leucemia Eritroblástica Aguda/diagnóstico , Animais , Biópsia , Gerenciamento Clínico , Regulação Leucêmica da Expressão Gênica , Humanos , Leucemia Eritroblástica Aguda/etiologia , Leucemia Eritroblástica Aguda/metabolismo , Leucemia Eritroblástica Aguda/terapia , Guias de Prática Clínica como Assunto , Prognóstico , Transdução de Sinais
5.
Curr Opin Hematol ; 24(2): 146-151, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27875373

RESUMO

PURPOSE OF REVIEW: The 2016 WHO classification of hematopoietic and lymphoid neoplasms alters the diagnostic criteria for erythroleukemia, including eliminating the erythroid/myeloid type of acute erythroleukemia, which was a prior subcategory of acute myeloid leukemia, not otherwise specified. Only pure erythroid leukemia remains in the WHO classification. This review will summarize the literature that contributed to that classification change as well as recent literature on the significance of the change. RECENT FINDINGS: There is now a large body of literature on the negative prognostic impact of erythroid predominance, defined as 50% or more bone marrow erythroid cells, in myelodysplastic syndromes (MDSs). Recent studies have found similarities between erythroleukemia, especially the erythroid/myeloid type, and the erythroid-rich MDS cases. On the basis of these data, the WHO now reclassifies cases of the prior erythroid/myeloid acute erythroleukemia group based on the total blast cell count. This change moves such cases into an MDS category, usually MDS with excess blasts. This approach, however, may cloud the significance of erythroid predominance in this group of patients. SUMMARY: The report clarifies the current criteria for a diagnosis of erythroleukemia as well as the ongoing challenges in classifying this group of erythroid rich bone marrow disorders.


Assuntos
Leucemia Eritroblástica Aguda/diagnóstico , Medula Óssea/patologia , Humanos , Leucemia Eritroblástica Aguda/etiologia , Guias de Prática Clínica como Assunto , Organização Mundial da Saúde
6.
Leuk Lymphoma ; 57(4): 812-9, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26293512

RESUMO

This study followed 28 patients with myelodysplastic syndromes (MDS) who showed a rise of bone marrow (BM) erythroids to ≥ 50% following three cycles (1-60) of hypomethylating agent (HMA) therapy. If BM blasts were calculated as a percentage of non-erythroids, 12 (42.9%) patients met the diagnostic criteria for acute erythroleukemia, erythroid/myeloid (AEL). However, none of the patients showed clonal cytogenetic evolution or new mutations. When compared to 47 de novo AEL patients, these 12 patients were less anemic and thrombocytopenic, had less complex karyotypes (p = 0.044) and showed a longer survival, either calculated from diagnosis (p < 0.001) or from the time of AEL (p = 0.005). These findings illustrate that ≥ 50% erythroids may appear in BM post-HMA therapy, likely a combination of reduction of BM granulocytes (p < 0.001) and promotion of normal or abnormal erythroid proliferation. Enumeration of blasts as a percentage of non-erythroid cells may lead to a diagnosis of AEL and mis-interpretation as disease progression.


Assuntos
Antineoplásicos/uso terapêutico , Metilação de DNA/efeitos dos fármacos , Leucemia Eritroblástica Aguda/etiologia , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/genética , Segunda Neoplasia Primária/etiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Azacitidina/administração & dosagem , Azacitidina/efeitos adversos , Azacitidina/análogos & derivados , Azacitidina/uso terapêutico , Biópsia , Medula Óssea/patologia , Aberrações Cromossômicas , Decitabina , Feminino , Humanos , Hibridização in Situ Fluorescente , Leucemia Eritroblástica Aguda/diagnóstico , Leucemia Eritroblástica Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/mortalidade , Segunda Neoplasia Primária/diagnóstico , Segunda Neoplasia Primária/mortalidade , Análise de Sobrevida , Resultado do Tratamento , Adulto Jovem
7.
Oncotarget ; 6(35): 37678-94, 2015 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-26462019

RESUMO

Ewing sarcoma is an aggressive tumor of bone and soft tissue affecting predominantly children and young adults. Tumor-specific chromosomal translocations create EWS-FLI1 and similar aberrant ETS fusion proteins that drive sarcoma development in patients. ETS family fusion proteins and over-expressed ETS proteins are also found in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) patients. Transgenic expression of EWS-FLI1 in mice promotes high penetrance erythroid leukemia with dense hepatic and splenic infiltrations. We identified a small molecule, YK-4-279, that directly binds to EWS-FLI1 and inhibits its oncogenic activity in Ewing sarcoma cell lines and xenograft mouse models. Herein, we tested in vivo therapeutic efficacy and potential side effects of YK-4-279 in the transgenic mouse model with EWS-FLI1 induced leukemia. A two-week course of treatment with YK-4-279 significantly reduced white blood cell count, nucleated erythroblasts in the peripheral blood, splenomegaly, and hepatomegaly of erythroleukemic mice. YK-4-279 inhibited EWS-FLI1 target gene expression in neoplastic cells. Treated animals showed significantly better overall survival compared to control mice that rapidly succumbed to leukemia. YK-4-279 treated mice did not show overt toxicity in liver, spleen, or bone marrow. In conclusion, this in vivo study highlights the efficacy of YK-4-279 to treat EWS-FLI1 expressing neoplasms and support its therapeutic potential for patients with Ewing sarcoma and other ETS-driven malignancies.


Assuntos
Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Indóis/farmacologia , Leucemia Eritroblástica Aguda/tratamento farmacológico , Leucemia Eritroblástica Aguda/etiologia , Proteínas de Fusão Oncogênica/antagonistas & inibidores , Proteínas de Fusão Oncogênica/toxicidade , Proteína Proto-Oncogênica c-fli-1/antagonistas & inibidores , Proteína Proto-Oncogênica c-fli-1/toxicidade , Proteína EWS de Ligação a RNA/antagonistas & inibidores , Proteína EWS de Ligação a RNA/toxicidade , Animais , Western Blotting , Imunoprecipitação da Cromatina , Citometria de Fluxo , Humanos , Técnicas Imunoenzimáticas , Leucemia Eritroblástica Aguda/patologia , Camundongos , Camundongos Transgênicos , Proteínas de Fusão Oncogênica/administração & dosagem , Proteína Proto-Oncogênica c-fli-1/administração & dosagem , RNA Mensageiro/genética , Proteína EWS de Ligação a RNA/administração & dosagem , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ressonância de Plasmônio de Superfície
9.
Blood Cells Mol Dis ; 52(2-3): 126-33, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24119518

RESUMO

Anemia of inflammation or chronic disease is a highly prevalent form of anemia. The inflammatory cytokine interleukin-6 (IL-6) negatively correlates with hemoglobin concentration in many disease states. The IL-6-hepcidin antimicrobial peptide axis promotes iron-restricted anemia; however the full role of IL-6 in anemia of inflammation is not well-defined. We previously reported that chronic inflammation had a negative impact on maturation of erythroid progenitors in a mouse model. We hypothesized that IL-6 may be responsible for impaired erythropoiesis, independent of iron restriction. To test the hypothesis we utilized the human erythroleukemia TF-1 cell line to model erythroid maturation and exposed them to varying doses of IL-6 over six days. At 10 ng/ml, IL-6 significantly repressed erythropoietin-dependent TF-1 erythroid maturation. While IL-6 did not decrease the expression of genes associated with hemoglobin synthesis, we observed impaired hemoglobin synthesis as demonstrated by decreased benzidine staining. We also observed that IL-6 down regulated expression of the gene SLC4a1 which is expressed late in erythropoiesis. Those findings suggested that IL-6-dependent inhibition of hemoglobin synthesis might occur. We investigated the impact of IL-6 on mitochondria. IL-6 decreased the mitochondrial membrane potential at all treatment doses, and significantly decreased mitochondrial mass at the highest dose. Our studies indicate that IL-6 may impair mitochondrial function in maturing erythroid cells resulting in impaired hemoglobin production and erythroid maturation. Our findings may indicate a novel pathway of action for IL-6 in the anemia of inflammation, and draw attention to the potential for new therapeutic targets that affect late erythroid development.


Assuntos
Eritropoese/efeitos dos fármacos , Interleucina-6/farmacologia , Leucemia Eritroblástica Aguda/etiologia , Antígenos de Superfície/metabolismo , Linhagem Celular Tumoral , Eritropoese/genética , Humanos , Imunofenotipagem , Leucemia Eritroblástica Aguda/metabolismo , Leucemia Eritroblástica Aguda/patologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo
11.
Intern Med ; 50(24): 3031-5, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22185999

RESUMO

Pure erythroid leukemia (PEL) is an extremely rare disorder characterized by neoplastic proliferation of immature erythroblasts. A 66-year-old man, who had received chemoradiotherapy for hypopharyngeal cancer, was admitted because of pancytopenia. Bone marrow was infiltrated with 81% proerythroblasts positive for CD71 and CD235a. An increased number of macrophages with active hemophagocytosis was also present. Chromosome analysis showed hypodiploid complex abnormalities. The patient died of progressive disease despite induction chemotherapy. Erythroblastic infiltration into the liver and hemophagocytosis in the spleen were found at autopsy. Therapy-related PEL with hemophagocytic syndrome and hepatic infiltration of PEL has never been reported.


Assuntos
Leucemia Eritroblástica Aguda/etiologia , Linfo-Histiocitose Hemofagocítica/etiologia , Segunda Neoplasia Primária/etiologia , Idoso , Medula Óssea/patologia , Carcinoma de Células Escamosas/terapia , Eritroblastos/patologia , Evolução Fatal , Humanos , Neoplasias Hipofaríngeas/terapia , Leucemia Eritroblástica Aguda/patologia , Fígado/patologia , Linfo-Histiocitose Hemofagocítica/patologia , Masculino , Segunda Neoplasia Primária/patologia , Baço/patologia
12.
Arch Pathol Lab Med ; 134(9): 1261-70, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20807044

RESUMO

CONTEXT: Acute erythroid leukemia (AEL) is an uncommon type of acute myeloid leukemia (AML), representing less than 5% of all cases. Acute erythroid leukemia is characterized by a predominant erythroid proliferation, and in the current World Health Organization (WHO) classification scheme there are 2 subtypes: erythroleukemia (erythroid/myeloid leukemia) and pure erythroid leukemia. Morphologic findings are most important for establishing the diagnosis. The erythroleukemia subtype, which is most common, is defined as the presence of 50% or more erythroid precursors and 20% or more blasts in the nonerythroid component. The pure erythroid leukemia subtype is composed of 80% or more immature erythroblasts. Although these morphologic criteria appear straightforward, AEL overlaps with other types of AML and myelodysplastic syndrome that are erythroid rich. OBJECTIVE: To provide an update of AEL, including clinical presentation, morphologic features, immunophenotype, and cytogenetic and molecular data. As the erythroleukemia subtype is most common, the literature and this review are biased towards this subtype of AEL. DATA SOURCES: Clinicopathologic, cytogenetic, and molecular information were extracted from our review of pertinent literature and a subset of AEL cases in the files of The University of Texas M. D. Anderson Cancer Center (Houston) and University of South Alabama (Mobile). CONCLUSIONS: The current WHO criteria for establishing the diagnosis of AEL reduce the frequency of this entity, as cases once classified as the erythroleukemia subtype are now reclassified as other types of AML, particularly AML with myelodysplasia-related changes and therapy-related AML. This reclassification also may have prognostic significance for patients with the erythroleukemia subtype of AEL. In contrast, the current WHO criteria appear to have little impact on the frequency and poor prognosis of patients with the pure erythroid leukemia subtype of AEL. Molecular studies, preferably using high-throughput methods, are needed for a better understanding of the pathogenesis of AEL, and for developing diagnostic and prognostic markers.


Assuntos
Células Eritroides/patologia , Leucemia Eritroblástica Aguda/patologia , Biomarcadores Tumorais/análise , Análise Citogenética , Células Eritroides/imunologia , Citometria de Fluxo , Humanos , Imunofenotipagem , Leucemia Eritroblástica Aguda/classificação , Leucemia Eritroblástica Aguda/etiologia , Mutação , Organização Mundial da Saúde
13.
Blood ; 116(3): 428-36, 2010 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-20445019

RESUMO

The activation of Fli-1, an Ets transcription factor, is the critical genetic event in Friend murine leukemia virus (F-MuLV)-induced erythroleukemia. Fli-1 overexpression leads to erythropoietin-dependent erythroblast proliferation, enhanced survival, and inhibition of terminal differentiation, through activation of the Ras pathway. However, the mechanism by which Fli-1 activates this signal transduction pathway has yet to be identified. Down-regulation of the Src homology 2 (SH2) domain-containing inositol-5-phosphatase-1 (SHIP-1) is associated with erythropoietin-stimulated erythroleukemic cells and correlates with increased proliferation of transformed cells. In this study, we have shown that F-MuLV-infected SHIP-1 knockout mice display accelerated erythroleukemia progression. In addition, RNA interference (RNAi)-mediated suppression of SHIP-1 in erythroleukemia cells activates the phosphatidylinositol 3-kinase (PI 3-K) and extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathways, blocks erythroid differentiation, accelerates erythropoietin-induced proliferation, and leads to PI 3-K-dependent Fli-1 up-regulation. Chromatin immunoprecipitation and luciferase assays confirmed that Fli-1 binds directly to an Ets DNA binding site within the SHIP-1 promoter and suppresses SHIP-1 transcription. These data provide evidence to suggest that SHIP-1 is a direct Fli-1 target, SHIP-1 and Fli-1 regulate each other in a negative feedback loop, and the suppression of SHIP-1 by Fli-1 plays an important role in the transformation of erythroid progenitors by F-MuLV.


Assuntos
Leucemia Eritroblástica Aguda/etiologia , Monoéster Fosfórico Hidrolases/metabolismo , Proteína Proto-Oncogênica c-fli-1/metabolismo , Animais , Sequência de Bases , Sítios de Ligação/genética , Linhagem Celular , DNA/genética , DNA/metabolismo , Primers do DNA/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Retroalimentação Fisiológica , Vírus da Leucemia Murina de Friend/patogenicidade , Humanos , Inositol Polifosfato 5-Fosfatases , Leucemia Eritroblástica Aguda/genética , Leucemia Eritroblástica Aguda/virologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Modelos Biológicos , Dados de Sequência Molecular , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases , Monoéster Fosfórico Hidrolases/antagonistas & inibidores , Monoéster Fosfórico Hidrolases/deficiência , Monoéster Fosfórico Hidrolases/genética , Fosforilação , Regiões Promotoras Genéticas , Proteína Proto-Oncogênica c-fli-1/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Interferente Pequeno/genética
14.
Leukemia ; 23(12): 2275-80, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19741728

RESUMO

Acute erythroleukemia (AML-M6) is an uncommon subtype of acute myeloid leukemia (AML); it is considered to have a poor prognosis. From 1 January 1980 to 21 May 2008, 91 patients with newly diagnosed AML-M6 were seen at the University of Texas-M.D. Anderson Cancer Center (UT-MDACC). Forty-five patients (50%) had a history of myelodysplatic syndrome (MDS), compared with 41% in our control group (patients with other AML subtypes) (P=0.08). Poor-risk cytogenetics were more common in patients with AML-M6 (61% versus 38%, P=0.001). Complete remission rates were 62% for patients with AML-M6, comparing with 58% for the control group (P=0.35). Median disease free survival (DFS) for patients with AML-M6 was 32 weeks, versus 49 weeks for the control group (P=0.05). Median overall survival (OS) of patients with AML-M6 was 36 weeks, compared with 43 weeks for the control group (P=0.60). On multivariate analysis for DFS and OS, AML-M6 was not an independent risk factor. AML-M6 is commonly associated with a previous diagnosis of MDS and poor-risk karyotype. The diagnosis of AML-M6 does not impart by itself a worse prognosis, and treatment decisions on this disease should be guided by well known AML prognostic factors.


Assuntos
Leucemia Eritroblástica Aguda/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estudos de Casos e Controles , Análise Citogenética , Feminino , Humanos , Leucemia Eritroblástica Aguda/etiologia , Leucemia Eritroblástica Aguda/genética , Leucemia Eritroblástica Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/complicações , Prognóstico , Indução de Remissão , Estudos Retrospectivos , Análise de Sobrevida , Adulto Jovem
15.
Acta Haematol ; 122(1): 36-8, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19713696

RESUMO

A 54-year-old female patient developed acute erythroleukemia after an 8-year course of primary myelofibrosis. The latter harbors the JAK2-V617F mutation and was treated with hydroxyurea and anagrelide. A bone marrow trephine biopsy disclosed 2 morphologically distinct areas of chronic primary myelofibrosis and acute erythroleukemia. Microdissection and a separate molecular pathological analysis was performed. Although the activating JAK2-V617F mutation was not maintained in blasts of acute erythroleukemia, it was detectable in the chronic phase of primary myelofibrosis, indicating that this mutation did not play a role in the leukemic transformation of erythroid cells.


Assuntos
Janus Quinase 2/genética , Leucemia Eritroblástica Aguda/genética , Mielofibrose Primária/complicações , Mielofibrose Primária/genética , Transformação Celular Neoplásica/genética , Evolução Fatal , Feminino , Humanos , Leucemia Eritroblástica Aguda/etiologia , Pessoa de Meia-Idade
16.
Oncogene ; 28(38): 3349-59, 2009 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-19581930

RESUMO

Leukemogenesis requires two classes of mutations, one that promotes proliferation and one that blocks differentiation. The erythroleukemia induced by Friend virus is a multistage disease characterized by an early proliferative stage driven by the interaction of the viral glycoprotein, gp55, with Sf-Stk and the EpoR, and a late block to differentiation resulting from retroviral insertion in the Pu.1 locus. We demonstrate here that activation of Stat3 by Sf-Stk in the early stage of disease is essential for the progression of erythroleukemia in the presence of differentiation signals induced by the EpoR, but is dispensable in the late stages of the disease. Furthermore, we identify Pu.1 as a Stat3 target gene in the early stages of erythroleukemia development. Our results support a model whereby the activation of Stat3 in the early stage of disease plays a pivotal role in regulating differentiation through the upregulation of Pu.1, thus inhibiting differentiation and favoring the expansion of infected erythroblasts and enhancing the pool of progenitors available for the acquisition of additional mutations, including insertional activation of Pu.1, resulting in full leukemic transformation.


Assuntos
Eritroblastos/citologia , Regulação da Expressão Gênica , Leucemia Eritroblástica Aguda/etiologia , Proteínas Proto-Oncogênicas/genética , Fator de Transcrição STAT3/fisiologia , Transativadores/genética , Proteínas Adaptadoras de Transdução de Sinal , Animais , Diferenciação Celular , Vírus da Leucemia Murina de Friend , Camundongos , Camundongos Endogâmicos BALB C , Fosfoproteínas/fisiologia
19.
Blood ; 109(7): 3007-14, 2007 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-17132716

RESUMO

Overexpression of the transcription factor Spi-1/PU.1 in mice leads to acute erythroleukemia characterized by a differentiation block at the proerythroblastic stage. In this study, we made use of a new cellular system allowing us to reach graded expression of Spi-1 in preleukemic cells to dissect mechanisms of Spi-1/ PU-1 in erythroleukemogenesis. This system is based on conditional production of 1 or 2 spi-1-interfering RNAs stably inserted into spi-1 transgenic proerythroblasts. We show that Spi-1 knock-down was sufficient to reinstate the erythroid differentiation program. This differentiation process was associated with an exit from the cell cycle. Evidence is provided that in the presence of erythropoietin (Epo), Spi-1 displays an antiapoptotic role that is independent of its function in blocking erythroid differentiation. Apoptosis inhibited by Spi-1 did not involve activation of the Fas/FasL signaling pathway nor a failure to activate Epo receptor (EpoR). Furthermore, we found that reducing the Spi-1 level yields to ERK dephosphorylation and increased phosphorylation of AKT and STAT5, suggesting that Spi-1 may affect major signaling pathways downstream of the EpoR in erythroid cells. These findings reveal 2 distinct roles for Spi-1 during erythroleukemogenesis: Spi-1 blocks the erythroid differentiation program and acts to impair apoptotic death in cooperation with an Epo signaling.


Assuntos
Eritropoetina/fisiologia , Leucemia Eritroblástica Aguda/etiologia , Proteínas Proto-Oncogênicas/fisiologia , Transativadores/fisiologia , Animais , Apoptose/fisiologia , Sequência de Bases , Ciclo Celular/fisiologia , Diferenciação Celular , Eritroblastos/patologia , Eritroblastos/fisiologia , Eritropoese/fisiologia , Humanos , Leucemia Eritroblástica Aguda/genética , Leucemia Eritroblástica Aguda/patologia , Leucemia Eritroblástica Aguda/fisiopatologia , Camundongos , Camundongos Transgênicos , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/genética , RNA Interferente Pequeno/genética , Receptores da Eritropoetina/fisiologia , Transdução de Sinais/fisiologia , Transativadores/antagonistas & inibidores , Transativadores/genética
20.
Br J Haematol ; 135(5): 642-50, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17054431

RESUMO

Pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) and granulocyte colony-stimulating factor (G-CSF) promote haematopoietic progenitor cell maturation. We reviewed the findings for healthy volunteers/donors who developed haematological malignancies following PEG-rHuMGDF or G-CSF administration. Information was reviewed for three of 538 volunteers who received PEG-rHuMGDF in clinical trials and two of 200 donors who underwent G-CSF mobilised stem cell harvesting procedures for sibling stem cell transplants. Mantle cell, diffuse large B-cell lymphoma and chronic lymphocytic leukaemia were diagnosed 1-5 years after PEG-rHuMGDF exposure among three volunteers. For one patient, thrombocytopenia due to autoantibodies to PEG-rHuMGDF developed shortly after PEG-rHuMGDF administration and persisted until chemotherapy was administered. All three achieved complete remission, although one patient relapsed. Acute myeloid leukaemia was diagnosed 4 and 5 years after G-CSF mobilisation in two donors who underwent peripheral blood stem cell donation for sibling allogeneic haematopoietic stem cell transplantation. Following intensive chemotherapy, one died from acute leukaemia and the second is in complete remission. Controversy exists over the appropriateness of administering haematopoietic growth factors to healthy individuals. While a causal relationship with haematological malignancies cannot be demonstrated, long-term follow-up among healthy individuals who receive haematopoietic growth factors is needed.


Assuntos
Neoplasias Hematológicas/etiologia , Fatores de Crescimento de Células Hematopoéticas/efeitos adversos , Doadores de Tecidos , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Autoanticorpos/imunologia , Ensaios Clínicos como Assunto , Feminino , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/genética , Humanos , Leucemia Eritroblástica Aguda/tratamento farmacológico , Leucemia Eritroblástica Aguda/etiologia , Leucemia Eritroblástica Aguda/genética , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/etiologia , Leucemia Monocítica Aguda/tratamento farmacológico , Leucemia Monocítica Aguda/etiologia , Leucemia Monocítica Aguda/genética , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/etiologia , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/etiologia , Masculino , Pessoa de Meia-Idade , Transplante de Células-Tronco de Sangue Periférico , Polietilenoglicóis/efeitos adversos , Proteínas Recombinantes/efeitos adversos , Trombopoetina/efeitos adversos , Trombopoetina/imunologia
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