RESUMO
A 68-year-old woman consulted us because of anemia and elevated LDH serum levels >1,000 U/l. No particular disease was observed by various screening tests. Since she was taking atorvastatin despite low cholesterol level, we discontinued the drug, which improved her complaints. We later experienced similar patients with hyperlipidemia induced by other drugs, such as rosuvastatin and pravastatin. These drugs are widely used in patients with hyperlipidemia and more recently in tyrosine kinase inhibitor users. It is important to monitor cholesterol levels and discontinue the drug use when they are unnecessarily administered.
Assuntos
Anemia , Atorvastatina/efeitos adversos , Hipercolesterolemia , Idoso , Anemia/induzido quimicamente , LDL-Colesterol , Feminino , Fluorbenzenos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases , SinvastatinaRESUMO
The histone demethylase JHDM1B has been implicated in cell cycle regulation and tumorigenesis. In addition, it has been reported that JHDM1B is highly expressed in various human tumors, including leukemias. However, it is not clearly understood how JHDM1B contributes to acute myeloid leukemia (AML) cell proliferation. In this study, we investigated the cellular and molecular function of JHDM1B in AML cells. In AML cell lines and AML-derived ALDH(hi) (high aldehyde dehydrogenase activity)/CD34(+) cells, the levels of JHDM1B mRNA were significantly higher than in normal ALDH(hi) /CD34(+) cells. Reduction of JHDM1B expression in AML cells inhibited cell proliferation compared to control cells, through induction of G1 cell cycle arrest, an increase in the p15(Ink4b) mRNA and protein expression. JHDM1B mRNA was overexpressed in all 133 AML clinical specimens tested (n = 22, 57, 34, and 20 for M1, 2, 4, and 5 subtypes respectively). Compared to normal ALDH(hi) /CD34(+) cells, JHDM1B gene expression was 1.57- to 1.87-fold higher in AML-derived ALDH(hi) /CD34(+) cells. Moreover, the JHDM1B protein was more strongly expressed in AML-derived ALDH(hi) /CD34(+) cells from compared to normal ALDH(hi) /CD34(+) cells. In addition, depletion of JHDM1B reduced colony formation of AML-derived ALDH(hi) /CD34(+) cells due to induction of p15(Ink4b) expression through direct binding to p15(Ink4b) promoter and loss of demethylation of H3K36me2. In summary, we found that JHDM1B mRNA is predominantly expressed in AML-derived ALDH(hi) /CD34(+) cells, and that aberrant expression of JHDM1B induces AML cell proliferation through modulation of cell cycle progression. Thus, inhibition of JHDM1B expression represents an attractive target for AML therapy.
Assuntos
Ciclo Celular , Proliferação de Células , Inibidor de Quinase Dependente de Ciclina p15/metabolismo , Proteínas F-Box/metabolismo , Leucemia Mieloide Aguda/metabolismo , Oxirredutases N-Desmetilantes/metabolismo , Inibidores de Proteínas Quinases/metabolismo , Adulto , Idoso , Aldeído Desidrogenase/metabolismo , Antígenos CD34/análise , Linhagem Celular Tumoral , Humanos , Histona Desmetilases com o Domínio Jumonji , Pessoa de Meia-Idade , Células-Tronco Neoplásicas/metabolismoRESUMO
Bcr-Abl activates various signaling pathways in chronic myelogenous leukemia (CML) cells. The proliferation of Bcr-Abl transformed cells is promoted by c-Myc through the activation of Akt, JAK2 and NF-κB. However, the mechanism by which c-Myc regulates CML cell proliferation is unclear. In our study, we investigated the role of Thanatos-associated protein 11 (THAP11), which inhibits c-Myc transcription, in CML cell lines and in hematopoietic progenitor cells derived from CML patients. The induction of THAP11 expression by Abl kinase inhibitors in CML cell lines and in CML-derived hematopoietic progenitor cells resulted in the suppression of c-Myc. In addition, over-expression of THAP11 inhibited CML cell proliferation. In colony forming cells derived from CML-aldehyde dehydrogenase (ALDH)(hi) /CD34(+) cells, treatment with Abl kinase inhibitors and siRNA depletion of Bcr-Abl induced THAP11 expression and reduced c-Myc expression, resulting in inhibited colony formation. Moreover, overexpression of THAP11 significantly decreased the colony numbers, and also inhibited the expression of c-myc target genes such as Cyclin D1, ODC and induced the expression of p21(Cip1) . The depletion of THAP11 inhibited JAK2 or STAT5 inactivation-mediated c-Myc reduction in ALDH(hi) /CD34(+) CML cells. Thus, the induced THAP11 might be one of transcriptional regulators of c-Myc expression in CML cell. Therefore, the induction of THAP11 has a potential possibility as a target for the inhibition of CML cell proliferation.
Assuntos
Proteínas de Fusão bcr-abl/metabolismo , Genes myc , Proteínas Repressoras/fisiologia , Benzamidas , Linhagem Celular Tumoral , Proliferação de Células , Regulação para Baixo , Células HL-60 , Células-Tronco Hematopoéticas/metabolismo , Humanos , Mesilato de Imatinib , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Masculino , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologiaRESUMO
Routine laboratory data are discussed by time series analysis in reversed clinicopathological conferences (R-CPC) at Shinshu University School of Medicine. We can identify fine changes in the laboratory data and the importance of negative data (without any changes) using time series analysis. Routine laboratory tests can be performed repeatedly and relatively cheaply, and time series analysis can be performed. The examination process of routine laboratory data in the R-CPC is almost the same as the process of taking physical findings. Firstly, general findings are checked and then the state of each organ is examined. Although routine laboratory data are cheap, we can obtain much more information about a patient's state than from physical examinations. In this R-CPC, several specialists in the various fields of laboratory medicine discussed the routine laboratory data of a patient, and we tried to understand the detailed state of the patient. R-CPC is an educational method to examine laboratory data and we, reconfirmed the usefulness of R-CPC to elucidate the clinical state of the patient.
Assuntos
Testes Diagnósticos de Rotina , Auditoria Médica , Patologia Clínica , Adulto , Testes de Química Clínica , Diagnóstico Diferencial , Hematologia/normas , Humanos , Contagem de Leucócitos/normas , Masculino , Estudos RetrospectivosRESUMO
Clinicopathological conferences (CPC) are one of the most important clinical conferences, and processes of both diagnosis and treatment performed in an autopsy case are retrospectively and finely checked to offer better medical treatment in the future. In CPC, the medical history, physical findings, laboratory data, image findings, diagnosis and treatment are discussed in the order that a physician examines a patient. Differential diagnoses usually decrease and several important diagnoses remain as the CPC discussion progresses. Medical treatment is also reexamined to identify a better approach. In this CPC, several medical doctors in various special fields try to understand the detailed state of the patient from each standpoint, and such a CPC is called an Expert CPC at Shinshu University School of Medicine. This CPC is carried out followed by reversed-CPC (R-CPC) of the same case. The purpose of this CPC is to understand the importance of R-CPC and to understand the correct interpretation of routine laboratory data.
Assuntos
Patologia Clínica/educação , Autopsia , Medula Óssea/patologia , Testes de Química Clínica , Educação Médica , Humanos , Rim/patologia , Fígado/patologia , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Estômago/patologia , Trombose/patologiaRESUMO
Chronic myelogenous leukemia (CML) is characterized by a reciprocal chromosomal translocation (9;22) that generates the Bcr-Abl fusion gene. BCR-ABL transforming activity is mediated by critical downstream signaling pathways that are aberrantly activated by tyrosine kinases. However, the mechanisms of BCR-ABL anti-apoptotic effects and the signaling pathways by which BCR-ABL influences apoptosis in BCR-ABL-expressing cells are poorly defined. In this study, we found that treatment with ABL kinase inhibitors or depletion of BCR-ABL induced the expression of RAB45 messenger RNA and protein and induced apoptosis via reduction of mitochondrial membrane potential and p38 activation in CML cell lines and BCR-ABL(+) progenitor cells from CML patients. Overexpressed RAB45 induced the activation of caspases-3 and -9 and reduced the expression of Survivin, XIAP, c-IAP1 and c-IAP2 in CML cells. Moreover, in colony-forming cells derived from CML-aldehyde dehydrogenase(hi)/CD34(+) cells, treatment with ABL kinase inhibitors induced RAB45 expression and reduced mitochondrial membrane potential, resulting in inhibited colony formation of Bcr-Abl(+) progenitor cells. The overexpression of RAB45 significantly decreased colony numbers and induced apoptosis through the activation of caspases-3 and -9. Furthermore, the overexpression of RAB45 increased the phosphorylation levels of p38, resulting in the induction of apoptosis and inhibition of proliferation of CML progenitor cells. Our results identify a new signaling molecule involved in BCR-ABL modulation of apoptosis and suggest that RAB45 induction strategies may have therapeutic utility in patients with CML.
Assuntos
Apoptose/fisiologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Células-Tronco Neoplásicas/patologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Fatores ras de Troca de Nucleotídeo Guanina/fisiologia , Sequência de Bases , Western Blotting , Caspase 3/metabolismo , Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Primers do DNA , Ativação Enzimática , Genes abl , Humanos , Imunoprecipitação , Leucemia Mielogênica Crônica BCR-ABL Positiva/enzimologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Potenciais da Membrana , Fosforilação , Interferência de RNA , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores ras de Troca de Nucleotídeo Guanina/genéticaRESUMO
Chronic myelogenous leukemia (CML) is characterized by a reciprocal chromosomal translocation (9;22) that generates the Bcr-Abl fusion gene. The Ras/Raf-1/MEK/ERK pathway is constitutively activated in Bcr-Abl-transformed cells, and Ras activity enhances the oncogenic ability of Bcr-Abl. However, the mechanism by which Bcr-Abl activates the Ras pathway is not completely understood. Raf kinase inhibitor protein (RKIP) inhibits activation of MEK by Raf-1 and its downstream signal transduction, resulting in blocking the MAP kinase pathway. In the present study, we found that RKIP was depleted in CML cells. We investigated the interaction between RKIP and Bcr-Abl in CML cell lines and Bcr-Abl(+) progenitor cells from CML patients. The Abl kinase inhibitors and depletion of Bcr-Abl induced the expression of RKIP and reduced the pERK1/2 status, resulting in inhibited proliferation of CML cells. Moreover, RKIP up-regulated cell cycle regulator FoxM1 expression, resulting in G(1) arrest via p27(Kip1) and p21(Cip1) accumulation. In colony-forming unit granulocyte, erythroid, macrophage, megakaryocyte, colony-forming unit-granulocyte macrophage, and burst-forming unit erythroid, treatment with the Abl kinase inhibitors and depletion of Bcr-Abl induced RKIP and reduced FoxM1 expressions, and inhibited colony formation of Bcr-Abl(+) progenitor cells, whereas depletion of RKIP weakened the inhibition of colony formation activity by the Abl kinase inhibitors in Bcr-Abl(+) progenitor cells. Thus, Bcr-Abl represses the expression of RKIP, continuously activates pERK1/2, and suppresses FoxM1 expression, resulting in proliferation of CML cells.
Assuntos
Proliferação de Células , Fatores de Transcrição Forkhead/genética , Proteínas de Fusão bcr-abl/fisiologia , Regulação Neoplásica da Expressão Gênica , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteína de Ligação a Fosfatidiletanolamina/genética , Regulação para Baixo/genética , Proteína Forkhead Box M1 , Humanos , Inibidores de Proteínas Quinases/farmacologia , Células-Tronco/patologia , Células Tumorais CultivadasRESUMO
FOXM1 is an important cell cycle regulator and regulates cell proliferation. In addition, FOXM1 has been reported to contribute to oncogenesis in various cancers. However, it is not clearly understood how FOXM1 contributes to acute myeloid leukemia (AML) cell proliferation. In this study, we investigated the cellular and molecular function of FOXM1 in AML cells. The FOXM1 messenger RNA (mRNA) expressed in AML cell lines was predominantly the FOXM1B isoform, and its levels were significantly higher than in normal high aldehyde dehydrogenase activity (ALDH(hi)) cells. Reduction of FOXM1 expression in AML cells inhibited cell proliferation compared with control cells, through induction of G(2)/M cell cycle arrest, a decrease in the protein expression of Aurora kinase B, Survivin, Cyclin B1, S-phase kinase-associated protein 2 and Cdc25B and an increase in the protein expression of p21(Cip1) and p27(Kip1). FOXM1 messenger RNA (mRNA) was overexpressed in all 127 AML clinical specimens tested (n = 21, 56, 32 and 18 for M1, M2, M4 and M5 subtypes, respectively). Compared with normal ALDH(hi) cells, FOXM1 gene expression was 1.65- to 2.26-fold higher in AML cells. Moreover, the FOXM1 protein was more strongly expressed in AML-derived ALDH(hi) cells compared with normal ALDH(hi) cells. In addition, depletion of FOXM1 reduced colony formation of AML-derived ALDH(hi) cells due to inhibition of Cdc25B and Cyclin B1 expression. In summary, we found that FOXM1B mRNA is predominantly expressed in AML cells and that aberrant expression of FOXM1 induces AML cell proliferation through modulation of cell cycle progression. Thus, inhibition of FOXM1 expression represents an attractive target for AML therapy.
Assuntos
Proteínas de Ciclo Celular/metabolismo , Ciclo Celular , Proliferação de Células , Fatores de Transcrição Forkhead/fisiologia , Leucemia Mieloide Aguda/patologia , Adulto , Idoso , Aldeído Desidrogenase/genética , Aldeído Desidrogenase/metabolismo , Apoptose , Aurora Quinase B , Aurora Quinases , Western Blotting , Proteínas de Ciclo Celular/genética , Células Cultivadas , Ciclina B1/genética , Ciclina B1/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Inibidor de Quinase Dependente de Ciclina p27 , Progressão da Doença , Imunofluorescência , Proteína Forkhead Box M1 , Humanos , Proteínas Inibidoras de Apoptose , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Linfócitos/metabolismo , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Pessoa de Meia-Idade , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , RNA Mensageiro/genética , RNA Interferente Pequeno/farmacologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteínas Quinases Associadas a Fase S/genética , Proteínas Quinases Associadas a Fase S/metabolismo , SurvivinaRESUMO
CEM, MOLT4 and SUP-B15 cells were transduced with lentivirus-mediated siRNA KIS gene. The mRNA expressions of KIS were successfully reduced in all cell lines. On the other hand, the mRNA expressions of p27(Kip1) in CEM, MOLT4 and SUP-B15 cells were not affected by the transduction with siRNA KIS gene. We showed that KIS protein directly interacted with p27(Kip1) protein, and reduction of KIS inhibited the S10 phosphorylation of p27(Kip1) in leukemia cells. On these cells transfected with siRNA KIS, the inhibition of S10 phosphorylation of p27(Kip1) was strongly suppressed cell proliferation in a time-dependent manner. Moreover, the inhibition of S10 phosphorylation of p27(Kip1) increased a significant population in G0/G1 fraction. These data demonstrated that the KIS activity was induced during G0/G1, and it promotes cell cycle progression by phosphorylation of S10 on p27(Kip1). We showed that KIS mRNA expression was increased in primary leukemia specimens (acute myelogenous leukemia (AML); 37, myelodysplastic syndrome (MDS); 72, acute lymphoblastic leukemia (ALL); 23), and the mean ratios of KIS to G3PDH in AML, MDS and ALL specimens were 3.62+/-0.68, 3.27+/-0.73 and 3.17+/-0.58, respectively. Moreover, we found that KIS protein was overexpressed in all 132 adults cases of various leukemias, including 37 AML (8 M1, 12 M2, 2 M3, 7 M4, 8 M5), 72 MDS (42 RAEB-I, 30 REAB-II) and 23 ALL (23 L2). This study demonstrates that the elevated levels of KIS protein in leukemia cells promote the cell cycle progression in leukemia cells.
Assuntos
Ciclo Celular/fisiologia , Proliferação de Células , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Leucemia Mieloide Aguda/metabolismo , Síndromes Mielodisplásicas/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Proteínas Serina-Treonina Quinases/fisiologia , Adulto , Idoso , Western Blotting , Medula Óssea/metabolismo , Medula Óssea/patologia , Células Cultivadas , Inibidor de Quinase Dependente de Ciclina p27 , Humanos , Imunoprecipitação , Peptídeos e Proteínas de Sinalização Intracelular/genética , Leucemia Mieloide Aguda/genética , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/patologia , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/genética , Fosforilação , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/farmacologia , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
We report a rare case of adult Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) with an e1a3 fusion transcript. A 25-year-old female consulted our hospital for leukocytosis and thrombocytopenia. She was diagnosed with Ph-positive precursor B cell ALL. The patient's BCR-ABL fusion gene showed the e1a3 transcript. She received bone marrow transplantation (BMT) in the first complete remission (CR). However, the disease relapsed 4 months later, and she received a second BMT in the second CR, which caused lethal venoocculusive disease. The duration of the total clinical course was 18 months. We established a new cell line from the patient's leukemic cells at the time of relapse, which is very rare and useful for study as an atypical Ph-positive ALL model. The literature on Ph-positive leukemia lacking ABL exon 2 was also reviewed.
Assuntos
Genes abl/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Adulto , Pré-Escolar , Éxons/genética , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Cromossomo Filadélfia , Transcrição Gênica/genéticaRESUMO
We report an interesting case of acute myelogenous leukemia (AML) in a Jehovah's Witness patient. A 61-year-old woman, a Jehovah's Witness, consulted our hospital because of continuous fever and refractory pharyngitis. The white blood cell count was increased with myeloblasts and monoblasts, both of which showed positivity for CD33. The level of WT1 messenger RNA (mRNA) in the bone marrow was 130,000 copies/microg RNA. The patient's diagnosis was AML (M4). Because complete remission (CR) was not obtained with 2 courses of chemotherapy consisting of acrarubicin and cytarabine, we tried gemtuzumab ozogamicin (GO) with informed consent. No major side effects appeared, and CR was obtained after 2 courses of GO, which decreased the WT1 mRNA level to 480 copies/microg RNA. The patient has been in CR for 6 months with ubenimex. This case suggests that GO can be one of the treatment options in similar situations, although it should be used with considerable care.
Assuntos
Aminoglicosídeos/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Antineoplásicos/administração & dosagem , Testemunhas de Jeová , Leucemia Mieloide Aguda/tratamento farmacológico , Anticorpos Monoclonais Humanizados , Antimetabólitos Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Citarabina/administração & dosagem , Feminino , Gemtuzumab , Humanos , Contagem de Leucócitos , Pessoa de Meia-Idade , Compostos Orgânicos/administração & dosagem , Indução de Remissão , Índice de Gravidade de DoençaRESUMO
PURPOSE: To investigate the pharmacokinetics of arsenic species in Japanese patients with relapsed or refractory acute promyelocytic leukemia (APL) treated with arsenic trioxide (ATO) at a daily dose of 0.15 mg/kg. METHODS: Inorganic arsenic (AsIII and AsV) and the major metabolites monomethylarsonic acid (MAA(V)) and dimethylarsinic acid (DMAA(V)) in plasma and urine collected from 12 Japanese patients were quantified by HPLC/ICP-MS. RESULTS: The plasma concentrations of AsIII and AsV on day 1 reached the similar Cmax (12.4 +/- 8.4 and 10.2 +/- 3.9 ng/ml) immediately after completion of administration followed by a biphasic elimination. The AUC(0-infinity) of AsV was about twice that of AsIII. The appearance of methylated metabolites in the blood was delayed. During the repeated administration, the plasma concentrations of inorganic arsenic reached the steady state. In contrast, the MAA(V) and DMAA(V) concentrations increased in relation to increased administration frequency. The mean total arsenic excretion rate including inorganic arsenic and methylated arsenic was about 20% of daily dose on day 1 and remained at about 60% of daily dose during week 1-4. CONCLUSIONS: This study demonstrates that ATO is metabolized when administered intravenously to APL patients and methylated metabolites are promptly eliminated from the blood and excreted into urine after completion of administration, indicating no measurable accumulation of ATO in the blood.
Assuntos
Antineoplásicos/farmacocinética , Arsênio/farmacocinética , Arsenicais/farmacocinética , Leucemia Promielocítica Aguda/tratamento farmacológico , Óxidos/farmacocinética , Adulto , Idoso , Área Sob a Curva , Trióxido de Arsênio , Arsenicais/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Óxidos/administração & dosagem , Estudos ProspectivosRESUMO
We report a rare case of T-cell acute lymphoblastic leukemia (T-ALL) with an aberrant phenotype. A 52-year-old man was admitted to our hospital because of lymph node (LN) swelling in the bilateral neck. A computed tomographic scan showed LN swelling in the mediastinum and a right pleural effusion. The tumor cells in the neck LN showed positivity for cytoplasmic CD3, CD7, CD19, and CD79a, whereas the tumor cells in the bone marrow (BM) showed positivity for CD10 and CD13 in addition to the former 4 antigens. The chromosomes in the BM were normal. Neither T-cell receptor gamma nor immunoglobulin heavy chain rearrangement was detected in the neck LN. We diagnosed this case as T-ALL with an aberrant phenotype and started the standard chemotherapy for ALL. The response was so effective that complete remission (CR) was easily attained. The patient is now under maintenance therapy in the first CR without hematopoietic cell transplantation.
Assuntos
Antígenos CD19 , Antígenos CD7 , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Leucemia-Linfoma de Células T do Adulto/tratamento farmacológico , Derrame Pleural Maligno/tratamento farmacológico , Intervalo Livre de Doença , Neoplasias de Cabeça e Pescoço/diagnóstico por imagem , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Leucemia-Linfoma de Células T do Adulto/diagnóstico por imagem , Leucemia-Linfoma de Células T do Adulto/patologia , Masculino , Pessoa de Meia-Idade , Derrame Pleural Maligno/diagnóstico por imagem , Derrame Pleural Maligno/patologia , Radiografia , Indução de RemissãoRESUMO
We report an instructive case of diffuse large B-cell lymphoma presenting as acute heart failure. A 69-year-old human immunodeficiency virus-negative man was admitted to our hospital for general fatigue. A computed tomographic scan of the chest and abdomen showed pericardial effusion, but there was no evidence of tumor masses, lymph node enlargement, or hepatosplenomegaly. During the chemotherapy, increased lactate dehydrogenase and pleural effusion appeared. The tumor cells in the effusion showed positivity for CD5, CD19, CD20, kappa chain, and Bcl-2 and negativity for CD10 and CD23. The chromosomes showed t(8;14)(q24;q32) with c-myc/immunoglobulin (Ig)H rearrangement, and the MIB-1 index was not high (60%). Neither human herpes virus 8 nor Epstein-Barr virus DNA was detected in the cells by polymerase chain reaction. The response to chemotherapy was very poor, and the patient died 4 months after the diagnosis. A spectrum of the symptoms of CD5+ lymphoma encompasses pericardial effusion and also can accompany c-myc/IgH rearrangement.
Assuntos
Rearranjo Gênico , Linfoma de Células B/complicações , Linfoma de Células B/genética , Linfoma Difuso de Grandes Células B/complicações , Linfoma Difuso de Grandes Células B/genética , Derrame Pericárdico/etiologia , Derrame Pleural/etiologia , Idoso , Antígenos CD5/análise , Genes myc , Humanos , Imunoglobulinas , Linfoma de Células B/patologia , MasculinoRESUMO
CREB-binding protein (CBP) and highly related p300 protein are transcriptional co-activators that play an essential role in chromatin remodeling through histone acetyltransferase activity and interaction with other transcriptional regulators. In this study, various hematological malignancies, including nine cell lines and 45 clinical samples (32 acute myeloid leukemias (AML), nine acute lymphoblastic leukemias (ALL), two cases of myelodysplastic syndrome (MDS), one multiple myeloma, and one chronic myelogenous leukemia in blast crisis), were examined to ask whether mutation of the CBP and p300 genes could be involved in leukemogenesis. The answer was approached by employing the reverse transcription-polymerase chain reaction and single-strand conformation polymorphism (RT-PCR/SSCP) technique and subsequent sequence analysis. A T-lymphoblastic cell line, CEM had an in-frame 21-base-pair deletion within the bromodomain of its p300 cDNA. Genomic DNA analysis revealed aberrant splicing caused by mutation of the acceptor site of intron 17 from ag to gg, which should interfere with catalytic step II of the pre-mRNA splicing reaction. In 1 MDS patient, a missense mutation was detected, which caused a replacement from Ser to Gly at codon 507 of p300. This is the first report of CBP/p300 mutations in leukemias, which might be relatively rare but nonetheless contribute to pathogenesis in some fraction of cases.
Assuntos
Leucemia/genética , Leucemia/fisiopatologia , Mieloma Múltiplo/genética , Mieloma Múltiplo/fisiopatologia , Mutação de Sentido Incorreto , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/fisiopatologia , Proteínas Nucleares/genética , Transativadores/genética , Acetiltransferases , Proteína de Ligação a CREB , Análise Mutacional de DNA , Primers do DNA , Humanos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais CultivadasRESUMO
The incidence of the emergence of nonalbicans Candida species during fluconazole treatment was surveyed in leukemia patients who were severely immunocompromised due to either intensive chemotherapy or bone marrow transplantation during the 3-year period from April 1993 to March 1996. Thirty-three patients received either prophylactic or therapeutic fluconazole administration for at least 7 days. In 7 of these 33 patients (21.2%), nonalbicans Candida including C. krusei, C. glabrata, C. maris, and C. inconspicua emerged during, or immediately after, fluconazole administration, with C. inconspicua the most prevalent Candida spp. Since these yeast strains are resistant to fluconazole, it is possible that selection occurred favoring Candida spp. resistant to fluconazole. Therefore, surveillance for yeast strains resistant to fluconazole should be performed as a routine procedure during fluconazole administration. In cases of resistance, other effective antifungal agents should be administered.
RESUMO
An 18-year-old man was diagnosed as having lymphoblastic lymphoma in January 1997, and treated with chemotherapy. At the 1st relapse, bone marrow transplantation from HLA-identical sibling was performed in June 1998 with only acute graft-versus-host disease (GVHD). At the 2nd relapse, peripheral blood stem cell transplantation from the same donor was performed in October 2000 with both acute and chronic GVHD, which has continued for 25 months, and complete remission has also been maintained.
Assuntos
Transplante de Medula Óssea , Recidiva Local de Neoplasia/terapia , Transplante de Células-Tronco de Sangue Periférico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Doadores de Tecidos , Adolescente , Histocompatibilidade , Humanos , Masculino , Indução de Remissão , IrmãosRESUMO
We report a patient with chronic myelogenous leukemia that responded to imatinib mesilate after relapse of blastic crisis following allogeneic bone marrow transplantation. The patient received an unrelated bone marrow transplantation in the 3rd chronic phase, after which the 3rd blastic crisis occurred 5 months later. Since the case was refractory to chemotherapy at that time, imatinib mesilate (600 mg/day) was given, which resulted in a complete cytogenetical remission (CCR). The CCR has maintained for 11 months.
Assuntos
Antineoplásicos/uso terapêutico , Crise Blástica/tratamento farmacológico , Transplante de Medula Óssea , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Administração Oral , Adulto , Benzamidas , Esquema de Medicação , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Masculino , Indução de RemissãoRESUMO
The immediately-early response gene 5 (IER5) has been reported to be induced by γ-ray irradiation and to play a role in the induction of cell death caused by radiation. We previously identified IER5 as one of the 2,3,4-tribromo-3-methyl-1-phenylphospholane 1-oxide (TMPP)-induced transcriptional responses in AML cells, using microarrays that encompassed the entire human genome. However, the biochemical pathway and mechanisms of IER5 function in regulation of the cell cycle remain unclear. In this study, we investigated the involvement of IER5 in the cell cycle and in cell proliferation of acute myeloid leukemia (AML) cells. We found that the over-expression of IER5 in AML cell lines and in AML-derived ALDH(hi) (High Aldehyde Dehydrogenase activity)/CD34(+) cells inhibited their proliferation compared to control cells, through induction of G2/M cell cycle arrest and a decrease in Cdc25B expression. Moreover, the over-expression of IER5 reduced colony formation of AML-derived ALDH(hi)/CD34(+) cells due to a decrease in Cdc25B expression. In addition, over-expression of Cdc25B restored TMPP inhibitory effects on colony formation in IER5-suppressed AML-derived ALDH(hi)/CD34(+) cells. Furthermore, the IER5 reduced Cdc25B mRNA expression through direct binding to Cdc25B promoter and mediated its transcriptional attenuation through NF-YB and p300 transcriptinal factors. In summary, we found that transcriptional repression mediated by IER5 regulates Cdc25B expression levels via the release of NF-YB and p300 in AML-derived ALDH(hi)/CD34(+) cells, resulting in inhibition of AML progenitor cell proliferation through modulation of cell cycle. Thus, the induction of IER5 expression represents an attractive target for AML therapy.
Assuntos
Fator de Ligação a CCAAT/metabolismo , Proteína p300 Associada a E1A/metabolismo , Proteínas Imediatamente Precoces/metabolismo , Leucemia Mieloide Aguda/patologia , Células-Tronco Neoplásicas/patologia , Proteínas Nucleares/metabolismo , Transcrição Gênica , Fosfatases cdc25/genética , Antígenos CD34/metabolismo , Ciclo Celular , Proliferação de Células , Separação Celular , Regulação Leucêmica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Proteínas Imediatamente Precoces/genética , Leucemia Mieloide Aguda/genética , Proteínas Nucleares/genética , Regiões Promotoras Genéticas/genética , Ligação Proteica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Repressoras/metabolismo , Ensaio Tumoral de Célula-TroncoRESUMO
The constitutive activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway commonly occurs in cancers and is a crucial event in tumorigenesis. Chronic myelogenous leukemia (CML) is characterized by a reciprocal chromosomal translocation (9;22) that generates the Bcr-Abl fusion gene. The PI3K/Akt pathway is activated by Bcr-Abl chimera protein and mediates the leukemogenesis in CML. However, the mechanism by which Bcr-Abl activates the PI3K/Akt pathway is not completely understood. In the present study, we found that pleckstrin homology domain leucine-rich repeat protein phosphatases 1 and 2 (PHLPP1 and PHLPP2) were depleted in CML cells. We investigated the interaction between PHLPPs and Bcr-Abl in CML cell lines and Bcr-Abl+ progenitor cells from CML patients. The Abl kinase inhibitors and depletion of Bcr-Abl induced the expression of PHLPP1 and PHLPP2, which dephosphorylated Ser-473 on Akt1, -2, and -3, resulting in inhibited proliferation of CML cells. The reduction of PHLPP1 and PHLPP2 expression by short interfering RNA in CML cells weakened the Abl kinase inhibitor-mediated inhibition of proliferation. In colony-forming unit-granulocyte, erythroid, macrophage, megakaryocyte; colony-forming unit-granulocyte, macrophage; and burst-forming unit-erythroid, treatment with the Abl kinase inhibitors and depletion of Bcr-Abl induced PHLPP1 and PHLPP2 expression and inhibited colony formation of Bcr-Abl+ progenitor cells, whereas depletion of PHLPP1 and PHLPP2 weakened the inhibition of colony formation activity by the Abl kinase inhibitors in Bcr-Abl+ progenitor cells. Thus, Bcr-Abl represses the expression of PHLPP1 and PHLPP2 and continuously activates Akt1, -2, and -3 via phosphorylation on Ser-473, resulting in the proliferation of CML cells.