RESUMO
Multiple myeloma (MM) is characterized by the accumulation of a population of malignant plasma cells within the bone marrow and its microenvironment. A hypoxic niche is located within the microenvironment, which causes myeloma cells to become quiescent, anti-apoptotic, glycolytic, and immature. Cell heterogeneity may be related to distinct gene expression profiles under hypoxic and normoxic conditions. During hypoxia, myeloma cells acquire these phenotypes by downregulating interferon regulatory factor 4 (IRF4), an essential transcription factor in myeloma oncogenesis. To identify essential microRNAs and their targets regulated under hypoxic conditions, we undertook microRNA and cDNA microarray analyses using hypoxia-exposed primary MM samples and myeloma cell lines. Under hypoxia, only miR-210 was highly upregulated and was accompanied by direct downregulation of an 18S rRNA base methyltransferase, DIMT1. This inverse expression correlation was validated by quantitative RT-PCR for primary MM samples. We further determined that DIMT1 has an oncogenic potential as its knockdown reduced tumorigenicity of myeloma cells through regulation of IRF4 expression. Notably, by analyzing gene expression omnibus datasets in the National Center for Biotechnology Information database, we found that DIMT1 expression increased gradually with MM progression. In summary, by screening for targets of hypoxia-inducible microRNA-210, we identified DIMT1 as a novel diagnostic marker and therapeutic target for all molecular subtypes of MM.
Assuntos
Regulação Neoplásica da Expressão Gênica , Fatores Reguladores de Interferon/genética , Metiltransferases/genética , MicroRNAs/genética , Mieloma Múltiplo/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Western Blotting , Carcinogênese/genética , Hipóxia Celular , Linhagem Celular Tumoral , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Hipóxia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Fatores Reguladores de Interferon/metabolismo , Masculino , Metiltransferases/metabolismo , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Pessoa de Meia-Idade , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Interferência de RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transplante HeterólogoRESUMO
A 71-year-old male patient began FOLFOX6 plus panitumumab treatment for unresectable recurrent rectal cancer. He developed thrombocytopenia after 2 courses of treatment and therefore a platelet transfusion was performed. The day after transfusion, the patient developed jaundice and hematuria. His lactate dehydrogenase levels had increased and a peripheral blood smear review revealed the presence of schistocytes. Anti-ADAMTS13 antibodies were present, and there was a reduction in ADAMTS13 activity. The patient was diagnosed with thrombotic thrombocytopenic purpura and treated with a plasma exchange. The day after the plasma exchange, his clinical condition rapidly worsened and he died. Thrombocytopenia due to chemotherapy often appears as myelosuppression. If conditions such as jaundice, indirect bilirubinemia, or hematuria appear during the course of chemotherapy, this condition must be considered as a differential diagnosis.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Púrpura Trombocitopênica Trombótica/complicações , Neoplasias Retais/tratamento farmacológico , Proteínas ADAM/metabolismo , Proteína ADAMTS13 , Idoso , Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Progressão da Doença , Evolução Fatal , Fluoruracila/administração & dosagem , Humanos , Leucovorina/administração & dosagem , Masculino , Compostos Organoplatínicos/administração & dosagem , Panitumumabe , Troca Plasmática , Púrpura Trombocitopênica Trombótica/enzimologia , Púrpura Trombocitopênica Trombótica/terapia , Neoplasias Retais/complicações , Neoplasias Retais/patologia , RecidivaRESUMO
Achievement of complete molecular response in patients with chronic phase chronic myeloid leukemia has been recognized as an important milestone in therapy cessation and treatment-free remission; the identification of predictors of complete molecular response in these patients is, therefore, important. This study evaluated complete molecular response rates in imatinib-treated chronic phase chronic myeloid leukemia patients with major molecular response by using the international standardization for quantitative polymerase chain reaction analysis of the breakpoint cluster region-Abelson1 gene. The correlation of complete molecular response with various clinical, pharmacokinetic, and immunological parameters was determined. Complete molecular response was observed in 75/152 patients (49.3%). In the univariate analysis, Sokal score, median time to major molecular response, ABCG2 421C>A, and regulatory T cells were significantly lower in chronic phase chronic myeloid leukemia patients with complete molecular response than in those without complete molecular response. In the multivariate analysis, duration of imatinib treatment (odds ratio: 1.0287, P=0.0003), time to major molecular response from imatinib therapy (odds ratio: 0.9652, P=0.0020), and ABCG2 421C/C genotype (odds ratio: 0.3953, P=0.0284) were independent predictors of complete molecular response. In contrast, number of natural killer cells, BIM deletion polymorphisms, and plasma trough imatinib concentration were not significantly associated with achieving a complete molecular response. Several predictive markers for achieving complete molecular response were identified in this study. According to our findings, some chronic myeloid leukemia patients treated with imatinib may benefit from a switch to second-generation tyrosine kinase inhibitors (ClinicalTrials.gov, UMIN000004935).
Assuntos
Benzamidas/uso terapêutico , Internacionalidade , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Reação em Cadeia da Polimerase em Tempo Real/normas , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzamidas/sangue , Feminino , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Masculino , Pessoa de Meia-Idade , Piperazinas/sangue , Pirimidinas/sangue , Reação em Cadeia da Polimerase em Tempo Real/métodos , Resultado do Tratamento , Adulto JovemRESUMO
Human herpesvirus-8 (HHV8)-positive, human immunodeficiency virus (HIV)-negative multicentric Castleman disease (MCD) is a rare and age-related lymphoproliferative disorder caused by cytokine storm. Rituximab treatment is currently recommended because B-cell depletion eliminates the primary reservoir for HHV8. We report the first case of effective rituximab treatment of a Japanese patient (an 87-year-old woman) with this disorder. Her inflammatory symptoms and lymphadenopathy improved after medium-dose steroid therapy, but these symptoms recurred during steroid tapering. After one course of rituximab therapy, she achieved sustained remission. HHV8-associated MCD should be considered as a possible diagnosis in HIV-negative patients with inflammatory symptoms and lymphadenopathy.
Assuntos
Hiperplasia do Linfonodo Gigante/tratamento farmacológico , Rituximab/administração & dosagem , Rituximab/uso terapêutico , Administração Oral , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Povo Asiático , Subpopulações de Linfócitos B/imunologia , Hiperplasia do Linfonodo Gigante/diagnóstico , Hiperplasia do Linfonodo Gigante/imunologia , Hiperplasia do Linfonodo Gigante/virologia , Feminino , HIV , Humanos , Masculino , Pessoa de Meia-Idade , Prednisolona/administração & dosagem , Recidiva , Indução de RemissãoRESUMO
Side population (SP) cells in cancers, including multiple myeloma, exhibit tumor-initiating characteristics. In the present study, we isolated SP cells from human myeloma cell lines and primary tumors to detect potential therapeutic targets specifically expressed in SP cells. We found that SP cells from myeloma cell lines (RPMI 8226, AMO1, KMS-12-BM, KMS-11) express CD138 and that non-SP cells include a CD138-negative population. Serial transplantation of SP and non-SP cells into NOD/Shi-scid IL-2γnul mice revealed that clonogenic myeloma SP cells are highly tumorigenic and possess a capacity for self-renewal. Gene expression analysis showed that SP cells from five MM cell lines (RPMI 8226, AMO1, KMS-12-BM, KMS-11, JJN3) express genes involved in the cell cycle and mitosis (e.g., CCNB1, CDC25C, CDC2, BIRC5, CENPE, SKA1, AURKB, KIFs, TOP2A, ASPM), polycomb (e.g., EZH2, EPC1) and ubiquitin-proteasome (e.g., UBE2D3, UBE3C, PSMA5) more strongly than do non-SP cells. Moreover, CCNB1, AURKB, EZH2 and PSMA5 were also upregulated in the SPs from eight primary myeloma samples. On that basis, we used an aurora kinase inhibitor (VX-680) and a proteasome inhibitor (bortezomib) with RPMI 8226 and AMO1 cells to determine whether these agents could be used to selectively target the myeloma SP. We found that both these drugs reduced the SP fraction, though bortezomib did so more effectively than VX-680 due to its ability to reduce levels of both phospho-histone H3 (p-hist. H3) and EZH2; VX-680 reduced only p-hist. H3. This is the first report to show that certain oncogenes are specifically expressed in the myeloma SP, and that bortezomib effectively downregulates expression of their products. Our approach may be useful for screening new agents with which to target a cell population possessing strong tumor initiating potential in multiple myeloma.
Assuntos
Antineoplásicos/farmacologia , Ácidos Borônicos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Mieloma Múltiplo/genética , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas do Grupo Polycomb/antagonistas & inibidores , Pirazinas/farmacologia , Ubiquitinas/antagonistas & inibidores , Animais , Bortezomib , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Linhagem Celular Tumoral , Feminino , Humanos , Interleucina-2/deficiência , Interleucina-2/genética , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Mitose/efeitos dos fármacos , Mitose/genética , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Transplante de Neoplasias , Piperazinas/farmacologia , Proteínas do Grupo Polycomb/genética , Proteínas do Grupo Polycomb/metabolismo , Cultura Primária de Células , Células da Side Population/efeitos dos fármacos , Células da Side Population/metabolismo , Células da Side Population/patologia , Transdução de Sinais/efeitos dos fármacos , Sindecana-1/genética , Sindecana-1/metabolismo , Ubiquitinas/genética , Ubiquitinas/metabolismoRESUMO
It has been demonstrated that the chromosomal translocation t(7;11)(p15;p15) in patients with human acute myelogenous leukemia (AML) and chronic myelogenous leukemia (CML) invariably involves fusion of the nucleoporin gene, NUP98, on chromosome 11 and the class 1 HOX gene, HOXA9, on chromosome 7, and that the fusion gene NUP98-HOXA9 is an important gene in myeloid leukemogenesis. Here are reported 2 novel chromosome 7p15 targets of the t(7;11)(p15;p15) chromosomal translocation in 2 patients with CML and myelodysplastic syndrome (MDS). Southern blot and polymerase chain reaction (PCR) analyses of leukemia cell DNA failed to show rearrangement of HOXA9, whereas NUP98 was found to be rearranged in both cases. Reverse transcription-PCR analysis using a NUP98 primer and a degenerate primer corresponding to the third helix of the homeodomain of HOXA demonstrated that NUP98 was fused in-frame to HOXA11 in the patient with CML and to HOXA13 in the patient with MDS. The chromosomal breakpoints on 7p15 were located within introns of HOXA11 or HOXA13 genes. In both patients chimeric NUP98-HOXA9 transcripts were also observed. These findings suggest that AbdB-type HOXA genes are common targets of t(7;11)(p15;p15) chromosomal translocations and that a single translocation can produce more than one NUP98-HOXA fusion gene, presumably because of altered splicing.