RESUMO
The bromodomain and extraterminal (BET) protein BRD2-4 inhibitors hold therapeutic promise in preclinical models of hematologic malignancies. However, translation of these data to molecules suitable for clinical development has yet to be accomplished. Herein we expand the mechanistic understanding of BET inhibitors in multiple myeloma by using the chemical probe molecule I-BET151. I-BET151 induces apoptosis and exerts strong antiproliferative effect in vitro and in vivo. This is associated with contrasting effects on oncogenic MYC and HEXIM1, an inhibitor of the transcriptional activator P-TEFb. I-BET151 causes transcriptional repression of MYC and MYC-dependent programs by abrogating recruitment to the chromatin of the P-TEFb component CDK9 in a BRD2-4-dependent manner. In contrast, transcriptional upregulation of HEXIM1 is BRD2-4 independent. Finally, preclinical studies show that I-BET762 has a favorable pharmacologic profile as an oral agent and that it inhibits myeloma cell proliferation, resulting in survival advantage in a systemic myeloma xenograft model. These data provide a strong rationale for extending the clinical testing of the novel antimyeloma agent I-BET762 and reveal insights into biologic pathways required for myeloma cell proliferation.
Assuntos
Antineoplásicos/uso terapêutico , Benzodiazepinas/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Benzodiazepinas/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Humanos , Camundongos , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas de Ligação a RNA/genética , Fatores de Transcrição , Ativação Transcricional/efeitos dos fármacos , Células Tumorais CultivadasRESUMO
Invariant natural killer T (iNKT) cells are powerful immunomodulatory cells that in mice regulate a variety of immune responses, including acute GVHD (aGVHD). However, their clinical relevance and in particular their role in clinical aGVHD are not known. We studied whether peripheral blood stem cell (PBSC) graft iNKT-cell dose affects on the occurrence of clinically significant grade II-IV aGVHD in patients (n = 57) undergoing sibling, HLA-identical allogeneic HSCT. In multivariate analysis, CD4(-) iNKT-cell dose was the only graft parameter to predict clinically significant aGVHD. The cumulative incidence of grade II-IV aGVHD in patients receiving CD4(-) iNKT-cell doses above and below the median were 24.2% and 71.4%, respectively (P = .0008); low CD4(-) iNKT-cell dose was associated with a relative risk of grade II-IV aGVHD of 4.27 (P = .0023; 95% CI, 1.68-10.85). Consistent with a role of iNKT cells in regulating aGVHD, in mixed lymphocyte reaction assays, CD4(-) iNKT cells effectively suppressed T-cell proliferation and IFN-γ secretion in a contact-dependent manner. In conclusion, higher doses of CD4(-) iNKT cells in PBSC grafts are associated with protection from aGVHD. This effect could be harnessed for prevention of aGVHD.
Assuntos
Doença Enxerto-Hospedeiro/etiologia , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Células T Matadoras Naturais/citologia , Células T Matadoras Naturais/transplante , Adulto , Idoso , Doação Dirigida de Tecido , Feminino , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/imunologia , Neoplasias Hematológicas/epidemiologia , Neoplasias Hematológicas/imunologia , Transplante de Células-Tronco Hematopoéticas/estatística & dados numéricos , Teste de Histocompatibilidade , Humanos , Incidência , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Irmãos , Doadores de Tecidos , Imunologia de Transplantes/imunologia , Imunologia de Transplantes/fisiologia , Transplante HomólogoRESUMO
Primary lymphoma of bone is extremely rare. There are increasing reports of lymphoma arising in bone adjacent to metallic prostheses. Herein, we describe the case of a 76-year-old man who developed diffuse large B cell lymphoma in the tibia 3 years after total knee arthroplasty for osteoarthritis. A review of the literature has identified 11 other cases of lymphoma arising in the context of orthopaedic metallic implants. To our knowledge this is the first reported case of a primary lymphoma arising in bone adjacent to a knee prosthesis. Possible pathogenetic mechanisms may include chronic antigenic stimulation of lymphocytes, proliferation of EBV-infected B lymphocytes, and direct mutagenic effects of metallic ions. Further research is required to investigate this intriguing link between metallic orthopaedic prostheses and localized lymphoma.
Assuntos
Artroplastia do Joelho , Neoplasias Ósseas/cirurgia , Linfoma Difuso de Grandes Células B/cirurgia , Idoso , Humanos , Masculino , Tomografia por Emissão de PósitronsRESUMO
A 20 year old woman, admitted with acute pancreatitis, subsequently developed microangiopathic haemolytic anaemia, thrombocytopenia and mild neurological compromise. A diagnosis of thrombotic thrombocytopenic purpura (TTP) was made, and she was treated with plasma exchange leading to complete resolution of this condition. TTP is a rare multisystem disorder which may be life threatening if not treated promptly. The increasing recognition of acute pancreatitis as a potential aetiological factor offers new insights into the pathogenesis, diagnosis and treatment of TTP.
Assuntos
Pancreatite/patologia , Púrpura Trombocitopênica Trombótica/patologia , Doença Aguda , Adulto , Feminino , Humanos , Pancreatite/sangue , Pancreatite/terapia , Púrpura Trombocitopênica Trombótica/diagnóstico , Púrpura Trombocitopênica Trombótica/terapia , Adulto JovemRESUMO
We describe an unusual case of oscillating platelet counts in a patient with polycythaemia vera. Following commencement of cytoreductive hydroxycarbamide therapy, episodes of thrombocytopenia were followed regularly by thrombocytosis. Platelet counts fluctuated periodically between approximately 200 and 800 x 109/l, with a 28 day cycle duration. Frequent adjustment of the hydroxycarbamide dose was not successful in preventing the oscillations in platelet count. In contrast, maintenance of a constant dose led to a gradual damping of the cycles and thus termination of the large oscillations. The case further implicates hydroxycarbamide as a potential cause of cyclic variations in platelet counts, and demonstrates that cessation of this drug is not always necessary in order to treat this phenomenon.
Assuntos
Antineoplásicos/administração & dosagem , Hidroxiureia/administração & dosagem , Policitemia Vera/sangue , Policitemia Vera/tratamento farmacológico , Feminino , Humanos , Pessoa de Meia-Idade , Contagem de Plaquetas , Fatores de Tempo , Resultado do TratamentoRESUMO
Chimeric antigen receptor anti-CD19 (CAR19)-T cell immunotherapy-induced clinical remissions in CD19+ B cell lymphomas are often short lived. We tested whether CAR19-engineering of the CD1d-restricted invariant natural killer T (iNKT) cells would result in enhanced anti-lymphoma activity. CAR19-iNKT cells co-operatively activated by CD1d- and CAR19-CD19-dependent interactions are more effective than CAR19-T cells against CD1d-expressing lymphomas in vitro and in vivo. The swifter in vivo anti-lymphoma activity of CAR19-iNKT cells and their enhanced ability to eradicate brain lymphomas underpinned an improved tumor-free and overall survival. CD1D transcriptional de-repression by all-trans retinoic acid results in further enhanced cytotoxicity of CAR19-iNKT cells against CD19+ chronic lymphocytic leukemia cells. Thus, iNKT cells are a highly efficient platform for CAR-based immunotherapy of lymphomas and possibly other CD1d-expressing cancers.
Assuntos
Antígenos CD1d/genética , Terapia Baseada em Transplante de Células e Tecidos , Linfoma/tratamento farmacológico , Células T Matadoras Naturais/citologia , Animais , Antígenos CD19/genética , Antígenos CD19/imunologia , Antígenos CD1d/imunologia , Humanos , Imunoterapia/métodos , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/imunologia , Linfoma/imunologia , Camundongos , Células T Matadoras Naturais/imunologiaAssuntos
Neoplasias Encefálicas/diagnóstico por imagem , Leucemia de Células Pilosas/diagnóstico por imagem , Adulto , Células da Medula Óssea/ultraestrutura , Neoplasias Encefálicas/etiologia , Diagnóstico Diferencial , Humanos , Leucemia de Células Pilosas/patologia , Leucemia de Células Pilosas/fisiopatologia , Imageamento por Ressonância Magnética , Masculino , Tomografia Computadorizada por Raios XRESUMO
This report describes a rare complication in a woman who underwent thoracic spinal surgery. One month postoperatively, her rehabilitation was interrupted by the development of a severe headache, nausea, vomiting, and a right-side occulomotor nerve palsy. Imaging of her brain revealed changes typical of intracranial hypotension, and subsequent imaging of the spine revealed a cerebrospinal fluid (CSF) leak at the site of surgery. The CSF was seen to track into the right pleural space via a dural-pleural fistula. Surgical repair of the fistula led to a definitive resolution in symptoms, thus highlighting the importance of early recognition of this highly unusual complication.