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2.
Leukemia ; 31(12): 2642-2651, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28439107

RESUMO

Multiple myeloma (MM) is characterized by the clonal expansion and metastatic spread of malignant plasma cells to multiple sites in the bone marrow (BM). Recently, we implicated the sialyltransferase ST3Gal-6, an enzyme critical to the generation of E-selectin ligands, in MM BM homing and resistance to therapy. Since E-selectin is constitutively expressed in the BM microvasculature, we wished to establish the contribution of E-selectin ligands to MM biology. We report that functional E-selectin ligands are restricted to a minor subpopulation of MM cell lines which, upon expansion, demonstrate specific and robust interaction with recombinant E-selectin in vitro. Moreover, an increase in the mRNA levels of genes involved in the generation of E-selectin ligands was associated with inferior progression-free survival in the CoMMpass study. In vivo, E-selectin ligand-enriched cells induced a more aggressive disease and were completely insensitive to Bortezomib. Importantly, this resistance could be reverted by co-administration of GMI-1271, a specific glycomimetic antagonist of E-selectin. Finally, we report that E-selectin ligand-bearing cells are present in primary MM samples from BM and peripheral blood with a higher proportion seen in relapsed patients. This study provides a rationale for targeting E-selectin receptor/ligand interactions to overcome MM metastasis and chemoresistance.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Selectina E/antagonistas & inibidores , Selectina E/metabolismo , Mieloma Múltiplo/metabolismo , Animais , Bortezomib/farmacologia , Adesão Celular , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Ligantes , Camundongos , Mieloma Múltiplo/genética , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Prognóstico , Ligação Proteica , Recidiva , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Leukemia ; 31(11): 2426-2434, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28344315

RESUMO

The extracellular matrix (ECM) is a major component of the tumor microenvironment, contributing to the regulation of cell survival, proliferation, differentiation and metastasis. In multiple myeloma (MM), interactions between MM cells and the bone marrow (BM) microenvironment, including the BM ECM, are critical to the pathogenesis of the disease and the development of drug resistance. Nevertheless, composition of the ECM in MM and its role in supporting MM pathogenesis has not been reported. We have applied a novel proteomic-based strategy and defined the BM ECM composition in patients with monoclonal gammopathy of undetermined significance (MGUS), newly diagnosed and relapsed MM compared with healthy donor-derived BM ECM. In this study, we show that the tumor ECM is remodeled at the mRNA and protein levels in MGUS and MM to allow development of a permissive microenvironment. We further demonstrate that two ECM-affiliated proteins, ANXA2 and LGALS1, are more abundant in MM and high expression is associated with a decreased overall survival. This study points to the importance of ECM remodeling in MM and provides a novel proteomic pipeline for interrogating the role of the ECM in cancers with BM tropism.


Assuntos
Medula Óssea/metabolismo , Matriz Extracelular/metabolismo , Mieloma Múltiplo/metabolismo , Proteoma , Anexina A2/metabolismo , Estudos de Casos e Controles , Galectina 1/metabolismo , Perfilação da Expressão Gênica , Humanos , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Análise de Sobrevida , Microambiente Tumoral
4.
Leukemia ; 31(4): 853-860, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27773931

RESUMO

MYC is a major oncogenic driver of multiple myeloma (MM) and yet almost no therapeutic agents exist that target MYC in MM. Here we report that the let-7 biogenesis inhibitor LIN28B correlates with MYC expression in MM and is associated with adverse outcome. We also demonstrate that the LIN28B/let-7 axis modulates the expression of MYC, itself a let-7 target. Further, perturbation of the axis regulates the proliferation of MM cells in vivo in a xenograft tumor model. RNA-sequencing and gene set enrichment analyses of CRISPR-engineered cells further suggest that the LIN28/let-7 axis regulates MYC and cell cycle pathways in MM. We provide proof of principle for therapeutic regulation of MYC through let-7 with an LNA-GapmeR (locked nucleic acid-GapmeR) containing a let-7b mimic in vivo, demonstrating that high levels of let-7 expression repress tumor growth by regulating MYC expression. These findings reveal a novel mechanism of therapeutic targeting of MYC through the LIN28B/let-7 axis in MM that may impact other MYC-dependent cancers as well.


Assuntos
Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Mieloma Múltiplo/genética , Interferência de RNA , Proteínas de Ligação a RNA/genética , Animais , Estudos de Casos e Controles , Ciclo Celular/genética , Linhagem Celular Tumoral , Análise por Conglomerados , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Genes myc , Xenoenxertos , Humanos , Camundongos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Prognóstico , Proteínas de Ligação a RNA/metabolismo
6.
Bone Marrow Transplant ; 48(12): 1543-7, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23912663

RESUMO

Renal failure commonly complicates multiple myeloma (MM) and is associated with reduced survival. It is not clear whether auto-SCT results in improved renal function or attainment of independence from dialysis in patients with advanced renal impairment due to MM. We conducted a retrospective cohort study of all patients who underwent auto-SCT for MM complicated by advanced renal failure at our institution over a 10-year period (2000-2010). We aimed to assess the association between auto-SCT and renal outcome in patients with serum creatinine (SCr) over 3 mg/dL, attributable to MM, including those who were dialysis dependent. Thirty patients (2.8% of all auto-SCT patients) met inclusion criteria. Fourteen of 15 patients who were dialysis dependent before auto-SCT remained dialysis dependent in the long term despite hematological response (HR). Of the remaining 15 patients with SCr >3 mg/dL, an improvement in glomerular filtration rate (GFR) from 15 to 19.4 mL/min/1.73 m(2) was noted post auto-SCT (P=0.035); however, neither HR post auto-SCT or pre-existing renal function were independently associated with renal outcome. Auto-SCT was not associated with independence from dialysis in patients with renal failure due to MM at our institution. Although auto-SCT was associated with an improvement in GFR in patients with SCr >3 mg/dL, this improvement was not related to HR.


Assuntos
Mieloma Múltiplo/fisiopatologia , Mieloma Múltiplo/cirurgia , Insuficiência Renal/etiologia , Transplante de Células-Tronco/métodos , Condicionamento Pré-Transplante/métodos , Transplante Autólogo/métodos , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/sangue , Estudos Prospectivos , Insuficiência Renal/sangue , Insuficiência Renal/fisiopatologia , Estudos Retrospectivos , Transplante de Células-Tronco/efeitos adversos , Análise de Sobrevida , Condicionamento Pré-Transplante/efeitos adversos , Transplante Autólogo/efeitos adversos , Resultado do Tratamento
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