RESUMO
Over the last few years, several new agents have been under evaluation in preclinical studies and clinical trials, showing promise in treating chronic lymphocytic leukemia (CLL). Among these agents, monoclonal antibodies (mAbs) such as rituximab and alemtuzumab have changed the natural course of the disease. Nowadays there are several new promising monoclonal antibodies under investigation against the CD20, CD23, CD37 and CD40 molecules. Application of newer monoclonal antibodies represents an area of ongoing clinical research in CLL.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Anticorpos Monoclonais/imunologia , Antígenos CD/química , Antígenos CD/metabolismo , Antígenos CD20/química , Antígenos CD20/metabolismo , Antígenos de Neoplasias/química , Antígenos de Neoplasias/metabolismo , Antineoplásicos/imunologia , Antígenos CD40/antagonistas & inibidores , Antígenos CD40/metabolismo , Antígeno CD52 , Glicoproteínas/antagonistas & inibidores , Glicoproteínas/metabolismo , Humanos , Receptores de IgE/antagonistas & inibidores , Receptores de IgE/metabolismo , TetraspaninasRESUMO
The PI3K/Akt pathway is activated in response to various microenvironmental stimuli that regulate the survival and proliferation of chronic lymphocytic leukemia (CLL) B-cells, including triggering of the B-cell receptor (BCR). Although this pathway is frequently targeted in cancer, no significant alterations have yet been identified in CLL. We now show that the phosphatase PH domain leucin-rich repeat protein phosphatase (PHLPP1), a recently identified tumor suppressor and negative regulator of the Akt kinase, is absent or expressed at substantially reduced levels in CLL B-cells. To determine what the consequences of PHLPP1 loss on BCR signaling are, we downregulated or re-expressed PHLPP1 in lymphoma cell lines and primary CLL B-cells, respectively. Downregulation of PHLPP1 increased BCR-induced phosphorylation and activation of the Akt, GSK3 and ERK kinases, whereas re-expression had the opposite effect. Importantly, re-expression of PHLPP1 in primary CLL cells prevented upregulation of Mcl-1 and inhibited the increase in leukemic cell viability induced by sustained BCR engagement. Enforced expression of PHLPP1 also affected the response to other microenvironmental stimuli, particularly in terms of ERK phosphorylation. Collectively, these data show that CLL cells lack an important negative regulator of the Akt and ERK pathways, which could confer them a growth advantage by facilitating the propagation of crucial microenvironment-derived stimuli.
Assuntos
Leucemia Linfocítica Crônica de Células B/etiologia , Proteínas Nucleares/fisiologia , Fosfoproteínas Fosfatases/fisiologia , Receptores de Antígenos de Linfócitos B/fisiologia , Transdução de Sinais , Proteínas Supressoras de Tumor/fisiologia , Apoptose , Linhagem Celular Tumoral , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Proteínas Nucleares/análise , Proteínas Nucleares/genética , Fosfatidilinositol 3-Quinases/fisiologia , Fosfoproteínas Fosfatases/análise , Fosfoproteínas Fosfatases/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/análiseRESUMO
Waldenström's macroglobulinaemia is a form of monoclonal IgM gammopathy associated with a rare B-cell lympho-plasmacytic lymphoma, characterized by the involvement of bone marrow, lymph nodes and spleen. Neurological complications involving peripheral nerves are common and different pathogenic mechanisms have been reported. We describe a patient with severe multineuropathy associated with Waldenström's macroglobulinaemia. Nerve biopsy revealed copious light chain deposition which subverted the normal architecture of the endoneurium and epineurium resulting in massive fascicular hyalinosis and epineural arteries disruption, respectively. This report confirms that massive immunoglobulin deposition is one of the several mechanisms of nerve damage in IgM-related neuropathy. Since their recognition has important therapeutical consequences, nerve biopsy is an essential diagnostic tool in patients with an unusual clinical presentation of IgM-related neuropathies.
