RESUMO
The hallmark of chronic lymphocytic leukemia (CLL) is the relentless accumulation of mature lymphocytes, mostly due to their decreased apoptosis. CD74 was recently shown to serve as a survival receptor on CLL cells. In this study, we show that stimulation of CD74 with its natural ligand, migration inhibitory factor, initiates a signaling cascade that results in upregulation of TAp63, which directly regulates CLL survival. In addition, TAp63 expression elevates the expression of the integrin VLA-4, particularly during the advanced stage of the disease. Blocking of CD74, TAp63, or VLA-4 inhibits the in vivo homing of CLL cells to the bone marrow (BM). Thus, CD74 and its target genes TAp63 and VLA-4 facilitate migration of CLL cells back to the BM, where they interact with the supportive BM environment that rescues them from apoptosis. These results could form the basis of novel therapeutic strategies aimed at blocking homing of CLL cells in their return to the BM and attenuating their survival.
Assuntos
Antígenos de Diferenciação de Linfócitos B/fisiologia , Células da Medula Óssea/imunologia , Células da Medula Óssea/patologia , Regulação Neoplásica da Expressão Gênica/imunologia , Antígenos de Histocompatibilidade Classe II/fisiologia , Integrina alfa4beta1/genética , Leucemia Linfocítica Crônica de Células B/imunologia , Leucemia Linfocítica Crônica de Células B/patologia , Transativadores/fisiologia , Proteínas Supressoras de Tumor/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Anticorpos Bloqueadores/farmacologia , Antígenos de Diferenciação de Linfócitos B/imunologia , Antígenos de Diferenciação de Linfócitos B/metabolismo , Antígenos de Neoplasias/biossíntese , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/fisiologia , Proteínas Reguladoras de Apoptose/biossíntese , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/fisiologia , Inibição de Migração Celular/imunologia , Movimento Celular/genética , Movimento Celular/imunologia , Sobrevivência Celular/genética , Sobrevivência Celular/imunologia , Feminino , Antígenos de Histocompatibilidade Classe II/imunologia , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Integrina alfa4beta1/biossíntese , Oxirredutases Intramoleculares/antagonistas & inibidores , Oxirredutases Intramoleculares/fisiologia , Leucemia Linfocítica Crônica de Células B/genética , Fatores Inibidores da Migração de Macrófagos/antagonistas & inibidores , Fatores Inibidores da Migração de Macrófagos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Transdução de Sinais/imunologia , Transativadores/biossíntese , Transativadores/genética , Fatores de Transcrição , Proteínas Supressoras de Tumor/biossíntese , Proteínas Supressoras de Tumor/genética , Regulação para Cima/imunologiaRESUMO
Chronic lymphocytic leukemia (CLL) is a malignant disease of small mature lymphocytes. Previous studies have shown that CLL B lymphocytes express relatively large amounts of CD74 mRNA relative to normal B cells. In the present study, we analyzed the molecular mechanism regulated by CD74 in B-CLL cells. The results presented here show that activation of cell-surface CD74, expressed at high levels from an early stage of the disease by its natural ligand, macrophage migration-inhibition factor (MIF), initiates a signaling cascade that contributes to tumor progression. This pathway induces NF-kappaB activation, resulting in the secretion of IL-8 which, in turn, promotes cell survival. Inhibition of this pathway leads to decreased cell survival. These findings could form the basis of unique therapeutic strategies aimed at blocking the CD74-induced, IL-8- dependent survival pathway.
Assuntos
Antígenos de Diferenciação de Linfócitos B/fisiologia , Sobrevivência Celular , Antígenos de Histocompatibilidade Classe II/fisiologia , Interleucina-8/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , Western Blotting , Citometria de Fluxo , Humanos , Interleucina-8/genética , Interleucina-8/fisiologia , Leucemia Linfocítica Crônica de Células B/imunologia , Transdução de SinaisRESUMO
CD74 is an integral membrane protein that was thought to function mainly as an MHC class II chaperone. However, CD74 was recently shown to have a role as an accessory-signaling molecule. Our studies demonstrated that CD74 regulates B-cell differentiation by inducing a pathway leading to the activation of transcription mediated by the NF-kappaB p65/RelA homodimer and its coactivator, TAF(II)105. Here, we show that CD74 stimulation with anti-CD74 antibody leads to an induction of a signaling cascade resulting in NF-kappaB activation, entry of the stimulated cells into the S phase, elevation of DNA synthesis, cell division, and augmented expression of BCL-X(L). These studies therefore demonstrate that surface CD74 functions as a survival receptor.