RESUMO
Adult B-lymphoblastic leukemia (B-ALL) is a hematological malignancy characterized by genetic heterogeneity. Despite successful remission induction with classical chemotherapeutics and novel targeted agents, enduring remission is often hampered by disease relapse due to outgrowth of a pre-existing subclone resistant against the treatment. In this study, we show that small glycophosphatidylinositol (GPI)-anchor deficient CD52-negative B-cell populations are frequently present already at diagnosis in B-ALL patients, but not in patients suffering from other B-cell malignancies. We demonstrate that the GPI-anchor negative phenotype results from loss of mRNA expression of the PIGH gene, which is involved in the first step of GPI-anchor synthesis. Loss of PIGH mRNA expression within these B-ALL cells follows epigenetic silencing rather than gene mutation or deletion. The coinciding loss of CD52 membrane expression may contribute to the development of resistance to alemtuzumab (ALM) treatment in B-ALL patients resulting in the outgrowth of CD52-negative escape variants. Additional treatment with 5-aza-2'-deoxycytidine may restore expression of CD52 and revert ALM resistance.
Assuntos
Linfócitos B/metabolismo , Antígeno CD52/deficiência , Metilação de DNA/efeitos dos fármacos , Regulação Leucêmica da Expressão Gênica , Inativação Gênica , Glicosilfosfatidilinositóis/deficiência , Proteínas de Membrana/genética , Proteínas de Neoplasias/deficiência , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Alemtuzumab/uso terapêutico , Antimetabólitos Antineoplásicos/farmacologia , Antimetabólitos Antineoplásicos/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Linfócitos B/patologia , Antígeno CD52/biossíntese , Antígeno CD52/genética , Linhagem Celular Tumoral , Decitabina/farmacologia , Decitabina/uso terapêutico , Regulação para Baixo/efeitos dos fármacos , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Glicosilfosfatidilinositóis/biossíntese , Glicosilfosfatidilinositóis/genética , Humanos , Proteínas de Membrana/biossíntese , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Fenótipo , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genéticaRESUMO
Uveal melanoma (UM) is characterized by a number of genetic aberrations that follow a certain chronology and are tightly linked to tumor recurrence and survival. Loss of chromosome 3, bi-allelic loss of BAP1 expression, and gain in chromosome 8q have been associated with metastasis formation and death, while loss of chromosome 3 has been associated with the influx of macrophages and T cells. We used a set of genetically-classified UM to study immune infiltration in the context of their genetic evolution. We show in two independent cohorts that lack of BAP1 expression is associated with an increased density of CD3+ T cells and CD8+ T cells. The presence of extra copies of chromosome 8q in disomy 3 tumors with a normal BAP1 expression is associated with an increased influx of macrophages (but not T cells). Therefore, we propose that the genetic evolution of UM is associated with changes in the inflammatory phenotype. Early changes resulting in gain of chromosome 8q may activate macrophage infiltration, while sequential loss of BAP1 expression seems to drive T cell infiltration in UM.