RESUMO
The leukocyte adhesion cascade is important in chronic lymphocytic leukemia (CLL), as it controls migration of malignant cells into the pro-survival lymph node microenvironment. Circulating trisomy 12 CLL cells have increased expression of the integrins CD11a and CD49d, as well as CD38, but the tissue expression of these and other molecules, and the functional and clinical sequelae of these changes have not been described. Here, we demonstrate that circulating trisomy 12 CLL cells also have increased expression of the integrins CD11b, CD18, CD29, and ITGB7, and the adhesion molecule CD323. Notably, there was reduced expression of CD11a, CD11b, and CD18 in trisomy 12 cases with NOTCH1 mutations compared with wild type. Trisomy 12 cells also exhibit upregulation of intracellular integrin signaling molecules CALDAG-GEFI, RAP1B, and Ras-related protein ligand, resulting in enhanced very late antigen-4 [VLA-4] directed adhesion and motility. CD38 expression in CLL has prognostic significance, but the increased CD38 expression in trisomy 12 CLL cells must be taken into account in this subgroup, and the threshold of CD38 positivity should be raised to 40% for this marker to retain its prognostic value. In conclusion, trisomy 12 CLL cells exhibit functional upregulation of integrin signaling, with ß2-integrin expression being modulated by NOTCH1 mutation status.
Assuntos
Regulação Leucêmica da Expressão Gênica , Integrinas/biossíntese , Leucemia Linfocítica Crônica de Células B/metabolismo , Mutação , Proteínas de Neoplasias/metabolismo , Células Neoplásicas Circulantes/metabolismo , Receptor Notch1/metabolismo , Transdução de Sinais , Regulação para Cima , Idoso , Movimento Celular/genética , Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 12/metabolismo , Fatores de Troca do Nucleotídeo Guanina/genética , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Humanos , Integrinas/genética , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Células Neoplásicas Circulantes/patologia , Receptor Notch1/genética , Trissomia/genética , Trissomia/patologia , Proteínas rap de Ligação ao GTP/genética , Proteínas rap de Ligação ao GTP/metabolismoRESUMO
OBJECTIVE: To review retrospectively the causes of death in unselected patients with gestational trophoblastic neoplasia (GTN). STUDY DESIGN: Between 1975 and 2010, 905 patients with GTN were treated at the Sheffield Centre. Twenty-four of them died. The medical records of these patients were reviewed. RESULTS: Of the 24 patients, 11 died during initial treatment. A further 8 died from disease relapse and progression of the disease. The cause of death was unrelated in the other 5, who were excluded from analysis. For the remaining 19 patients, death was due to metastatic tumor in 13 and was treatment related in 6. Adverse prognostic features for death from GTN included histology (7 were placental site trophoblastic tumor [PSTT]), risk score (15 were high risk) and chemotherapy resistance. All 5 of the patients who died of acute treatment-related complications (invariably sepsis and/or multiorgan failure) still had active GTN at the time of death; all were treated prior to 1987. One multitreated patient died of acute myeloid leukemia 3 years posttreatment. CONCLUSION: Metastatic multidrug-resistant PSTT was and still is the single most important cause of death. Death from choriocarcinoma was with nonpulmonary metastases not responding to initial treatment. Early treatment-related death (from sepsis) is nowadays avoidable.