RESUMEN
Malignant cells generally acquire some immune escape mechanisms for clonal expansion. Immune escape mechanisms also contribute to the failure of graft-versus-leukemia (GVL) effect after allogeneic hematopoietic stem cell transplantation (allo-SCT). Infant leukemias with mixed-lineage leukemia (MLL) rearrangement have a remarkably short latency, and GVL effect after allo-SCT has not been clearly evidenced in these leukemias. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)- and FasL-mediated cytotoxic pathways play important roles in cytotoxic T-lymphocyte- and natural killer cell-mediated antitumor immunity and optimal GVL activity. We investigated the in vitro sensitivity of MLL-rearranged acute lymphoblastic leukemia (ALL) and acute myeloblastic leukemia (AML) cells to TRAIL- and FasL-mediated cytotoxicity. Most of cell lines and primary leukemia cells were highly resistant to TRAIL primarily owing to low cell-surface expression of death receptors in ALL and simultaneous expression of decoy receptors in AML. Nearly half of cell lines and majority of primary leukemia cells showed low sensitivity to FasL. These results suggest that resistance to death-inducing ligands, particularly to TRAIL, could be one of the mechanisms for a rapid clonal expansion and a poor sensitivity to the GVL effect in infant leukemias with MLL rearrangement.
Asunto(s)
Reordenamiento Génico , Leucemia/inmunología , Proteína de la Leucemia Mieloide-Linfoide/genética , Ligando Inductor de Apoptosis Relacionado con TNF/farmacología , Escape del Tumor , Resistencia a Antineoplásicos , Efecto Injerto vs Leucemia , N-Metiltransferasa de Histona-Lisina , Humanos , Lactante , Recién Nacido , Leucemia/tratamiento farmacológico , Leucemia/genética , FN-kappa B/antagonistas & inhibidores , FN-kappa B/metabolismo , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/análisisRESUMEN
Although autologous tandem hematopoietic SCT has improved the prognosis of patients with advanced high-risk neuroblastoma, the results remain unsatisfactory. In an attempt to induce the graft-versus-tumor effect, we performed autologous PBSCT followed by allogeneic cord blood transplantation in three consecutive advanced neuroblastoma cases with marked BM infiltration and high MYCN amplification. Severe acute complications did not occur in any patient and they have maintained disease-free survival for 37-60 months. This strategy appears to be feasible and effective for the treatment of extremely high-risk neuroblastoma cases.
Asunto(s)
Trasplante de Células Madre de Sangre del Cordón Umbilical/métodos , Neuroblastoma/terapia , Proteínas Nucleares/genética , Proteínas Oncogénicas/genética , Trasplante de Células Madre de Sangre Periférica/métodos , Médula Ósea/patología , Efecto Injerto vs Tumor , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Lactante , Masculino , Proteína Proto-Oncogénica N-Myc , Invasividad NeoplásicaRESUMEN
The Fcgamma receptor IIIb (FcgammaRIIIb), a receptor for the Fcgamma region of IgG, is specifically expressed on neutrophils. It has two allelic polymorphisms, NA1 and NA2, which are highly immunogenic and act as targets in alloimmune or autoimmune neutropenia. Thus, neutrophil antigens (NA) compatibility of donor/recipient pairs might be expected to affect the engraftment of neutrophils after allogeneic SCT (allo-SCT). Here, the impact of NA compatibility of 17 patients and their donors undergoing allo-SCT with a myeloablative regimen was determined. Leukocyte depletion filters were used for all transfusions before and post-SCT; most patients received G-CSF after transplant. Major mismatches for NA1 and NA2 were present in 1 and 7 patient/donor pairs, respectively. These eight patients receiving NA major-mismatched allo-SCT were compared with nine patients who received NA compatible allo-SCT. Engraftment of neutrophils and the incidence of post-engraftment neutropenia were found to be identical in the two groups. Despite the limitations in statistical power because of the small number of patients analyzed, these observations suggest that the major mismatching for NA2 antigen has little impact on the engraftment of neutrophils after myeloablative allo-SCT, at least in patients transfused using leukocyte depletion filters and receiving G-CSF after transplantation.