RESUMO
Aberrant expression of ecotropic viral integration site-1 (EVI1+) is associated with very poor outcomes in acute myeloid leukemia (AML), mechanisms of which are only partially understood. Using the green fluorescent protein reporter system to monitor EVI1 promoter activity, we demonstrated that Evi1high KMT2A-MLLT1-transformed AML cells possess distinct features from Evi1low cells: the potential for aggressive disease independent of stem cell activity and resistance to cytotoxic chemotherapy, along with the consistent gene expression profiles. RNA sequencing and chromatin immunoprecipitation sequencing in EVI1-transformed AML cells and normal hematopoietic cells combined with functional screening by cell proliferation-related short hairpin RNAs revealed that the erythroblast transformation-specific transcription factor ERG (E26 transformation-specific [ETS]-related gene) and cyclin D1 were downstream targets and therapeutic vulnerabilities of EVI1+ AML. Silencing Erg in murine EVI1+ AML models severely impaired cell proliferation, chemoresistance, and leukemogenic capacity. Cyclin D1 is also requisite for efficient EVI1-AML development, associated with gene expression profiles related to chemokine production and interferon signature, and T- and natural killer-cell exhaustion phenotype, depending on the interferon gamma (IFN-γ)/STAT1 pathway but not on CDK4/CDK6. Inhibiting the IFN-γ/STAT1 pathway alleviated immune exhaustion and impaired EVI1-AML development. Overexpression of EVI1 and cyclin D1 was associated with IFN-γ signature and increased expression of chemokines, with increased exhaustion molecules in T cells also in human AML data sets. These data collectively suggest that ERG and cyclin D1 play pivotal roles in the biology of EVI1+ AML, where ERG contributes to aggressive disease nature and chemoresistance, and cyclin D1 leads to IFN-γ signature and exhausted T-cell phenotypes, which could potentially be targeted.
Assuntos
Proteínas de Ligação a DNA , Leucemia Mieloide Aguda , Humanos , Animais , Camundongos , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Proteína do Locus do Complexo MDS1 e EVI1/genética , Ciclina D1/genética , Proto-Oncogenes , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Regulador Transcricional ERG/genética , Fatores de Transcrição/genéticaRESUMO
A 71-year-old female with type B3 thymoma developed severe aplastic anemia. Anti-thymocyte globulin was administered with glucocorticoids and cyclosporin A as the treatment for aplastic anemia. Computed tomography scan revealed that thymoma apparently shrank and remained without regrowth for at least 7 months. As previously reported, glucocorticoid has therapeutic effects on thymoma especially with abundant lymphocytes. Anti-thymocyte globulin also depletes peripheral lymphocytes, but its efficacy in the treatment of thymoma is unknown. Anti-thymocyte globulin and glucocorticoids may have cooperated with each other in reducing thymoma in our case. More cases should be accumulated to elucidate the effects of anti-thymocyte globulin on thymoma.
Assuntos
Anemia Aplástica , Timoma , Neoplasias do Timo , Idoso , Soro Antilinfocitário/uso terapêutico , Ciclosporina , Feminino , Humanos , Timoma/tratamento farmacológico , Neoplasias do Timo/tratamento farmacológicoRESUMO
Chylothorax is an intrathoracic leakage of chyle due to thoracic duct damage. Malignant lymphoma is the most common nontraumatic cause of chylothorax. In March 2019, a 74-year-old woman presented to our department with bilateral pleural effusion and mesenteric/retroperitoneal masses. She was diagnosed with diffuse large B-cell lymphoma upon performing a biopsy. In May 2019, she was hospitalized for dyspnea due to pleural effusion, and thoracentesis revealed abundant chyle. Although the tumor shrunk after chemotherapy, chylothorax improvement was poor; thus, she could not be discharged. For the management of refractory chylothorax, lymphangiography, thoracic duct embolization, and pleurodesis were performed, and the chylothorax improved immediately. However, in May 2020, right chylothorax recurred without a relapse of malignant lymphoma, which did not improve with conservative treatment. Lymphangiography was performed again; however, treatment via the lymphatic vessels was difficult. Thus, pleurodesis was performed four times, after which the chylothorax regressed. Chylothorax is often refractory. When chemotherapy for malignant lymphoma does not improve chylothorax, multidisciplinary treatment is effective.
