RESUMEN
The NUP98::NSD1 fusion gene is associated with extremely poor prognosis in patients with acute myeloid leukemia (AML). NUP98::NSD1 induces self-renewal and blocks differentiation of hematopoietic stem cells, leading to development of leukemia. Despite its association with poor prognosis, targeted therapy for NUP98::NSD1-positive AML is lacking, as the details of NUP98::NSD1 function are unknown. Here, we generated 32D cells (a murine interleukin-3 (IL-3)-dependent myeloid progenitor cell line) expressing mouse Nup98::Nsd1 to explore the function of NUP98::NSD1 in AML, including comprehensive gene expression analysis. We identified two properties of Nup98::Nsd1 + 32D cells in vitro. First, Nup98::Nsd1 promoted blocking of AML cell differentiation, consistent with a previous report. Second, Nup98::Nsd1 increased dependence on IL-3 for cell proliferation, due to overexpression of the alpha subunit of the IL-3 receptor (IL3-RA, also known as CD123). Consistent with our in vitro data, IL3-RA was also upregulated in samples from patients with NUP98::NSD1-positive AML. These results highlight CD123 as a potential new therapeutic target in NUP98::NSD1-positive AML.
Asunto(s)
Interleucina-3 , Animales , Ratones , N-Metiltransferasa de Histona-Lisina , Interleucina-3/genética , Interleucina-3/metabolismo , Subunidad alfa del Receptor de Interleucina-3/genética , Leucemia Mieloide Aguda/genética , Proteínas de Complejo Poro Nuclear/genéticaRESUMEN
Fanconi anemia (FA) is a rare genetic disorder that manifests as congenital abnormalities and bone marrow failure (BMF). Most patients with FA present with BMF within the first decade of life; however, neonate and early infancy BMF is rare. Recent studies have shown that a defective aldehyde dehydrogenase 2 (ALDH2) variant accelerates BMF development in patients with FA. Herein, we described an infant case of FA with compound heterozygous FANCI mutation and the defective ALDH2 variant. Our case developed BMF early probably because of ALDH2 deficiency, while the mild malformation might be because of the locus of FANCI mutation.
Asunto(s)
Anemia de Fanconi , Aldehído Deshidrogenasa Mitocondrial/genética , Anemia de Fanconi/genética , Proteínas del Grupo de Complementación de la Anemia de Fanconi/genética , Humanos , Lactante , Recién Nacido , MutaciónAsunto(s)
Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Gránulos Citoplasmáticos/patología , Leucemia Mieloide Aguda/genética , Proteínas de Fusión Oncogénica/genética , Proteína 1 Compañera de Translocación de RUNX1/genética , Síndrome de Chediak-Higashi/diagnóstico , Niño , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/patología , Masculino , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patologíaRESUMEN
Although bone marrow failure in patients with dyskeratosis congenita (DKC) can be successfully treated with allogeneic hematopoietic cell transplantation (allo-HCT) using a reduced intensity conditioning (RIC) regimen, the outcome of nonhematological disorders in patients with DKC treated with allo-HCT using RIC has not been fully elucidated. Here, we describe the clinical course of nonhematological disorders after allo-HCT with RIC in 3 consecutive patients with DKC. Allo-HCT with RIC was feasible in all cases; however, patient 1 developed lethal pulmonary disease and patient 2 experienced progression of hepatic fibrosis. Careful follow-up of patient-specific complications is required after allo-HCT in patients with DKC.
