RESUMEN
Transcriptional regulators are recurrently altered through translocations, deletions, or aberrant expression in acute myeloid leukemia (AML). Although critically important in leukemogenesis, the underlying pathogenetic mechanisms they trigger remain largely unknown. Here, we identified that Id1 (inhibitor of DNA binding 1) plays a pivotal role in acute myeloid leukemogenesis. Using genetically modified mice, we found that loss of Id1 inhibited t(8;21) leukemia initiation and progression in vivo by abrogating protein kinase B (AKT)1 activation, and that Id1 interacted with AKT1 through its C terminus. An Id1 inhibitor impaired the in vitro growth of AML cells and, when combined with an AKT inhibitor, triggered even greater apoptosis and growth inhibition, whereas normal hematopoietic stem/progenitor cells were largely spared. We then performed in vivo experiments and found that the Id1 inhibitor significantly prolonged the survival of t(8;21)(+) leukemic mice, whereas overexpression of activated AKT1 promoted leukemogenesis. Thus, our results establish Id1/Akt1 signaling as a potential therapeutic target in t(8;21) leukemia.
Asunto(s)
Proteína 1 Inhibidora de la Diferenciación/metabolismo , Leucemia Mieloide Aguda/etiología , Leucemia Mieloide Aguda/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Animales , Apoptosis , Carcinogénesis , Línea Celular Tumoral , Progresión de la Enfermedad , Técnicas de Silenciamiento del Gen , Humanos , Proteína 1 Inhibidora de la Diferenciación/deficiencia , Proteína 1 Inhibidora de la Diferenciación/genética , Proteínas Inhibidoras de la Diferenciación/antagonistas & inhibidores , Proteínas Inhibidoras de la Diferenciación/genética , Leucemia Mieloide Aguda/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Dominios y Motivos de Interacción de Proteínas , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Transducción de Señal , Translocación GenéticaRESUMEN
Management of higher-risk myelodysplastic syndromes (HR-MDS) is challenging in the real world. We studied 200 patients with HR-MDS within a large US community hospital network. We describe the clinical presentation, patient-related factors, prognostic characteristics, treatment patterns, clinical outcomes and resource utilization. Patients with HR-MDS, treated in our community setting, were elderly (median age 76 years) with a high comorbidity burden. First-line therapy was hypomethylating agent (HMA) monotherapy (20%), lenalidomide (2%), and venetoclax (2%), while the rest were treated with supportive care. Sixty-one percent of the 200, were subsequently hospitalized within 6 months of initial diagnosis. Overall survival was 11.8 months. Curative transplantation was infrequent, HMA-based therapy was underutilized, responses were not durable, most patients became transfusion-dependent or transformed to AML, and resource utilization was substantial and was highly correlated with total in-hospital days. There is a clear unmet need for tolerable treatments that can produce durable remissions in this population.