RESUMEN
ABSTRACT: The switch from fetal hemoglobin (γ-globin, HBG) to adult hemoglobin (ß-globin, HBB) gene transcription in erythroid cells serves as a paradigm for a complex and clinically relevant developmental gene regulatory program. We previously identified HIC2 as a regulator of the switch by inhibiting the transcription of BCL11A, a key repressor of HBG production. HIC2 is highly expressed in fetal cells, but the mechanism of its regulation is unclear. Here we report that HIC2 developmental expression is controlled by microRNAs (miRNAs), as loss of global miRNA biogenesis through DICER1 depletion leads to upregulation of HIC2 and HBG messenger RNA. We identified the adult-expressed let-7 miRNA family as a direct posttranscriptional regulator of HIC2. Ectopic expression of let-7 in fetal cells lowered HIC2 levels, whereas inhibition of let-7 in adult erythroblasts increased HIC2 production, culminating in decommissioning of a BCL11A erythroid enhancer and reduced BCL11A transcription. HIC2 depletion in let-7-inhibited cells restored BCL11A-mediated repression of HBG. Together, these data establish that fetal hemoglobin silencing in adult erythroid cells is under the control of a miRNA-mediated inhibitory pathway (let-7 ⣠HIC2 ⣠BCL11A ⣠HBG).
Asunto(s)
Hemoglobina Fetal , Factores de Transcripción de Tipo Kruppel , MicroARNs , Proteínas Represoras , Humanos , Globinas beta/genética , Globinas beta/metabolismo , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , ARN Helicasas DEAD-box/genética , ARN Helicasas DEAD-box/metabolismo , Eritroblastos/metabolismo , Eritroblastos/citología , Hemoglobina Fetal/genética , Hemoglobina Fetal/metabolismo , gamma-Globinas/genética , gamma-Globinas/metabolismo , Regulación de la Expresión Génica , Factores de Transcripción de Tipo Kruppel/genética , Factores de Transcripción de Tipo Kruppel/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Ribonucleasa III/genética , Ribonucleasa III/metabolismo , Transcripción GenéticaRESUMEN
Glioblastoma (GBM) is the most malignant brain tumor in adults, with a dismal prognosis despite aggressive multi-modal therapy. Immunotherapy is currently being evaluated as an alternate treatment modality for recurrent GBMs in clinical trials. These immunotherapeutic approaches harness the patient's immune response to fight and eliminate tumor cells. Standard MR imaging is not adequate for response assessment to immunotherapy in GBM patients even after using refined response assessment criteria secondary to amplified immune response. Thus, there is an urgent need for the development of effective and alternative neuroimaging techniques for accurate response assessment. To this end, some groups have reported the potential of diffusion and perfusion MR imaging and amino acid-based positron emission tomography techniques in evaluating treatment response to different immunotherapeutic regimens in GBMs. The main goal of these techniques is to provide definitive metrics of treatment response at earlier time points for making informed decisions on future therapeutic interventions. This review provides an overview of available immunotherapeutic approaches used to treat GBMs. It discusses the limitations of conventional imaging and potential utilities of physiologic imaging techniques in the response assessment to immunotherapies. It also describes challenges associated with these imaging methods and potential solutions to avoid them.
Asunto(s)
Neoplasias Encefálicas/diagnóstico por imagen , Diagnóstico por Imagen , Glioblastoma/diagnóstico por imagen , Animales , Neoplasias Encefálicas/etiología , Neoplasias Encefálicas/terapia , Toma de Decisiones Clínicas , Terapia Combinada/efectos adversos , Terapia Combinada/métodos , Diagnóstico por Imagen/métodos , Diagnóstico por Imagen/normas , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Glioblastoma/etiología , Glioblastoma/terapia , Humanos , Inmunoterapia/efectos adversos , Inmunoterapia/métodos , Imagen por Resonancia Magnética , Tomografía de Emisión de Positrones , Pronóstico , Resultado del TratamientoRESUMEN
The evolving field of chimeric antigen receptor (CAR) T-cell therapy, though promising, necessitates more comprehensive imaging methods to enhance therapeutic effectiveness and track cell trafficking in patients and ex vivo. This review examines the application of PET imaging in CAR T-cell trafficking and optimizing their therapeutic impact. The application of PET imaging using various radiotracers is promising in providing evaluation of CAR T-cell interaction within the host, thereby facilitating strategies for improved patient outcomes. As this technology progresses, further innovative strategies to streamline assessments of immunotherapeutic effectiveness are anticipated.