RESUMEN
Acute promyelocytic leukemia (APL) is a type of acute myeloid leukemia (AML) with a high mortality rate, and the production of PML-RARα fusion protein is the cause of its pathogenesis. Our group has synthesized a novel compound, 4-amino-2-trifluoromethyl-phenyl retinate (ATPR), by structural modification of All-trans retinoic acid (ATRA), which has strong cell differentiation-inducing effects and inhibits the expression of PML-RARα. In this study, acute promyelocytic leukemia NB4 cells before and after ATPR induction were analyzed by whole transcriptome microarray, and the expression of lncRNA CONCR was found to be significantly downregulated. The role of CONCR in ATPR-induced cell differentiation and cycle arrest was explored through overexpression and silencing of CONCR. And then the database was used to predict that CONCR may bind to DEAD/H-Box Helicase 11 (DDX11) protein to further explore the role of CONCR binding to DDX11. The results showed that ATPR could reduce the expression of CONCR, and overexpression of CONCR could reverse the ATPR-induced cell differentiation and cycle blocking effect, and conversely silencing of CONCR could promote this effect. RNA immunoprecipitation (RIP) experiments showed that CONCR could bind to DDX11, the protein expression levels of DDX11 and PML-RARα were elevated after overexpression of CONCR. These results suggest that ATPR can regulate the expression of DDX11 through CONCR to affect the expression of PML-RARα fusion protein, which in turn induces the differentiation and maturation of APL cells.
Asunto(s)
Puntos de Control del Ciclo Celular , Diferenciación Celular , ARN Helicasas DEAD-box , Leucemia Promielocítica Aguda , Proteínas de Fusión Oncogénica , ARN Largo no Codificante , Transducción de Señal , Humanos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Puntos de Control del Ciclo Celular/genética , Línea Celular Tumoral , ARN Helicasas DEAD-box/efectos de los fármacos , ARN Helicasas DEAD-box/genética , ARN Helicasas DEAD-box/metabolismo , Regulación Leucémica de la Expresión Génica , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/metabolismo , Leucemia Promielocítica Aguda/patología , Proteínas de Fusión Oncogénica/efectos de los fármacos , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , ARN Largo no Codificante/efectos de los fármacos , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Tretinoina/farmacologíaRESUMEN
TTMV::RARA is a recently reported fusion gene associated with acute promyelocytic leukemia (APL), caused by the integration of torque teno mini virus (TTMV) genomic fragments into the second intron of the RARA gene. Currently, there have been only six documented cases, with clinical presentations showing significant variability. Although initial responses to all-trans retinoic acid (ATRA) treatment may be observed in patients with TTMV::RARA-APL, the overall prognosis remains unfavorable among infrequent reported cases. This article presents a pediatric case that manifested as PML::RARA-negative APL with central nervous system involvement at onset. The patient experienced both intramedullary and extramedullary relapse one year after undergoing allogeneic hematopoietic stem cell transplantation. Upon identification as TTMV::RARA-APL and subsequent administration of two rounds of ATRA-based treatment, the patient rapidly developed multiple RARA ligand-binding domain mutations and demonstrated extensive resistance to ATRA and various other therapeutic interventions. Additionally, the patient experienced ARID1A mutant clone expansion and progressed MYC-targeted gene activation. This case represents the first documentation of extramedullary involvement at both the initial diagnosis and relapse stages, emphasizing the intricate clinical features and challenges associated with the rapid accumulation of multiple ATRA-resistant mutations in TTMV::RARA-APL, characterizing it as a distinct and complex sub-entity of atypical APL.
RESUMEN
This study reports a case of differentiation syndrome, a rare complication of ATRA (all-trans-retinoic-acid) therapy, observed in a 20-year-old male with acute promyelocytic leukemia (APML). Following the initiation of ATRA therapy for APML, the patient presented with fever, bleeding gums, bloody stool, and mouth ulcers. After 36 hours, he developed respiratory distress, hypotension, tachycardia, and hypoxemia, leading to the diagnosis of differentiation syndrome. ATRA therapy was promptly discontinued, and the patient, exhibiting type 1 respiratory failure, necessitated intubation. The management included hydroxyurea, dexamethasone, vasopressors, intravenous fluids, and furosemide. After seven days, significant improvement was observed, underscoring the importance of recognizing and promptly addressing differentiation syndrome in APML patients undergoing ATRA therapy. This case emphasizes the necessity of ATRA discontinuation, coupled with the judicious use of steroids and hydroxyurea, in the effective management of differentiation syndrome.
