RESUMEN
Genetic heterogeneity is the basis of clinical heterogeneity among different subtypes of AML. We have successfully cloned a gene related to AML termed FAMLF from a FAB-M2 patient's sample of a second largest AML pedigree. Then we revealed at least three splice variants, named as FAMLF-1, FAMLF-2 and FAMLF-3, and found miR181a1/b1 in the second intron of FAMLF gene family. Higher expression of FAMLF-1 was related to a higher complete remission (CR) rate, but shorter relapse free survival (RFS) in AML. We further found that the FAMLF-1 single nucleotide polymorphism (SNP) haplotype and its expression were positively correlated to clinical parameters of acute myeloid leukemia partially differentiated (FAB-M2) patients, but not FAB non-M2 patients or Acute Monocytic Leukemia (FAB-M5) patients. GTAGG SNP haplotype of FAMLF gene might increase FAB-M2 susceptibility in Han population and act as a useful candidate biomarker for FAB-M2 screening. We also demonstrated that FAMLF-1 gene silencing in FAB-M2 cells could lead to proliferation inhibition, cell cycle G0/G1 phase arrest, and differentiation promotion independent of its intronic miR-181a1, which might be related to Akt/c-Myc pathway. These findings reveal a role of FAMLF-1 as a potential pathogenic gene for FAB-M2.
RESUMEN
Recent reports have described a new post-transcriptional regulation that RNA transcripts can crosstalk with each other by competing for their common microRNAs. These RNA transcripts termed competing endogenous RNAs (ceRNAs) regulate the distribution of miRNAs on their targets. One corollary from ceRNA interaction is that chromosomal translocation in acute promyelocytic leukemia (APL) would perturb ceRNA regulation due to altered expression of 3'UTRs. In our study, we demonstrate that expression of PML/RARα, the APL-associated fusion oncogene is repressed by c-Myc mRNA transcript independent of protein-coding function but dependent upon microRNA. Attenuation of c-Myc transcript results in PML/RARα-degraded cellular phenotypes in APL cells, but these Myc reduction-associated cell phenotypes are sufficient to abrogate in a microRNA dependent manner. We also show that let-7 microRNA family members promote differentiation of All-Trans-Retinoic Acid (ATRA)-induced NB4 cells and their activities are affected by expression levels of both c-Myc and PML/RARα through altering miRNA targets. These results indicate that c-Myc mRNA represses PML/RARα expression via altering the distribution of let-7 miRNAs on their targets. Our findings reveal a previously unrecognized role of c-Myc as a potential ceRNA for PML/RARα in APL.
Asunto(s)
Regulación Neoplásica de la Expresión Génica , Leucemia Promielocítica Aguda/genética , MicroARNs/metabolismo , Proteínas de Fusión Oncogénica/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , ARN Mensajero/metabolismo , Regiones no Traducidas 3'/genética , Antineoplásicos/farmacología , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Humanos , Leucemia Promielocítica Aguda/patología , Proteínas Proto-Oncogénicas c-myc/genética , Interferencia de ARN , ARN Mensajero/genética , ARN Interferente Pequeño/metabolismo , Translocación Genética , Tretinoina/farmacologíaAsunto(s)
Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Proteínas/genética , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Femenino , Regulación Leucémica de la Expresión Génica , Estudios de Asociación Genética , Humanos , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/terapia , Masculino , Persona de Mediana Edad , Pronóstico , Resultado del TratamientoRESUMEN
An inherited predisposition to acute myeloid leukaemia (AML) is exceedingly rare, but the investigation of these families will aid in the delineation of the underlying mechanisms of the more common, sporadic cases. Three AML predisposition genes, RUNX1, CEBPA and GATA2, have been recognised, but the culprit genes in the majority of AML pedigrees remain obscure. We applied a combined strategy of linkage analysis and next-generation sequencing (NGS) technology in an autosomal-dominant AML Chinese family with 11 cases in four generations. A genome-wide linkage scan using a 500K SNP genotyping array was conducted to identify a previously unreported candidate region on 20p13 with a maximum multipoint heterogeneity LOD (HLOD) score of 3.56 (P=0.00005). Targeted NGS within this region and whole-exome sequencing (WES) revealed a missense mutation in TGM6 (RefSeq, NM_198994.2:c.1550T>G, p.(L517W)), which cosegregated with the phenotype in this family, and was absent in 530 healthy controls. The mutated amino acid was located in a highly conserved position, which may be deleterious and affect the activation of TGM6. Our results strongly support the candidacy of TGM6 as a novel familial AML-associated gene.
Asunto(s)
Leucemia Mieloide Aguda/genética , Mutación Missense , Transglutaminasas/genética , Adulto , Estudios de Casos y Controles , Niño , Femenino , Humanos , Leucemia Mieloide Aguda/diagnóstico , Escala de Lod , Masculino , Persona de Mediana Edad , Linaje , Fenotipo , Polimorfismo de Nucleótido SimpleRESUMEN
OBJECTIVE: To investigate the efficacy of transabdominal rectopexy with mesh repair for adults with full-thickness rectal prolapse (II-III degree). METHODS: Between January 2005 and March 2009, 11 adult patients with full-thickness rectal prolapse (II-III degree) were treated by transabdominal rectopexy with mesh repair. Clinical data were analyzed retrospectively. RESULTS: Of the 11 cases of rectal prolapse, 7 cases were in II degree, 4 in III degree. Operative time ranged from 1.8 to 2.6 hours. Estimated blood loss during operation ranged from 50 to 300 ml. There was only one patient developed urinary retention postoperatively and no other complications were observed. After follow-up from 1 to 3 years, no recurrence was found. Patients had good anal function during the follow up. CONCLUSION: Transabdominal recopexy with mesh repair is a simple procedure with low recurrence rate.
