BACKGROUND Primary squamous cell carcinoma(SCC)of the middle ear is rare,with nonkeratinizing basaloid types being exceptionally uncommon.Distinguishing these cancers,often caused by viral factors(e.g.,human papilloma...BACKGROUND Primary squamous cell carcinoma(SCC)of the middle ear is rare,with nonkeratinizing basaloid types being exceptionally uncommon.Distinguishing these cancers,often caused by viral factors(e.g.,human papillomavirus or Epstein-Barr virus),or specific genetic alterations(e.g.,bromodomain-containing protein 4-nuclear protein in testis fusion gene or Ewing sarcoma breakpoint region 1 gene fused with FLI chromosomal rearrangement),from other cranial conditions,is difficult.The recently identified DEK::AFF2 non-keratinizing SCC(NKSCC)is a novel subtype,fitting the World Health Organization classification of head and neck neoplasms.Less than 30 cases have been reported,highlighting the need for further studies.CASE SUMMARY A 55-year-old female patient first exhibited signs of illness over 10 years ago with persistent discomfort in the left external auditory canal,accompanied by skin irritation and bleeding.One month prior to seeking professional help,she experienced hearing loss and a sensation of obstruction in the affected ear,intermittently accompanied by ringing sounds,but no dizziness.An unusual mass was detected in the left auditory canal,confirmed through biopsy as moderately differentiated epithelial squamous cancer cells.This led to her admission to our hospital,where the final diagnosis confirmed as“NKSCC linked to a positive DEK::AFF2 fusion”.The patient underwent surgical excision,followed by three cycles of local radiation therapy.Yet,metastasis to the lumbar vertebrae occurred 19 months post-treatment,followed by neck lymph node swelling detected three months after a physical examination.The patient died nine months later despite surgical removal of the metastatic lesion.CONCLUSION DEK::AFF2 gene fusion-associated NKSCC of the middle ear carries a grim prognosis and presents an emerging challenge.展开更多
胰腺癌是消化道常见的恶性肿瘤之一,由于发病隐匿,早期多无症状,被发现时多为疾病晚期,且部分患者已有周围组织侵犯及其他脏器转移,错过最佳手术时机,因此预后极差。胰腺癌诊断主要借助影像学及血清标志物检查,治疗方案是早期手术切除,...胰腺癌是消化道常见的恶性肿瘤之一,由于发病隐匿,早期多无症状,被发现时多为疾病晚期,且部分患者已有周围组织侵犯及其他脏器转移,错过最佳手术时机,因此预后极差。胰腺癌诊断主要借助影像学及血清标志物检查,治疗方案是早期手术切除,术后行一系列辅助治疗,但临床效果显示胰腺癌患者生存期仍较短。有研究表明,miR-429存在于胰腺癌组织及血液中,胰腺癌中还存在XIST/miR-429轴,在分子水平上,AFF3与X-非活性特异性转录本(X-inactive specific transcript,XIST)相关,但AFF3与胰腺癌相关的报道却十分罕见。本文对miR-429与AFF3进行介绍,预测它们可能是胰腺癌的治疗靶点,有望成为胰腺癌诊断及预后标志物。展开更多
Six countries, 300 delegates, the AFF (Asian Fashion Federation) army has got bigger in size and this time set in a bigger location, too. China has successfully hosted the Third time running AFF con-
AFF1 and AFF4 belong to the AFF （AF4/FMR2） family of proteins, which function as scaffolding proteins linking two different transcription elongation factors, positive elongation factor b （P-TEFb） and ELL1/2, in su...AFF1 and AFF4 belong to the AFF （AF4/FMR2） family of proteins, which function as scaffolding proteins linking two different transcription elongation factors, positive elongation factor b （P-TEFb） and ELL1/2, in super elongation complexes （SECs）. Both AFF1 and AFF4 regulate gene transcription through elongation and chromatln remodeling. However, their function in the osteogenic differentiation of mesenchymal stem cells （MSCs） is unknown. In this study, we show that small interfering RNA （siRNA）-mediated depletion of AFF1 in human MSCs leads to increased alkaline phosphatase （ALP） activity, enhanced mineralization and upregulated expression of osteogenic-related genes. On the contrary, depletion of AFF4 significantly inhibits the osteogenic potential of MSCs. In addition, we confirm that overexpression of AFF1 and AFF4 differentially affects osteogenic differentiation in vitro and MSC-mediated bone formation in vivo. Mechanistically, we find that AFFI regulates the expression of DKK1 via binding to its promoter region. Depletion of DKK1 in HA-AFFl-overexpressing MSCs abrogates the impairment of osteogenic differentiation. Moreover, we detect that AFF4 is enriched in the promoter region of ID1. AFF4 knockdown blunts the BRE luciferase activity, SP7 expression and ALP activity induced by BMP2 treatment. In conclusion, our data indicate that AFF1 and AFF4 differentially regulate the osteogenic differentiation of human MSCs.AFF1 and AFF4 belong to the AFF （AF4/FMR2） family of proteins, which function as scaffolding proteins linking two different transcription elongation factors, positive elongation factor b （P-TEFb） and ELL1/2, in super elongation complexes （SECs）. Both AFFI and AFF4 regulate gene transcription through elongation and chromatln remodeling. However, their function in the osteogenic differentiation of mesenchymal stem cells （MSCs） is unknown. In this study, we show that small interfering RNA （siRNA）-mediated depletion of AFF1 in human MSCs leads to increased alkaline phosphatase （ALP） activity, enhanced mineralization and upregulated expression of osteogenic-related genes. On the contrary, depletion of AFF4 significantly inhibits the osteogenic potential of MSCs. In addition, we confirm that overexpression of AFF1 and AFF4 differentially affects osteogenic differentiation in vitro and MSC-mediated bone formation in vivo. Mechanistically, we find that AFFI regulates the expression of DKK1 via binding to its promoter region. Depletion of DKK1 in HA-AFFl-overexpressing MSCs abrogates the impairment of osteogenic differentiation. Moreover, we detect that AFF4 is enriched in the promoter region of ID1. AFF4 knockdown blunts the BRE luciferase activity, SP7 expression and ALP activity induced by BMP2 treatment. In conclusion, our data indicate that AFF1 and AFF4 differentially regulate the osteogenic differentiation of human MSCs.展开更多
The super elongation complex(SEC)containing positive transcription elongation factor b plays a critical role in regulating transcription elongation.AFF1 and AFF4,two members of the AF4/FMR2 family,act as central scaff...The super elongation complex(SEC)containing positive transcription elongation factor b plays a critical role in regulating transcription elongation.AFF1 and AFF4,two members of the AF4/FMR2 family,act as central scaffold proteins of SEC and are associated with various human diseases.However,their precise roles in transcriptional control remain unclear.Here,we investigate differences in the genomic distribution patterns of AFF1 and AFF4 around transcription start sites(TSSs).AFF1 mainly binds upstream of the TSS,while AFF4 is enriched downstream of the TSS.Notably,disruption of AFF4 results in slow elongation and early termination in a subset of AFF4-bound active genes,whereas AFF1 deletion leads to fast elongation and transcriptional readthrough in the same subset of genes.Additionally,AFF1 knockdown increases AFF4 levels at chromatin,and vice versa.In summary,these findings demonstrate that AFF1 and AFF4 function antagonistically to regulate RNA polymerase Ⅱ transcription.展开更多
文摘BACKGROUND Primary squamous cell carcinoma(SCC)of the middle ear is rare,with nonkeratinizing basaloid types being exceptionally uncommon.Distinguishing these cancers,often caused by viral factors(e.g.,human papillomavirus or Epstein-Barr virus),or specific genetic alterations(e.g.,bromodomain-containing protein 4-nuclear protein in testis fusion gene or Ewing sarcoma breakpoint region 1 gene fused with FLI chromosomal rearrangement),from other cranial conditions,is difficult.The recently identified DEK::AFF2 non-keratinizing SCC(NKSCC)is a novel subtype,fitting the World Health Organization classification of head and neck neoplasms.Less than 30 cases have been reported,highlighting the need for further studies.CASE SUMMARY A 55-year-old female patient first exhibited signs of illness over 10 years ago with persistent discomfort in the left external auditory canal,accompanied by skin irritation and bleeding.One month prior to seeking professional help,she experienced hearing loss and a sensation of obstruction in the affected ear,intermittently accompanied by ringing sounds,but no dizziness.An unusual mass was detected in the left auditory canal,confirmed through biopsy as moderately differentiated epithelial squamous cancer cells.This led to her admission to our hospital,where the final diagnosis confirmed as“NKSCC linked to a positive DEK::AFF2 fusion”.The patient underwent surgical excision,followed by three cycles of local radiation therapy.Yet,metastasis to the lumbar vertebrae occurred 19 months post-treatment,followed by neck lymph node swelling detected three months after a physical examination.The patient died nine months later despite surgical removal of the metastatic lesion.CONCLUSION DEK::AFF2 gene fusion-associated NKSCC of the middle ear carries a grim prognosis and presents an emerging challenge.
文摘胰腺癌是消化道常见的恶性肿瘤之一,由于发病隐匿,早期多无症状,被发现时多为疾病晚期,且部分患者已有周围组织侵犯及其他脏器转移,错过最佳手术时机,因此预后极差。胰腺癌诊断主要借助影像学及血清标志物检查,治疗方案是早期手术切除,术后行一系列辅助治疗,但临床效果显示胰腺癌患者生存期仍较短。有研究表明,miR-429存在于胰腺癌组织及血液中,胰腺癌中还存在XIST/miR-429轴,在分子水平上,AFF3与X-非活性特异性转录本(X-inactive specific transcript,XIST)相关,但AFF3与胰腺癌相关的报道却十分罕见。本文对miR-429与AFF3进行介绍,预测它们可能是胰腺癌的治疗靶点,有望成为胰腺癌诊断及预后标志物。
文摘Six countries, 300 delegates, the AFF (Asian Fashion Federation) army has got bigger in size and this time set in a bigger location, too. China has successfully hosted the Third time running AFF con-
基金supported by grants from the National Natural Science Foundation of China(NSFC,81722014,81571001,81500354,and 81621062)Sichuan Province Science and Technology Innovation Team Program(2017TD0016)State Key Laboratory of Oral Diseases(SKLOD201704)
文摘AFF1 and AFF4 belong to the AFF （AF4/FMR2） family of proteins, which function as scaffolding proteins linking two different transcription elongation factors, positive elongation factor b （P-TEFb） and ELL1/2, in super elongation complexes （SECs）. Both AFF1 and AFF4 regulate gene transcription through elongation and chromatln remodeling. However, their function in the osteogenic differentiation of mesenchymal stem cells （MSCs） is unknown. In this study, we show that small interfering RNA （siRNA）-mediated depletion of AFF1 in human MSCs leads to increased alkaline phosphatase （ALP） activity, enhanced mineralization and upregulated expression of osteogenic-related genes. On the contrary, depletion of AFF4 significantly inhibits the osteogenic potential of MSCs. In addition, we confirm that overexpression of AFF1 and AFF4 differentially affects osteogenic differentiation in vitro and MSC-mediated bone formation in vivo. Mechanistically, we find that AFFI regulates the expression of DKK1 via binding to its promoter region. Depletion of DKK1 in HA-AFFl-overexpressing MSCs abrogates the impairment of osteogenic differentiation. Moreover, we detect that AFF4 is enriched in the promoter region of ID1. AFF4 knockdown blunts the BRE luciferase activity, SP7 expression and ALP activity induced by BMP2 treatment. In conclusion, our data indicate that AFF1 and AFF4 differentially regulate the osteogenic differentiation of human MSCs.AFF1 and AFF4 belong to the AFF （AF4/FMR2） family of proteins, which function as scaffolding proteins linking two different transcription elongation factors, positive elongation factor b （P-TEFb） and ELL1/2, in super elongation complexes （SECs）. Both AFFI and AFF4 regulate gene transcription through elongation and chromatln remodeling. However, their function in the osteogenic differentiation of mesenchymal stem cells （MSCs） is unknown. In this study, we show that small interfering RNA （siRNA）-mediated depletion of AFF1 in human MSCs leads to increased alkaline phosphatase （ALP） activity, enhanced mineralization and upregulated expression of osteogenic-related genes. On the contrary, depletion of AFF4 significantly inhibits the osteogenic potential of MSCs. In addition, we confirm that overexpression of AFF1 and AFF4 differentially affects osteogenic differentiation in vitro and MSC-mediated bone formation in vivo. Mechanistically, we find that AFFI regulates the expression of DKK1 via binding to its promoter region. Depletion of DKK1 in HA-AFFl-overexpressing MSCs abrogates the impairment of osteogenic differentiation. Moreover, we detect that AFF4 is enriched in the promoter region of ID1. AFF4 knockdown blunts the BRE luciferase activity, SP7 expression and ALP activity induced by BMP2 treatment. In conclusion, our data indicate that AFF1 and AFF4 differentially regulate the osteogenic differentiation of human MSCs.
基金supported by grants from the National Key R&D Program of China(2018YFA0800100 to C.L.,2018YFA0800103 to Z.L.)the National Natural Science Foundation of China(32030017 and 31970617 to C.L.,31970626 to Z.L.)Shenzhen Science and Technology Program(JCYJ20210324133602008 to C.L.,JCYJ20210324133601005 to Z.L.).
文摘The super elongation complex(SEC)containing positive transcription elongation factor b plays a critical role in regulating transcription elongation.AFF1 and AFF4,two members of the AF4/FMR2 family,act as central scaffold proteins of SEC and are associated with various human diseases.However,their precise roles in transcriptional control remain unclear.Here,we investigate differences in the genomic distribution patterns of AFF1 and AFF4 around transcription start sites(TSSs).AFF1 mainly binds upstream of the TSS,while AFF4 is enriched downstream of the TSS.Notably,disruption of AFF4 results in slow elongation and early termination in a subset of AFF4-bound active genes,whereas AFF1 deletion leads to fast elongation and transcriptional readthrough in the same subset of genes.Additionally,AFF1 knockdown increases AFF4 levels at chromatin,and vice versa.In summary,these findings demonstrate that AFF1 and AFF4 function antagonistically to regulate RNA polymerase Ⅱ transcription.
