CGG repeat expansions in LOC642361/NUTM2B-AS1 have recently been identified as a cause of oculo-pharyngeal myopathy with leukoencephalopathy.However,since only three patients from a single family were reported,it remains unknown whether their clinicopathological features are typical for CGG repeat expansions in LOC642361/NUTM2B-AS1.Here,using repeat-primed-polymerase chain reaction and long-read sequencing,we identify 12 individuals from 3 unrelated families With CGG repeat expansions in LOC642361/NUTM2B-AS1,typically presenting with oculopharyngodistal myopathy.The CGG repeat ex-pansions range from 161 to 669 repeat units.Most of the patients present with ptosis,restricted eye movements,dysphagia,dysarthria,and diffuse limb muscle weakness.Only one patient shows T2-weighted hyperintensity in the cerebellar white matter surrounding the deep cerebellar nuclei on brain magnetic resonance imaging.Muscle biopsies from three patients show a myopathic pattern and rimmed vacuoles.Analyses of muscle biopsies suggest that CGG repeat expansions in LOC642361/NUTM2B-AS1 may deleteriously affect aggrephagic capacity,suggesting that RNA toxicity and mitochondrial dysfunction may contribute to pathogenesis.Our study thus expands the phenotypic spectrum for the CGG repeat expansion of LOC642361/NUTM2B-AS1 and indicates that this genetic variant typically manifests as oculopharyngodistal myopathy with chronic myopathic changes with rimmed vacuoles and filamentous intranuclear inclusions in muscle fibers.

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is characterized by genetic alterations with high heterogeneity.Precise subtypes with distinct genomic and/or gene expression patterns have been recently revealed using high-throughput sequencing technology.Most of these profiles are associated with recurrent non-overlapping rearrangements or hotspot point mutations that are analogous to the established subtypes,such as DUX4 rearrangements,MEF2D rearrangements,ZNF384/ZNF362 rearrangements,NUTM1 rearrangements,BCL2/MYC and/or B CL6 rearrangements,ETV6-RUNX1-llke gene expression,PAX5alt (diverse PAX5 alterations,including rearrangements,intragenic amplifications,or mutations),and hotspot mutations PAX5 (p.Pro80Arg)with biallellc PAX5 alterations,IKZF1 (p.Asn159Tyr),and ZEB2 (p.His1038Arg).These molecular subtypes could be classified by gene expression patterns with RNA-seq technology.Refined molecular classification greatly improved the treatment strategy.Multiagent therapy regimens,including target inhibitors (e.g.,imatinib),immunomodulators,monoclonal antibodies,and chimeric antigen receptor T-cell (CAR-T) therapy,are transforming the clinical practice from chemotherapy drugs to personalized medicine in the field of risk-directed disease management.We provide an update on our knowledge of emerging molecular subtypes and therapeutic targets in BCP-ALL.

目的 探讨长链非编码RNA(lncRNA)NUTM2B-AS1在口腔鳞状细胞癌组织中的表达及对口腔鳞状细胞癌细胞侵袭和迁移的影响及分子机制.方法 采用癌症基因组图谱(The Cancer Genome Atlas,TCGA)数据库分析口腔鳞状细胞癌组织和癌旁组织中NUTM2B-AS1表达水平.qRT-PCR法检测口腔上皮角质细胞HOK、口腔鳞状细胞癌细胞系Cal-27、SCC-25、SCC-9、HSC-3中NUTM2B-AS1表达水平.Cal-27细胞分别转染NUTM2B-AS1过表达载体(pmirGLO-NUTM2B-AS1)和空载体(pmirGLO),记为NUTM2B-AS1组和对照组,qRT-PCR验证每组细胞中NUTM2B-AS1表达水平.Transwell侵袭实验和细胞划痕实验检测Cal-27细胞侵袭和迁移.生物信息学方法和双荧光素酶报告基因实验验证NUTM2B-AS1和miR-770-5p的靶向关系.qRT-PCR检测Cal-27细胞miR-770-5 p的表达,Western blot检测Cal-27细胞Sirt7/Smad4信号通路蛋白(Sirt7、E-cadherin、Smad4、MMP-7、Vimentin)的表达.结果 与癌旁组织比较,口腔鳞状细胞癌组织中NUTM2B-AS1表达显著降低(P<0.01).与HOK细胞比较,口腔鳞状细胞癌细胞系Cal-27、SCC-25、SCC-9、HSC-3中NUTM2B-AS1表达显著降低(P<0.01),Cal-27细胞中NUTM2B-AS1表达最低(P<0.01).与对照组比较,NUTM2B-AS1组Cal-27细胞中NUTM2B-AS1表达显著升高(P<0.01).与对照组比较,NUTM2B-AS1组Cal-27细胞侵袭数显著降低(P<0.01),Cal-27细胞划痕愈合率显著降低(P<0.01).miR-770-5p是NUTM2B-AS1的靶向结合基因(P<0.01).与对照组相比,NUTM2B-AS1组Cal-27细胞中miR-770-5p表达显著降低(P<0.01),Sirt7、E-cadherin蛋白表达显著升高(P<0.01),Smad4、MMP-7、Vimentin蛋白表达下降(P<0.01).结论 NUTM2B-AS1在口腔鳞状细胞癌组织和细胞系中低表达,高表达NUTM2B-AS1可抑制口腔鳞状细胞癌细胞侵袭和迁移,其作用机制与靶向下调miR-770-5 p表达有关.