更新于：2024-09-19

BCOR

更新于：2024-09-19

基本信息

别名

BCL-6 corepressor、BCL6 corepressor、BCOR

+ [2]

简介

Transcriptional corepressor. May specifically inhibit gene expression when recruited to promoter regions by sequence-specific DNA-binding proteins such as BCL6 and MLLT3. This repression may be mediated at least in part by histone deacetylase activities which can associate with this corepressor. Involved in the repression of TFAP2A; impairs binding of BCL6 and KDM2B to TFAP2A promoter regions. Via repression of TFAP2A acts as a negative regulator of osteo-dentiogenic capacity in adult stem cells; the function implies inhibition of methylation on histone H3 'Lys-4' (H3K4me3) and 'Lys-36' (H3K36me2).

关联

100 项与 BCOR 相关的临床结果

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100 项与 BCOR 相关的转化医学

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0 项与 BCOR 相关的专利（医药）

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731

项与 BCOR 相关的文献（医药）

2024-12-31·Hematology

Next generation sequencing reveals the mutation landscape of Chinese MDS patients and the association between mutations and AML transformations

Article

作者: Ma, Jun ; Cheng, Mei ; Liu, Yu ; Gong, Tiejun ; Sun, Meng ; Cheng, Huanchen

BACKGROUND/OBJECTIVEApproximately 30% of patients with MDS eventually develop to acute myeloid leukemia (AML). Our study aimed to investigate the mutation landscape of Chinese MDS patients and identify the mutated genes which are closely implicated in the transformation of MDS to AML.METHODSIn total, 412 sequencing data collected from 313 patients were used for analysis. Mutation frequencies between different groups were compared by Fisher's exact. A predictive model for risk of transformation/death of newly diagnosed patients was constructed by logistic regression.RESULTSThe most frequently mutated genes in newly diagnosed patients were TP53, TET2, RUNX1, PIGA, and BCOR and mutations of RUNX1, TP53, BCORL1, TET2, and BCOR genes were more common in the treated MDS patients. Besides, we found that the mutation frequencies of IDH2, TET2, and EZH2 were significantly higher in MDS patients aged over 60 years. Moreover, two mutation sites, KRAS^G12A and TP53^H140N were detected only at transformation in one patient, while not detected at diagnosis. In addition, the mutation frequencies of EZH2 ^V704F and TET2 ^I1873N were stable from diagnosis to transformation in two patients. Finally, we constructed a predictive model for risk of transformation/death of newly diagnosed patients combing detected data of 10 genes and the number of to leukocyte, with a sensitivity of 63.3% and a specificity of 84.6% in distinguishing individuals with and without risk of transformation/death.CONCLUSIONIn summary, our study found several mutations associated with the transformation from MDS to AML, and constructed a predictive model for risk of transformation/death of MDS patients.

2024-12-01·Blood Research

What is new in acute myeloid leukemia classification?

Review

作者: Park, Hee Sue

AbstractRecently, the International Consensus Classification (ICC) and the 5th edition of the World Health Organization classification (WHO2022) introduced diagnostically similar yet distinct approaches, which has resulted in practical confusion. This review compares these classification systems for acute myeloid leukemia (AML), building up on the revised 4th edition of WHO (WHO2016). Both classifications retain recurrent genetic abnormalities as a primary consideration. However, they differ in terms of blast threshold. The ICC mandates a minimum of 10% blasts in the bone marrow or peripheral blood, whereas the WHO2022 does not specify a blast cut-off. AML with BCR::ABL1 requires > 20% blast count in both classifications. In WHO2022, AML with CEBPA mutation requires > 20% blasts. TP53 mutation, a new entity is exclusive to ICC, diagnosed with > 20% blasts and variant allele frequency > 10%. AML with myelodysplasia-related changes is defined by cytogenetic or gene mutation-based criteria, not morphological dysplasia. Eight genes were common to both groups: ASXL1, BCOR, EZH2, SF3B1, SRSF2, STAG2, U2AF1, and ZRSR2. An additional gene, RUNX1, was included in the ICC classification. AML cases defined by differentiation (WHO2022) and AML not otherwise specified (ICC) are categorized as lacking specific defining genetic abnormalities, WHO2022 labels this as a myeloid neoplasm post cytotoxic therapy (MN-pCT), described as an appendix after specific diagnosis. Similarly, in ICC, it can be described as “therapy-related”, without a separate AML category.

2024-10-01·Clinical Genetics

Novel molecular, structural and clinical findings in an Italian cohort of congenital cataract

Article

作者: Mazza, Marco ; Lecca, Mauro ; Del Longo, Alessandra ; Signorini, Sabrina ; Plumari, Massimo ; Gana, Simone ; Mauri, Lucia ; Galli, Jessica ; Morelli, Federica ; Cavallari, Ugo ; Sirchia, Fabio ; Valente, Enza Maria ; Errichiello, Edoardo ; Nicotra, Roberta

AbstractThe current genetic diagnostic workup of congenital cataract (CC) is mainly based on NGS panels, whereas exome sequencing (ES) has occasionally been employed. In this multicentre study, we investigated by ES the detection yield, mutational spectrum and genotype–phenotype correlations in a CC cohort recruited between 2020 and mid‐2022. The cohort consisted of 67 affected individuals from 51 unrelated families and included both non‐syndromic (75%) and syndromic (25%) phenotypes, with extra‐CC ocular/visual features present in both groups (48% and 76%, respectively). The functional effect of variants was predicted by 3D modelling and hydropathy properties changes. Variant clustering was used for the in‐depth assessment of genotype–phenotype correlations. A diagnostic (pathogenic or likely pathogenic) variant was identified in 19 out of 51 probands/families (~37%). In a further 14 probands/families a candidate variant was identified: in 12 families a VUS was detected, of which 9 were considered plausibly pathogenic (i.e., 4 or 5 points according to ACMG criteria), while in 2 probands ES identified a single variant in an autosomal recessive gene associated with CC. Eighteen probands/families, manifesting primarily non‐syndromic CC (15/18, 83%), remained unsolved. The identified variants (8 P, 12 LP, 10 VUS‐PP, and 5 VUS), half of which were unreported in the literature, affected five functional categories of genes involved in transcription/splicing, lens formation/homeostasis (i.e., crystallin genes), membrane signalling, cell–cell interaction, and immune response. A phenotype‐specific variant clustering was observed in four genes (KIF1A, MAF, PAX6, SPTAN1), whereas variable expressivity and potential phenotypic expansion in two (BCOR, NHS) and five genes (CWC27, KIF1A, IFIH1, PAX6, SPTAN1), respectively. Finally, ES allowed to detect variants in six genes not commonly included in commercial CC panels. These findings broaden the genotype–phenotype correlations in one of the largest CC cohorts tested by ES, providing novel insights into the underlying pathogenetic mechanisms and emphasising the power of ES as first‐tier test.

项与 BCOR 相关的新闻（医药）

2024-06-20

·信达生物

【学术前沿】STTT发表：信迪利单抗联合西达本胺为复发/难治结外NK/T细胞淋巴瘤提供治疗新选择

转载自：聊聊血液结外NK/T细胞淋巴瘤复发或难治性结外NK/T细胞淋巴瘤(RR-ENKTL)的预后较差，5年生存率不足30%。抗PD-1单抗在RR-ENKTL中可产生较高缓解率，但完全缓解率(CR)和反应持续时间(DOR)均有待提高，需要探索新的治疗方法与免疫疗法的结合。表观遗传药物与PD-1单抗具有协同作用，因此结合表观遗传学药物可能是一种潜在的治疗策略，以提高免疫治疗对RR-ENKTL的疗效。中山大学肿瘤防治中心黄慧强教授牵头一项1b/2期研究，评估了信迪利单抗联合西达本胺治疗38例RR-ENKTL患者的安全性和有效性，并探索性进行了生物标志物分析。研究结果近日发表于《Signal Transduction and Targeted Therapy》。研究方法&结果研究方法该研究为多中心、单臂、开放标签1b/2期研究，纳入18-75岁、组织学证实、天冬酰胺酶为基础方案或放化疗后复发或难治的ENKTL（WHO分类）。治疗期包括两个阶段，1b期和2期扩展期。剂量递增阶段采用标准3+3设计，确定第一周期西达本胺的最大耐受剂量（MTD）、剂量限制性毒性（DLT）和确定推荐的II期剂量(RP2D)。在1b期，患者接受每周2次递增剂量的口服西达本胺(20、25和30mg)，同时每21天静脉注射一次固定剂量的200mg信迪利单抗。在2期部分，患者每21天接受固定剂量的200mg 信迪利单抗+西达本胺(RP2D)。CR或PR患者继续联合治疗，直到疾病进展、死亡、无法耐受的毒性或撤回同意，最长12个月(18个总周期)；12个月后可选择维持治疗、停止治疗或移植。2期分为1个阶段，第1阶段入组7例患者，如果有4例患者缓解，则第2阶段继续入组21例患者，共28例。预期联合治疗的客观缓解率(ORR)为80%。患者特征共入组38例患者（治疗人群）并接受至少1剂治疗（图1）。所有38例患者均纳入安全性分析，意向治疗人群(n=37)包括31例疗效可评估、接受推荐的2期剂量(RP2D)治疗的患者。基线特征见表1。总体而言，中位年龄为43岁，25例(65.8%)筛查时为III-IV期，22例(57.9%) PINK-E评分≥3，17例(44.7%)既往接受过≥2线全身治疗。从末次治疗到本研究的中位时间为6.5个月。14例(36.8%)患者从末次治疗到入组的中位间隔时间小于3个月。疗效 1b期共9例患者，西达本胺20、25和30mg剂量组各3例，同时联合信迪利单抗固定剂量200 mg。未发生DLT，因此MTD为30mg，西达本胺的RP2D为30mg每周两次。2期部分有29例患者，接受西达本胺的RP2D联合信迪利单抗200mg。共32例患者接受西达本胺30mg治疗。在1b期，9例患者中有6例缓解(ORR：66.7%)，5例(55.6%)获得CR。在2期第一阶段入组8例患者，7例患者的疗效可评估；ORR为85.7%(6/7)，5例患者(71.4%)达到CR，超过了预定的第二阶段入组疗效边界。在2期所有28例2期患者中，16例获得缓解，ORR为57.1% (16/28)，CR率为46.4%(13/28)。在意向治疗人群(n=37)中，22例患者(59.5%)达到客观缓解，其中18例(48.6%)CR(表2)。10例患者接受过检查点抑制剂（ICI）(6例)或西达本胺(4例)治疗，信迪利单抗联合西达本胺治疗后，分别有6例(60.0%，6/10)和4例(40.0%，4/10)患者获得ORR和CR。中位随访38.7个月。在22例缓解患者中，中位至缓解时间(TTR)为1.5个月，中位DOR为25.3个月。接受治疗人群的中位PFS为23.2个月，中位OS为32.9个月 (图2a, b)，36个月 OS和PFS率分别为47.4% 和38.8%。获得CR或部分缓解(PR)的患者的生存率明显优于疾病稳定(SD)或进展性疾病(PD)的患者(图2c, d)。多因素分析显示，ECOG评分为2分(p=0.008)、骨髓受累(p=0.032)与较差的OS相关，ECOG评分为2 (p=0.018)、远处淋巴结受累(p=0.044)与PFS较差相关。2例(5.2%)患者接受信利迪单抗联合西达本胺作为维持治疗，没有患者接受自体造血干细胞移植(ASCT)(图3)。接受治疗的人群和缓解持续超过1年人群的中位周期分别为6和25。3例(7.8%)患者出现超进展(HPD)，HPD的中位OS为1.3个月。探索性生物标志物评估在28例可获得福尔马林固定石蜡包埋组织标本和外周血的患者中，有12例(42.8%)PD-L1表达超过50%，采用预测ORR的受试者工作特征(ROC)曲线确定截止值。综合阳性评分(CPS)中位值为50，截止值为32.5。中位肿瘤突变负荷(TMB)为5.6 mut/Mb，临界值为6.5 mut/Mb。治疗前外周血中常见(>10%)突变包括STAT3 (n=9)、BCOR (n=7)、DNMT3A (n=5)、ARID1A (n=4)、DDX3X (n=4)、KMT2D (n=4)、TP53 (n=4)、CHEK2 (n=3)和FAT1 (n=3)，见图4。单因素分析发现，PD-L1表达≥25%、CPS≥32.5、TMB <6.5Mb的患者ORR高于其他患者， TMB <6.5Mb与预后良好相关。对28例患者167份血浆样本进行动态循环肿瘤DNA (ctDNA)分析和定量，中位检测数为5。信迪利单抗联合西达本胺治疗未缓解的患者中ctDNA持续呈阳性。还评估了1年内动态血浆EB病毒(EBV)-DNA变化的作用，发现EBV-DNA在缓解患者中下降得更明显，直到检测不到，而未缓解的患者中EBV-DNA持续升高或保持不变。动态血浆ctDNA结合EBV-DNA比单独ctDNA或EBV-DNA可以更好地预测预后(图5a-f)。单因素分析显示，与OS显著相关的基因有STAT3 (p=0.014)、BOCR (p=0.001)、FAT1 (p=0.001)、EP300 (p=0.02)、KRAS (p=0.02)、CREBBP (p=0.01)、NSD1 (p=0.002)，与PFS显著相关的基因有STAT3 (p=0.006)、BCOR (p < 0.001)、PPM1D (p=0.02)、KRAS (p=0.02)、CREBBP (p=0.04)、NSD1 (p=0.003)、GNAS (p=0.05)。在多因素分析中，STAT3是OS和PFS的独立预后因素。收集了27例患者的治疗前基线血清T细胞淋巴细胞亚群和Th1/Th2细胞因子，发现下列患者从信迪利单抗联合西达本胺治疗中获益更多：CD4+/CD8+比值较高(>0.71)、CD19+较高 (>7.8)、CD3+CD8+较低(≤34)、血浆IL-6水平较低(≤2.5 pg/mL)、IL-10水平较低(≤8.5 pg/mL)。安全性治疗相关不良事件(TRAE)见表3。38例(100%)患者报告TRAE。最常见的TRAE(≥20%)包括中性粒细胞减少症(65.8%)、血小板减少症(44.7%)、贫血(44.7%)、甲状腺功能减退症(47.4%)、APTT缩短(39.5%)、低蛋白血症(36.8%)、转氨酶水平升高(26.3%)、恶心和呕吐(26.2%)、肌酸激酶升高(26.3%)、血浆纤维蛋白原升高(23.7%)和羟基丁酸脱氢酶升高(23.7%)。最常见的≥3级TRAE(≥10%)为中性粒细胞减少症(28.9%)和血小板减少症(10.5%)。18例(47.4%)患者报告免疫相关不良事件(irAE)，包括1例4级中毒性表皮坏死松解和1例间质性肺炎。最常见的irAE为1级甲状腺功能减退和皮疹。研究不推荐预防性药物治疗，也没有进行预防性药物治疗。联合治疗中未发现既往治疗的毒性明显增加。2例(5.3%)患者发生导致永久性停药的TRAE。没有死亡与研究药物有关。总结该1b/2期研究中，预期联合治疗的客观缓解率(ORR)为80%。患者接受递增剂量的西达本胺，与固定剂量信迪利单抗联合用药，周期21天，最长可达12个月。未观察到剂量限制性毒性，西达本胺的RP2D为30mg每周2次。2期研究部分共纳入29例患者。在意向治疗人群(n=37)中，ORR为59.5%，CR率为48.6%。中位DOR、PFS和OS分别为25.3个月、23.2个月和32.9个月。最常见的≥3级TRAE为中性粒细胞减少症(28.9%)和血小板减少症(10.5%)，18例(47.3%)患者报告与免疫相关AE。探索性生物标志物评估表明，动态血浆ctDNA结合EBV-DNA在预后中起着重要作用。此外STAT3突变预后不良。虽然没有达到预期的ORR，但信迪利单抗联合西达本胺具有可控的安全性，并且首次在RR-ENKTL中产生较高的CR率和DOR。对于这一人群来说，信迪利单抗联合西达本胺是一种很有前途的治疗选择，表观遗传调节剂与抗pd -1单抗协同作用可显著增强RR-ENKTL治疗的抗肿瘤效果。此外动态血浆ctDNA联合EBV-DNA可发挥重要的预后作用。参考文献 Gao, Y., He, H., Li, X. et al. Sintilimab (anti-PD-1 antibody) plus chidamide (histone deacetylase inhibitor) in relapsed or refractory extranodal natural killer T-cell lymphoma (SCENT): a phase Ib/II study. Sig Transduct Target Ther 9, 121 (2024). https://doi-org.libproxy1.nus.edu.sg/10.1038/s41392-024-01825-0 本文旨在为医疗卫生专业人士传递更多医学信息，不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，信达不推荐任何未获批的药品/适应症使用。

免疫疗法临床2期临床结果

2024-06-06

·PMLiVE

ICR researchers identify new treatment pathway for rare set of childhood brain tumours

Researchers from the Institute of Cancer Research (ICR) have identified a new treatment pathway for a rare set of childhood brain tumours known as gliomatosis cerebri. Published in the journal Neuro-Oncology and funded by the Rudy A Menon Foundation and the Ollie Young Foundation, the decade-long study could lead to more effective treatments to treat this set of conditions. Affecting approximately 100 people every year in the US, gliomatosis cerebri is a highly aggressive form of glioma that presents as a spider’s web of cancer threads that spread deep into the brain. No chemotherapy has proven to be effective when treating this form of brain cancer, which is almost impossible to remove with surgery and is difficult to treat with radiotherapy. Carried out by the High-Grade Glioma Working Group on behalf of the International Society for Paediatric Oncology Europe, researchers collected brain tissue samples to carry out the study involving 104 children and adolescents living with the disease. The team used tumour profiling to understand what molecules are driving cancer and was able to identify a molecular profile for gliomatosis cerebri. The results revealed two subtypes known as pedHGG_RTK2A/B and pedHGG_A/B, which were both associated with paediatric gliomatosis cerebri. In addition, researchers revealed that mutations in the epidermal growth factor receptor protein and the BCOR gene, along with rearrangements of chromosome 6, were the most common genetic features. Findings from the study could help researchers identify potential drug targets for this condition. Chris Jones, professor of childhood brain tumour biology, ICR, commented: “We demonstrated that gliomatosis cerebri tumours behave very aggressively and differ from other types of gliomas found in children. “Contrary to previous research, the… study has shown that there are distinct molecular and clinical features of gliomatosis cerebri and this provides evidence that it ought to be re-considered as a separate entity.” Co-founder of the Rudy A Menon Foundation, Vidhu Menon, said that this “research has led to significant progress” and “will become the cornerstone for further understanding and finding effective treatments for this disease globally”.

临床结果

2024-05-28

·奇点网

《自然·免疫学》：哮喘治愈性疗法重大突破！清华团队开发出新型“永生”CAR-T，双管齐下抗哮喘，有望实现一次治疗长期有效

*仅供医学专业人士阅读参考这个CAR-T细胞，感觉有点东西。今天，清华大学彭敏课题组在《自然·免疫学》杂志发表论文，研究者们搞出来的这个5TIF4细胞，可真是一副武功大成的模样。通过基因修饰，5TIF4细胞实现了集干性和功能性于一身，拥有类似诱导多能干细胞的无限自我更新能力，可在体内终生存在，因此续航力超强，实验中单次输注能维持至少1年。疗效上，5TIF4细胞瞄准了嗜酸性粒细胞和IL4/IL13两大重度哮喘关键病理，可持久抑制肺部炎症、预防哮喘发作。精彩啊。论文题图5TIF4细胞，名字长得有点复杂，根据功能各取一字，好单纯好不做作好不一目了然，咱们拆开来看都是啥意思。TIF细胞是研究者们此前已经发表在JEM的研究成果。TIF细胞通过CRISPR敲除了T细胞中的BCOR和ZC3H12A两个基因，这两个基因与mRNA衰变和转录抑制有关。敲除后的TIF细胞因此获得了类似诱导多功能干细胞（iPSC）的无限自我更新能力，可在体内终生存在。优秀的是，在获得了干性的同时，TIF细胞也很好地保留了T细胞的功能性，这个IF指的就是“类永生化功能性”（Immortal-like and Functional）。这样，5TIF4细胞同时解决了CAR-T细胞寿命和必须基于化疗的预处理两大难点。5TIF4细胞里剩下的5和4就来自它的作用机制了。大多数哮喘源自过敏性气道炎症，2型炎症因子是病理关键，如驱动嗜酸性粒细胞炎症的IL-5、与粘液产生和气道高反应性有关的IL-4和IL-13。5TIF4细胞中的5指的就是IL-5 CAR，使5TIF4细胞可以识别和杀死表达IL-5R的嗜酸性粒细胞。这与重症哮喘生物制剂benralizumab的机制是类似的。5TIF4细胞的IL-5 CAR5TIF4细胞的4，指的是5TIF4细胞可以分泌一种IL-4蛋白突变体，可结合并沉默IL-4Rα，IL-4Rα同时是IL-4和IL-13的信号受体。这条通路的有效性已经在过敏领域重磅药物度普利尤单抗身上得到了验证。不过IL-4蛋白突变体本身因为半衰期太短，治疗效果并不好。IL-4突变蛋白的作用通路接下来，研究者们在卵清蛋白（OVA）诱导的小鼠哮喘模型中进行了实验。单次注射5TIF4细胞即可有效减少小鼠气道超敏反应和组织病理。实验设计5TIF4细胞有效缓解哮喘持续给予小鼠OVA刺激诱导慢性哮喘，6个月内，5TIF4细胞都能有效存续并抑制肺部炎症。5TIF4细胞对慢性哮喘有长期疗效研究者在给小鼠输注5TIF4细胞后监测了一年，期间小鼠身体状况良好，证实了5TIF4细胞的长期安全性。同时，小鼠体内嗜酸性粒细胞水平也持续保持在低水平。使用屋尘螨（HDM）作为过敏原诱导的哮喘小鼠，同样可被5TIF4细胞有效治疗。在研究的最后，研究者也在人类T细胞中验证了工程改造的可行性，但同期配发的评论文章中，有学者指出，临床转化之前还需要更多安全性考量。人类肺纤毛细胞的部分亚群同样表达IL-5R，这些重要的屏障细胞被误伤绝不是好事；同样的，B1细胞中也有IL-5R表达，这可能会带来自身免疫或癌症的风险。TIF细胞“永生”的阴暗面也未能完全排除。此前有研究发现，体细胞BCOR缺失或失活与人类和小鼠的T细胞癌症/霍奇金淋巴瘤发展有关。目前，以2型炎症因子为靶点的生物制剂已经在临床上开始了广泛应用，但这些药物并没有一种能够真正改变疾病进程，也无法停药。脱敏疗法则因不良反应风险并不适用于重度哮喘。5TIF4细胞带来的长期疗效是患者所期望的，而从花费方面考虑，生物制剂属于较贵的药物，长远来看就算是昂贵的CAR-T细胞说不定也能成为经济之选。参考资料：[1]https://www-nature-com.libproxy1.nus.edu.sg/articles/s41590-024-01834-9[2]https://www-nature-com.libproxy1.nus.edu.sg/articles/s41590-024-01851-8[3]https://www-tsinghua-edu-cn.libproxy1.nus.edu.sg/info/1175/111775.htm本文作者丨代丝雨

免疫疗法细胞疗法