更新于：2024-05-01

RUNX1T1

RUNX1 partner transcriptional co-repressor 1

更新于：2024-05-01

基本信息

别名

AML1T1、CBFA2T1、CDR

+ [11]

简介

Transcriptional corepressor which facilitates transcriptional repression via its association with DNA-binding transcription factors and recruitment of other corepressors and histone-modifying enzymes (PubMed:12559562, PubMed:15203199, PubMed:10688654). Can repress the expression of MMP7 in a ZBTB33-dependent manner (PubMed:23251453). Can repress transactivation mediated by TCF12 (PubMed:16803958). Acts as a negative regulator of adipogenesis (By similarity). The AML1-MTG8/ETO fusion protein frequently found in leukemic cells is involved in leukemogenesis and contributes to hematopoietic stem/progenitor cell self-renewal (PubMed:23812588).

关联

100 项与 RUNX1T1 相关的临床结果

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100 项与 RUNX1T1 相关的转化医学

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0 项与 RUNX1T1 相关的专利（医药）

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1,087

项与 RUNX1T1 相关的文献（医药）

2024-02-14·Nature communications

Leukemic stem cells activate lineage inappropriate signalling pathways to promote their growth.

Article

作者: Sophie G Kellaway ; Sandeep Potluri ; Peter Keane ; Helen J Blair ; Luke Ames ; Alice Worker ; Paulynn S Chin ; Anetta Ptasinska ; Polina K Derevyanko ; Assunta Adamo ; Daniel J L Coleman ; Naeem Khan ; Salam A Assi ; Anja Krippner-Heidenreich ; Manoj Raghavan ; Peter N Cockerill ; Olaf Heidenreich ; Constanze Bonifer

Acute Myeloid Leukemia (AML) is caused by multiple mutations which dysregulate growth and differentiation of myeloid cells. Cells adopt different gene regulatory networks specific to individual mutations, maintaining a rapidly proliferating blast cell population with fatal consequences for the patient if not treated. The most common treatment option is still chemotherapy which targets such cells. However, patients harbour a population of quiescent leukemic stem cells (LSCs) which can emerge from quiescence to trigger relapse after therapy. The processes that allow such cells to re-grow remain unknown. Here, we examine the well characterised t(8;21) AML sub-type as a model to address this question. Using four primary AML samples and a novel t(8;21) patient-derived xenograft model, we show that t(8;21) LSCs aberrantly activate the VEGF and IL-5 signalling pathways. Both pathways operate within a regulatory circuit consisting of the driver oncoprotein RUNX1::ETO and an AP-1/GATA2 axis allowing LSCs to re-enter the cell cycle while preserving self-renewal capacity.

2024-01-24·Experimental hematology & oncology

A novel AML1-ETO/FTO positive feedback loop promotes leukemogenesis and Ara-C resistance via stabilizing IGFBP2 in t(8;21) acute myeloid leukemia.

Article

作者: Wei Zhou ; Siying Li ; Hong Wang ; Jingfeng Zhou ; Shuyi Li ; Guofeng Chen ; Wei Guan ; Xianli Fu ; Clara Nervi ; Li Yu ; Yonghui Li

BACKGROUND:

t(8;21)(q22;q22) is one of the most frequent chromosomal abnormalities in acute myeloid leukemia (AML), leading to the generation of the fusion protein AML1-ETO. Despite t(8;21) AML being considered as a subtype with a favorable prognosis, approximately 30-50% of patients experience drug resistance and subsequent relapse. N⁶-methyladenosine (m⁶A) is demonstrated to be involved in the development of AML. However, the regulatory mechanisms between AML1-ETO and m⁶A-related enzymes and the roles of dysregulated m⁶A modifications in the t(8;21)-leukemogenesis and chemoresistance remain elusive.

METHODS:

Chromatin immunoprecipitation, dual-luciferase reporter assay, m⁶A-qPCR, RNA immunoprecipitation, and RNA stability assay were used to investigate a regulatory loop between AML1-ETO and FTO, an m⁶A demethylase. Gain- and loss-of-function experiments both in vitro and in vivo were further performed. Transcriptome-wide RNA sequencing and m⁶A sequencing were conducted to identify the potential targets of FTO.

RESULTS:

Here we show that FTO is highly expressed in t(8;21) AML, especially in patients with primary refractory disease. The expression of FTO is positively correlated with AML1-ETO, which is attributed to a positive regulatory loop between the AML1-ETO and FTO. Mechanistically, AML1-ETO upregulates FTO expression through inhibiting the transcriptional repression of FTO mediated by PU.1. Meanwhile, FTO promotes the expression of AML1-ETO by inhibiting YTHDF2-mediated AML1-ETO mRNA decay. Inactivation of FTO significantly suppresses cell proliferation, promotes cell differentiation and renders resistant t(8;21) AML cells sensitive to Ara-C. FTO exerts functions by regulating its mRNA targets, especially IGFBP2, in an m⁶A-dependent manner. Regain of Ara-C tolerance is observed when IGFBP2 is overexpressed in FTO-knockdown t(8;21) AML cells.

CONCLUSION:

Our work reveals a therapeutic potential of targeting AML1-ETO/FTO/IGFBP2 minicircuitry in the treatment for t(8;21) patients with resistance to Ara-C.

2024-01-23·Genes

Dysregulation of the Skin-Liver Axis in Prurigo Nodularis: An Integrated Genomic, Transcriptomic, and Population-Based Analysis.

Article

作者: Melika Marani ; Vrinda Madan ; Thomas K Le ; Junwen Deng ; Kevin K Lee ; Emily Z Ma ; Shawn G Kwatra

Pruritus has long been linked to hepatic dysfunction; however, there are limited data characterizing the association between liver disease and prurigo nodularis (PN), a chronic inflammatory skin disease featuring severe pruritis. We thus conducted a cross-sectional analysis of hepatic comorbidities in PN patients using TriNetX, a large global health research network. This analysis revealed that PN patients had a higher risk (p < 0.001) of developing liver cirrhosis, acute and subacute hepatic failure, inflammatory liver disease, chronic hepatitis, nonalcoholic steatohepatitis, portal hypertension, fatty liver, chronic passive congestion of the liver, and hepatocellular carcinoma compared with healthy controls. The cumulative incidence of liver disease was about three times higher in PN patients compared with healthy controls. These findings provided the basis for translational studies to investigate a genetic mechanism for this association. Cutaneous transcriptomic analysis performed on PN patients revealed the dysregulation of genes related to hepatic failure in lesional PN compared with both nonlesional PN and control skin. Similarly, gene set variation analysis (GSVA) revealed a significantly increased (p < 0.05) activation of liver metabolism, chronic hepatic failure, acute hepatic failure, cholestatic liver disease, polycystic liver disease, and hepatocellular carcinoma pathways in lesional PN compared with control skin. A subsequent genome-wide association study (GWAS) identified shared single-nucleotide polymorphisms (SNPs) in the genes AR, EDIL3, MACROD2, PCSK5, RUNX1T1, TENM4, and ZEB2 between PN and liver disease from the FinnGen cohort. Significant dysregulation of the skin-liver axis in PN patients may explain the increased incidence and severity of hepatic comorbidities and help identify future therapeutic targets for PN.

项与 RUNX1T1 相关的新闻（医药）

2023-08-11

·生物谷

研究揭示骨髓微环境中ID1调控急性髓系白血病起始与进展新机制

该研究揭示了骨髓微环境中ID1通过促进ANGPTL7的表达调控白血病的发生发展，揭示了AML细胞通过分泌BMP6促进骨髓微环境中ID1的表达。这条骨髓微环境和AML细胞相互影响的环路或对临床AML治疗中国科学院上海营养与健康研究所王兰研究组在Blood上，在线发表了题为The cell non-autonomous function of ID1 promotes AML progression via ANGPTL7 from the microenvironment的研究成果。该研究揭示了骨髓微环境中转录调控因子ID1对急性髓系白血病（Acute myeloid leukemia，AML）起始与进展的关键作用，为急性髓系白血病（AML）治疗提供了新的思路和策略。 AML是起源于造血干/祖细胞的恶性疾病。它的特征是髓系前体细胞恶性克隆性增殖和分化为成熟血细胞的能力受阻。AML是常见的成人白血病，高度的异质性影响疾病预后与转归。目前，AML的诊疗随着药物和方法的更新已取得较大进步，但亟需提高对AML发生机制的认识，并开发新的治疗方法。 AML的发生发展往往伴随基因的异常表达。前期研究显示，ID1是致病融合蛋白AML1-ETO的直接靶基因，在白血病细胞中显著高表达。白血病细胞中ID1与AKT1发生直接相互作用促进AKT1的磷酸化，进而加速AML1-ETO驱动白血病的起始与进展。ID1在模拟儿童白血病的MLL-AF9驱动的白血病胎肝移植小鼠模型与模拟成人白血病的MLL-AF9驱动的白血病骨髓移植小鼠模型中具有相反功能。ID1促进儿童MLL-AF9驱动白血病干细胞的自我更新，抑制成人MLL-AF9驱动白血病的发生。研究发现，ID1在AML患者来源的骨髓间充质干细胞中高表达。这种高表达在AML1-ETO和MLL-AF9融合蛋白相关的白血病中更为显著。为了探讨AML骨髓微环境中ID1表达升高的原因，研究分析ChIP-seq发现，致病融合蛋白AML1-ETO和MLL-AF9直接结合于BMP6的启动子区域。科研人员在AML细胞中敲低BMP6，随后将这些细胞与基质细胞共培养。结果显示，AML细胞中BMP6的低表达显著降低了与之共培养的基质细胞中ID1的表达，表明AML细胞通过分泌BMP6促进基质细胞中ID1的表达。研究通过小鼠移植实验发现，在Id1缺失受体中，AML1-ETO9a和MLL-AF9诱导的AML起始与进展显著延缓，白血病干细胞的自我更新能力出现显著抑制。研究通过体外共培养实验发现，骨髓基质细胞中ID1缺失可显著抑制与之共培养的AML细胞的增殖并引起周期阻滞。机制上，研究利用定量蛋白组学分析了AML受体小鼠的骨髓液发现，骨髓微环境中Id1调控分泌型糖蛋白Angptl7表达加速了白血病的发生发展。研究表明，ANGPTL7可促进白血病干细胞的自我更新。科研人员向体外共培养系统中添加ANGPTL7重组蛋白发现，ID1缺失引起的AML细胞增殖抑制和周期阻滞现象得到明显逆转；通过向AML受体骨髓腔输注Angptl7重组蛋白发现，Id1缺失引起的AML受体白血病干细胞减少和生存期延缓现象得到明显逆转。为了进一步探究ID1如何调控ANGPTL7的表达，研究通过质谱分析与免疫共沉淀等实验发现，ID1羧基端与RNF4氨基端的SIM结构域发生直接相互作用。RNF4是SP1的E3泛素连接酶，ID1与RNF4相互作用显著抑制RNF4对SP1的泛素化修饰，从而维持了SP1蛋白水平。SP1是ANGPTL7的转录因子，因此AML骨髓微环境中ID1通过抑制RNF4-SP1相互作用促进了ANGPTL7的表达，从而影响AML的发生发展。该研究揭示了骨髓微环境中ID1通过促进ANGPTL7的表达调控白血病的发生发展，揭示了AML细胞通过分泌BMP6促进骨髓微环境中ID1的表达。这条骨髓微环境和AML细胞相互影响的环路或对临床AML治疗具有指导意义。研究工作获得国家重点研发计划、国家自然科学基金、上海市科技创新行动计划和营养与健康所公共技术平台等的支持。上海交通大学医学院附属瑞金医院、上海交通大学附属第六人民医院、上海交通大学医学院附属上海儿童医学中心、大连医科大学附属第二医院和复旦大学附属肿瘤医院的科研人员参与研究。骨髓微环境中ID1调控AML的分子机制示意图

临床研究临床结果

2023-03-25

·药时代

PARP抑制剂耐药机制以及解决耐药性方法

1DNA双链断裂（DSB）修复途径合成致死性是诱导细胞死亡的生物过程，其基于同时抑制在细胞存活所需的过程中的两种途径并行作用，仅抑制一种途径会导致细胞存活。合成致死策略已在抗癌治疗中得到广泛应用。由于一种途径可能由于转化相关变化而在癌细胞中失活，因此靶向另一种途径触发细胞死亡，同时保留健康细胞1。癌细胞的关键特征之一是由DNA损伤的积累，包括DNA双链断裂（DSB），这是细胞中最致命的DNA损伤之一。然而，癌细胞能够通过调节其DNA修复途径存活和增殖，这可能与正常细胞中的DNA修复途径不同1。DSB可以通过两种主要机制进行修复：BRCA1/2介导的同源重组（HR）和典型 DNA-PKcs介导的非同源末端连接（c-NHEJ）（图1）1。HR被认为是一种准确的DSB修复途径，因为它依赖于细胞周期S/G2期细胞的姐妹染色单体作为DNA合成和DSB修复的模板。因此，HR能够修复DSB，主要在增殖细胞中1。HR修复途径由两个经典的肿瘤抑制基因BRCA1和BRCA2编码的蛋白质进行全面调节，然后募集RAD51及其旁系同源物（包括RAD51B，RAD51C，RAD51D，XRCC2和XRCC3）和RAD54以识别同源DNA模板并进行链侵袭以修复DSBs。另一方面，NHEJ是一种容易出错的DSB修复机制。NHEJ可以是分为c-NHEJ和a-NHEJ（也称为MMEJ或TMEJ）两种途径1。图1. DNA双链断裂（DSB）修复途径包括同源重组（HR），规范非同源末端连接（c-NHEJ）和替代非同源末端连接（a-NHEJ）/微同源介导的末端连接（MMEJ）/DNA聚合酶θ（Polθ）介导的末端连接（TMEJ）2PARPi在造血恶性肿瘤中的治疗潜力最近的很多研究表明，即使在白血病中很少检测到BRCA1/2突变，PARP抑制剂（PARPi）诱导的合成致死性也可以有效地在 BRCA1/2 缺陷造血恶性细胞中起作用。此外，诱导造血恶性肿瘤的遗传改变，例如驱动骨髓和淋巴恶性肿瘤的癌基因，包括 AML1-ETO（也称为 RUNX1-RUNX1T1）、BCR-ABL1、PML-RARa、TCF3-HLF、IDH1/2mut和IGH-MYC以及肿瘤抑制基因（例如TET2、WT1）的功能缺失突变可导致HR和/或c-NHEJ活性失调，从而使细胞容易受到PARPi引发的合成致死效应的影响（图2和图3）1。图2. PARP抑制剂在造血恶性肿瘤和其他显示癌基因/突变（A）和酪氨酸激酶抑制剂（B）诱导的HR/c-NHEJ缺乏症的肿瘤中的应用此外，Bac等人描述了那些恶性造血细胞表达致癌酪氨酸激酶（OTK）（例如 BCR-ABL1、FLT3（ITD）、JAK2（V617F））由于ROS产量增加自发积累高水平的氧化DNA损伤和DSB 1。然而，OTK阳性细胞能够逃逸来自 DSB 的细胞毒性作用，这是由于增强/调节的 DSB 修复。FDA批准的特异性酪氨酸激酶抑制剂（TKi）（JAK1/2抑制剂鲁索利替尼，FLT3抑制剂奎扎替尼，ABL1抑制剂伊马替尼）对这些OTK的抑制导致急性HR / c-NHEJ缺乏症（由于BRCA1，BRCA2，RAD51和/或LIG4的下调）和对PARPi的敏感性（图2-4）。因此，TKi和PARPi的联合使用能够根除增殖和静止的恶性造血干细胞和祖细胞1。图3. 诱发HR / c-NHEJ缺乏症的癌基因/突变图4. 诱导HR/c-NHEJ缺乏的治疗药物3对PARPi的获得性耐药机制尽管 PARPi 在 DSB 修复缺陷的癌细胞中具有很强的效力，但在BRCA1/2 缺陷和 HRD 中已经报道了对 PARPi 诱导的合成致死性的抵抗力肿瘤细胞（图5）。PARPi的耐药性的主要原因是BRCA1/2突变癌细胞HR修复活性的恢复2。详细地说，BRCA1/2中的继发突变与原始突变导致的链终止子/移码的废除有关，导致全长 BRCA1/2 开放阅读框的恢复。因此，活性BRCA1/BRCA2蛋白表达被恢复，从而重新启动功能齐全的HR途径3,4。除了BRCA1/2中其他突变介导的耐药性外，还提出了BRCA1启动子甲基化的减少/丧失，从而恢复了BRCA1的表达而导致对PARPi的耐药性5。图5. 对PARPi的获得性耐药机制BRCA1-BRCA2-RAD51轴对于同源重组修复（HRR）至关重要。EMI1调节三阴性乳腺癌（TNBC）细胞中的 PARPi 敏感性。EMI1的F盒结构域组装一个SCF泛素连接酶复合物，该复合物靶向RAD51进行降解。在一部分对PARPi难治的BRCA1缺陷三阴性乳腺癌细胞中，EMI1表达的降低会损害EMI依赖性RAD51的降解，从而恢复HR修复活性导致对PARPi的耐药性（图6）6。图6. KEAP1的增加导致EMI1表达的降低导致对PARPi的耐药机制EMSY是I型干扰素反应的负调节因子，也抵消了HR修复途径，KEAP1靶向EMSY进行泛素介导的降解。因此，KEAP1的过表达破坏了EMSY的稳定性，导致HR恢复和对PARPi的抵抗。相反，由于基因突变引起的KEAP1失活导致EMSY的稳定和HR缺乏而使得非小细胞肺癌对PARPi变得敏感（图7）7。图7. EMI1表达的降低导致EMSY的减少，从而对PARPi的耐药机制PARP1的下调或者突变都可能导致BRCA1/2缺陷肿瘤细胞中的PARPi耐药性（图5）。通过53BP1-RIF1的复合物，53BP1介导的DSB末端切除术抑制导致c-NHEJ活性增强，减少对PARP1依赖性a-NHEJ的依赖性，从而引起PARPi耐药性8.因此，53BP1在BRCA1-null小鼠胚胎干细胞中的抑制促进DSB末端切除以限制c-NHEJ，从而使细胞对PARPi致敏。在BRCA1突变的乳腺癌细胞中，由于HR修复活性的部分恢复，53BP1的体细胞丢失导致奥拉帕尼耐药，从而降低BRCA1缺陷小鼠乳腺肿瘤对该抑制剂的反应（图5）。53BP1定位于DSB的阻断也有助于BRCA1缺陷肿瘤中PARPi的失活，这是由TIRR表达增加介导的9。SHLD1/2/3复合物的失活以及DSB末端切除术中其他蛋白（包括RIF1和REV7）的表达降低，恢复了HR的功能活性，降低了PARPi的疗效（图8）10。以相同的机制方式，TRIP13是SHLD1 /2 /3复合物的负调节因子，通过解离REV7-SHLD1/2/3去促进HR。因此，TRIP13的扩增诱导BRCA1/2突变癌症对PARPi的耐药11。图8. SHLD1/2的敲除在BRCA1敲除细胞中导致对PARPi的耐药机制除了在HR通路中起作用外，据报道，BRCA1和BRCA2在维持复制分叉的完整性方面发挥作用12。在BRCA1和BRCA2缺陷细胞中对PARPi获得性耐药可能是由于EZH2缺失导致MRE1和MUS81核酸酶表达降低，导致对复制叉的保护性反应（图9）12,13。图9. MRE1、MUS81和EZH2的下调导致对PARPi的耐药机制除了基于恢复HR或复制叉保护的获得性PARPi抗性机制之外，最近的一项研究报告称，通过恢复Okazaki片段处理（OFP）减少/丢失DNA复制间隙可以诱导抗性。基本上，据报道，复制间隙是BRCA1/2缺陷细胞中PARPi反应的主要决定因素。一般来说，BRCA1/2的缺乏会扩大复制间隙，导致细胞的PARPi敏感性1。然而，在同时敲除BRCA1和53BP1的细胞模型中，通过恢复XRCC1-LIG3恢复OFP，导致减少/耗尽复制差距，并最终对PARPi产生抵抗力。相反，双倍敲除53BP1和LIG3使BRCA1突变细胞对PARPi重新敏感（图10）14。图10. XRCC1-LIG3的增加恢复OFP对PARPi产生耐药性4预先存在的 PARPi 耐药性机制HR和/或c-NHEJ缺陷的血液系统恶性肿瘤在模拟外周血微环境（PBM）的条件下对PARPi介导的合成致死性敏感，在模拟骨髓微环境（BMM）的条件对 PARPi 产生抗性。Bac等人表明转化生长因子β1（TGF-1）由骨髓基质细胞产生的激活缺氧诱导的TGF-受体（TGF R）激酶-SMAD2/3在白血病细胞中的规范途径以促进DSB的修复（图11）1。TGFβR激酶抑制剂没有改变白血病细胞对PBM中PARPi的敏感性，表明DSB修复活动中TGFβR-SMAD3信号传导的调节在BMM中是排他性的。在机制上，TGFβR激酶信号通过BRCA1/2、ATM，DNA-PKcs和LIG4的上调刺激BMM中白血病细胞中DSB的修复。这一发现表明TGFβR激酶抑制剂在PARPi介导的造血恶性肿瘤干预中的潜在临床应用。事实上，TGFβR激酶的抑制剂galunisertib已经在临床上几种癌症的试验得到应用 15,16，恢复了BMM中白血病细胞的PARPi敏感性。因此，Bac等人假设在PARPi治疗中加入galunisertib应该改善治疗效果1。图11. 通过在缺氧骨髓微环境中激活TGF-β1—TGFβR—SMAD2/3信号传导，恢复HR/c-NHEJ缺陷白血病中的HR/c-NHEJ的PARP抑制剂耐药的预先存在机制除此之外，还有一些其它预先存在的对PARPi的耐药机制，比如DNMT3A的突变导致功能丧失，FLT3激酶与ITD融合突变导致FLT3激酶激活，JAK2的V617K突变导致JAK2激酶的激活，c-KIT的N822K突变导致c-KIT激酶的激活，EGFR的激活和IGF-1R的激酶等都可能导致预先存在的PARPi抑制剂的耐药（图12）1。图12. 预先存在的 PARPi 耐药性机制5小结鉴于负责PARPi耐药性的机制途径列表不断增加，必须实现对预先存在和获得的PARPi耐药的药理学抑制，以提高PARPi介导的合成的治疗效率杀伤力。例如，白血病细胞中预先存在的PARPi耐药性可以通过联合PARP和TGFβR激酶抑制剂（使BMM中的白血病细胞再敏化）、PARP和TET2双加氧酶抑制剂（使携带DNMT3A突变的白血病重新致敏）以及PARP和OTK抑制剂（FLT3（ITD）、JAK2（V617F）、c-KIT（N822K）、EGFR、IGF-1R）解决。获得性 PARPi 抗性可通过以下方式预防，如更具侵略性的“双重合成致死”方法（同时靶向PARP1和RAD52），可在更短的时间内消除更多的肿瘤细胞，从而减少抗性克隆出现的时间依赖性的机会。此外，如果 PARPi出现耐药性，这些克隆可以通过抑制另一种DNA修复机制来消除，例如Pol介导的TMEJ 17。参考文献：1.Bac Viet Le, Paulina Podszywałow-Bartnicka, Katarzyna Piwocka, and Tomasz Skorski, Pre-Existing and Acquired Resistance to PARP Inhibitor-Induced Synthetic Lethality, Cancers 2022, 14, 5795.2.Quigley, D.; Alumkal, J.J.; Wyatt, A.W.; Kothari, V.; Foye, A.; Lloyd, P.; Aggarwal, R.; Kim, W.; Lu, E.; Schwartzman, J.; et al. 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