The cranial base synchondroses,comprised of opposite-facing bidirectional chondrocyte layers,drive anteroposterior cranial base growth.In humans,RUNX2 haploinsufficiency causes cleidocranial dysplasia associated with ...The cranial base synchondroses,comprised of opposite-facing bidirectional chondrocyte layers,drive anteroposterior cranial base growth.In humans,RUNX2 haploinsufficiency causes cleidocranial dysplasia associated with deficient midfacial growth.However,how RUNX2 regulates chondrocytes in the cranial base synchondroses remains unknown.To address this,we inactivated Runx2 in postnatal synchondrosis chondrocytes using a tamoxifen-inducible Fgfr3-creER(Fgfr3-Runx2cKO)mouse model.Fgfr3-Runx2cKO mice displayed skeletal dwarfism and reduced anteroposterior cranial base growth associated with premature synchondrosis ossification due to impaired chondrocyte proliferation,accelerated hypertrophy,apoptosis,and osteoclast-mediated cartilage resorption.Lineage tracing reveals that Runx2-deficient Fgfr3+cells failed to differentiate into osteoblasts.Notably,Runx2-deficient chondrocytes showed an elevated level of FGFR3 and its downstream signaling components,pERK1/2 and SOX9,suggesting that RUNX2 downregulates FGFR3 in the synchondrosis.This study unveils a new role of Runx2 in cranial base chondrocytes,identifying a possible RUNX2-FGFR3-MAPK-SOX9 signaling axis that may control cranial base growth.展开更多
RUNX2是一种关键的转录因子,其在多种癌症的发生和发展中起着重要作用。由于RUNX2在多种癌症类型中对预后具有显著的影响,其作为癌症生物标志物的潜力引起了广泛关注。RUNX2通过与核心结合因子β (CBFβ)结合,增强对靶基因的调控,促进...RUNX2是一种关键的转录因子,其在多种癌症的发生和发展中起着重要作用。由于RUNX2在多种癌症类型中对预后具有显著的影响,其作为癌症生物标志物的潜力引起了广泛关注。RUNX2通过与核心结合因子β (CBFβ)结合,增强对靶基因的调控,促进癌细胞的增殖、迁移和侵袭。RUNX2与PI3K/AKT信号通路互作,激活肿瘤进展的关键途径。抑制RUNX2的表达和功能已显示出抑制肿瘤生长和迁移、促进癌细胞凋亡的潜力,使其成为癌症治疗中的有意义靶标。近年研究还发现,RUNX2影响肿瘤微环境和化疗耐药性,针对RUNX2的小分子抑制剂和靶向疗法的开发,为提高治疗效果和减少耐药现象提供了新的策略。RUNX2 is a critical transcription factor that plays an important role in the initiation and progression of various cancers. Due to its significant impact on prognosis across multiple cancer types, RUNX2 has garnered widespread attention as a potential biomarker for cancer. By interacting with core-binding factor β (CBFβ), RUNX2 enhances the regulation of target genes, promoting cancer cell proliferation, migration, and invasion. RUNX2 also interacts with the PI3K/AKT signaling pathway, activating key pathways involved in tumor progression. Inhibiting RUNX2 expression and function has demonstrated potential in suppressing tumor growth and migration, as well as inducing apoptosis in cancer cells, making it a meaningful therapeutic target in cancer treatment. Recent studies have also revealed that RUNX2 influences the tumor microenvironment and chemotherapy resistance. The development of small molecule inhibitors and targeted therapies against RUNX2 offers novel strategies to improve therapeutic efficacy and reduce resistance.展开更多
BACKGROUND Acute myeloid leukemia(AML)is a complicated disease with uncontrolled hematopoietic precursor proliferation induced by various genetic alterations.Runt-related transcription factor-1(RUNX1)is commonly disru...BACKGROUND Acute myeloid leukemia(AML)is a complicated disease with uncontrolled hematopoietic precursor proliferation induced by various genetic alterations.Runt-related transcription factor-1(RUNX1)is commonly disrupted by chromosomal translocations in hematological malignancies.AIM To characterize RUNX1 gene rearrangements and copy number variations in newly diagnosed adult AML patients,with an emphasis on the impact of clinical and laboratory features on the outcome.METHODS Fluorescence in situ hybridization was used to test RUNX1 gene alterations in 77 newly diagnosed adult AML cases.NPM1,FLT3/ITD,FLT3/TKD,and KIT mutations were tested by PCR.Prognostic clinical and laboratory findings were studied in relation to RUNX1 alterations.RESULTS RUNX1 abnormalities were detected by fluorescence in situ hybridization in 41.6%of patients:20.8%had translocations,22.1%had amplification,and 5.2%had deletion.Translocations prevailed in AML-M2(P=0.019)with a positive expression of myeloperoxidase(P=0.031),whereas deletions dominated in M4 and M5 subtypes(P=0.008)with a positive association with CD64 expression(P=0.05).The modal chromosomal number was higher in cases having amplifications(P=0.007)and lower in those with deletions(P=0.008).RUNX1 abnormalities were associated with complex karyotypes(P<0.001)and were mutually exclusive of NPM1 mutations.After 44 months of follow-up,RUNX1 abnormalities affected neither patients’response to treatment nor overall survival.CONCLUSION RUNX1 abnormalities were mutually exclusive of NPM1 mutations.RUNX1 abnormalities affected neither patients’response to treatment nor overall survival.展开更多
文摘目的探讨RUNX3、P16和DAPK基因启动子DNA甲基化与非小细胞肺癌(non-small cell lung cancer,NSCLC)化疗敏感性的关系。方法选取2023年2月至2025年2月于株洲市中心医院接受铂类化疗的初治晚期NSCLC患者116例为研究对象,根据化疗疗效将其分为敏感组(n=81)和耐受组(n=35)。比较两组患者的病灶组织标本RUNX3、P16、DAPK基因启动子DNA甲基化情况、基因转录水平绝对定量,采用受试者操作特征曲线(receiver operating characteristic curve,ROC曲线)评估RUNX3、P16、DAPK基因表达水平对铂类化疗耐药的预测价值。结果耐受组患者肺癌组织的RUNX3、P16和DAPK基因启动子DNA甲基化比例均显著高于敏感组(P<0.05)。耐受组患者肺癌组织的RUNX3、P16和DAPK基因转录水平均显著低于敏感组(P<0.05)。ROC曲线显示,肺癌组织RUNX3、P16、DAPK基因转录水平预测NSCLC患者化疗敏感的最佳截断值分别为2.93×10^(6)、5.22×10^(4)、6.420×10^(5),曲线下面积(area under the curve,AUC)分别为0.726、0.748、0.763。三者联合预测NSCLC患者化疗敏感的AUC为0.883,敏感度为81.82%、特异性为78.05%。结论RUNX3、P16、DAPK基因甲基化可能是晚期NSCLC患者铂类化疗耐药的原因之一,早期测定此类基因转录水平对预估化疗耐药、制定个体化治疗方案具有积极作用。
基金National Institutes of Health grant F30DE030675(S.A.H.)National Institutes of Health grant T32DE007057(S.A.H.)+7 种基金University of Michigan Rackham Graduate School Pre-Candidate Research Grant(S.A.H.)University of Michigan Rackham Graduate School Candidate Research Grant(S.A.H.)National Institutes of Health grant R35DE034348(N.O.)National Institutes of Health grant R01DE026666(N.O.)National Institutes of Health grant R01DE030630(N.O.)National Institutes of Health grant R01DE029465(R.T.F.)Department of Defense grant W81XWH2010571(R.T.F.)National Institutes of Health grant P30 AR069620(The Michigan Integrative Musculoskeletal.Health Core Center).
文摘The cranial base synchondroses,comprised of opposite-facing bidirectional chondrocyte layers,drive anteroposterior cranial base growth.In humans,RUNX2 haploinsufficiency causes cleidocranial dysplasia associated with deficient midfacial growth.However,how RUNX2 regulates chondrocytes in the cranial base synchondroses remains unknown.To address this,we inactivated Runx2 in postnatal synchondrosis chondrocytes using a tamoxifen-inducible Fgfr3-creER(Fgfr3-Runx2cKO)mouse model.Fgfr3-Runx2cKO mice displayed skeletal dwarfism and reduced anteroposterior cranial base growth associated with premature synchondrosis ossification due to impaired chondrocyte proliferation,accelerated hypertrophy,apoptosis,and osteoclast-mediated cartilage resorption.Lineage tracing reveals that Runx2-deficient Fgfr3+cells failed to differentiate into osteoblasts.Notably,Runx2-deficient chondrocytes showed an elevated level of FGFR3 and its downstream signaling components,pERK1/2 and SOX9,suggesting that RUNX2 downregulates FGFR3 in the synchondrosis.This study unveils a new role of Runx2 in cranial base chondrocytes,identifying a possible RUNX2-FGFR3-MAPK-SOX9 signaling axis that may control cranial base growth.
文摘RUNX2是一种关键的转录因子,其在多种癌症的发生和发展中起着重要作用。由于RUNX2在多种癌症类型中对预后具有显著的影响,其作为癌症生物标志物的潜力引起了广泛关注。RUNX2通过与核心结合因子β (CBFβ)结合,增强对靶基因的调控,促进癌细胞的增殖、迁移和侵袭。RUNX2与PI3K/AKT信号通路互作,激活肿瘤进展的关键途径。抑制RUNX2的表达和功能已显示出抑制肿瘤生长和迁移、促进癌细胞凋亡的潜力,使其成为癌症治疗中的有意义靶标。近年研究还发现,RUNX2影响肿瘤微环境和化疗耐药性,针对RUNX2的小分子抑制剂和靶向疗法的开发,为提高治疗效果和减少耐药现象提供了新的策略。RUNX2 is a critical transcription factor that plays an important role in the initiation and progression of various cancers. Due to its significant impact on prognosis across multiple cancer types, RUNX2 has garnered widespread attention as a potential biomarker for cancer. By interacting with core-binding factor β (CBFβ), RUNX2 enhances the regulation of target genes, promoting cancer cell proliferation, migration, and invasion. RUNX2 also interacts with the PI3K/AKT signaling pathway, activating key pathways involved in tumor progression. Inhibiting RUNX2 expression and function has demonstrated potential in suppressing tumor growth and migration, as well as inducing apoptosis in cancer cells, making it a meaningful therapeutic target in cancer treatment. Recent studies have also revealed that RUNX2 influences the tumor microenvironment and chemotherapy resistance. The development of small molecule inhibitors and targeted therapies against RUNX2 offers novel strategies to improve therapeutic efficacy and reduce resistance.
文摘BACKGROUND Acute myeloid leukemia(AML)is a complicated disease with uncontrolled hematopoietic precursor proliferation induced by various genetic alterations.Runt-related transcription factor-1(RUNX1)is commonly disrupted by chromosomal translocations in hematological malignancies.AIM To characterize RUNX1 gene rearrangements and copy number variations in newly diagnosed adult AML patients,with an emphasis on the impact of clinical and laboratory features on the outcome.METHODS Fluorescence in situ hybridization was used to test RUNX1 gene alterations in 77 newly diagnosed adult AML cases.NPM1,FLT3/ITD,FLT3/TKD,and KIT mutations were tested by PCR.Prognostic clinical and laboratory findings were studied in relation to RUNX1 alterations.RESULTS RUNX1 abnormalities were detected by fluorescence in situ hybridization in 41.6%of patients:20.8%had translocations,22.1%had amplification,and 5.2%had deletion.Translocations prevailed in AML-M2(P=0.019)with a positive expression of myeloperoxidase(P=0.031),whereas deletions dominated in M4 and M5 subtypes(P=0.008)with a positive association with CD64 expression(P=0.05).The modal chromosomal number was higher in cases having amplifications(P=0.007)and lower in those with deletions(P=0.008).RUNX1 abnormalities were associated with complex karyotypes(P<0.001)and were mutually exclusive of NPM1 mutations.After 44 months of follow-up,RUNX1 abnormalities affected neither patients’response to treatment nor overall survival.CONCLUSION RUNX1 abnormalities were mutually exclusive of NPM1 mutations.RUNX1 abnormalities affected neither patients’response to treatment nor overall survival.
