Pub Date : 2026-01-13DOI: 10.1158/1538-7445.fusionpositive26-pr002
Chinmay S. Sankhe, Delia Calderon, Cenny Taslim, Melissa Sammons, Lindsay Ryan, Amy C. Gross, Joanna Cyrta, Olivier Delattre, Ryan D. Roberts, Genevieve C. Kendall
Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in children and has molecular features of immature skeletal muscle development. Spindle-cell RMS subtype in infant patients has been associated with the presence of chromosomal translocation event in the form of fusion-oncogenes. The most common fusion-oncogene in these patients is VGLL2::NCOA2, the fusion between vestigial-like family member 2 (VGLL2) and nuclear receptor coactivator 2 (NCOA2). Conventional chemotherapeutic approaches do not target the fusion-oncogene itself, are broadly toxic, and often impose lifelong adverse side effects that decrease the patient’s quality of life. Previous work from our lab has shown that the VGLL2::NCOA2 fusion is oncogenic in zebrafish and mouse allograft models, with tumors forming without requiring secondary mutations. Importantly, these tumors histologically and transcriptionally recapitulated the human disease. Understanding fusion-oncogene biology is critical to identifying novel molecular therapeutic targets to improve patient outcomes. Here, we implemented a structure-function-based strategy to define the requirements of each functional domain of VGLL2::NCOA2 in fusion-driven tumorigenesis. We hypothesize that the protein domains retained in the fusion-oncogene influence tumorigenic mechanisms. We generated deletions of the functional protein domain vestigial/Tondu (TDU) of VGLL2 and activating domains (AD1 and AD2) of NCOA2, both of which are retained in the fusion. We transfected C2C12 mouse myoblast cells with either the full-length VGLL2::NCOA2 fusion construct or the mutant domain deletion constructs. Using immunofluorescence staining and western blotting, we found that the VGLL2::NCOA2 fusion localized in the nucleus, whereas the single deletions of the TDU and AD1 domains resulted in decreased nuclear localization. C2C12 cells transfected with the full-length fusion readily formed colonies in soft agar; however, removing the TDU and AD1 domains suppressed colony formation. We complemented our in vitro studies with a mouse allograft approach. Mice injected with the C2C12 cells stably expressing VGLL2::NCOA2 with deletions of TDU and/or AD1 had a delayed tumor onset with more differentiated tumors compared to mice injected with the full-length fusion. Furthermore, bulk RNA-sequencing transcriptional analysis of transfected cells demonstrated that deletion of the TDU and AD1 domains resulted in an upregulation of skeletal muscle myogenesis gene sets, suggesting promotion of muscle differentiation compared to cells expressing the full-length fusion. Overall, our results indicate that VGLL2::NCOA2 is dependent on the TDU and AD1 domains for supporting tumorigenic activities and that targeting these domains or their interacting protein partners represents a potential therapeutic opportunity. Citation Format: Chinmay S. Sankhe, Delia Calderon, Cenny Taslim, Melissa Sammons, Lindsay Ryan, Amy C. Gross, Joanna Cyrta, Olivier Delattre, Ryan
横纹肌肉瘤（Rhabdomyosarcoma， RMS）是儿童最常见的软组织肉瘤，具有未成熟骨骼肌发育的分子特征。婴儿患者的梭形细胞RMS亚型与融合癌基因形式的染色体易位事件的存在有关。这些患者中最常见的融合癌基因是VGLL2::NCOA2，即退化样家族成员2 （VGLL2）和核受体辅激活因子2 （NCOA2）之间的融合。传统的化疗方法不针对融合癌基因本身，具有广泛的毒性，并且经常造成终生的不良副作用，降低患者的生活质量。我们实验室之前的工作表明，VGLL2::NCOA2融合在斑马鱼和小鼠同种异体移植模型中具有致癌作用，肿瘤形成不需要继发性突变。重要的是，这些肿瘤在组织学和转录上再现了人类疾病。了解融合癌基因生物学对于确定新的分子治疗靶点以改善患者预后至关重要。在这里，我们实施了一种基于结构-功能的策略来定义融合驱动肿瘤发生中VGLL2::NCOA2的每个功能域的需求。我们假设融合癌基因中保留的蛋白结构域影响致瘤机制。我们删除了VGLL2的功能蛋白结构域退化/通度（TDU）和NCOA2的激活结构域（AD1和AD2），这两个结构域在融合中都被保留。我们用全长VGLL2::NCOA2融合构建体或突变结构域缺失构建体转染C2C12小鼠成肌细胞。通过免疫荧光染色和western blotting，我们发现VGLL2::NCOA2融合在细胞核中定位，而TDU和AD1结构域的单一缺失导致核定位降低。全长融合后的C2C12细胞在软琼脂中容易形成菌落；然而，去除TDU和AD1结构域抑制了菌落的形成。我们用小鼠同种异体移植方法补充了我们的体外研究。与注射全长融合的小鼠相比，注射稳定表达VGLL2::NCOA2并缺失TDU和/或AD1的C2C12细胞的小鼠肿瘤发生延迟，肿瘤分化程度更高。此外，转染细胞的大量rna测序转录分析表明，TDU和AD1结构域的缺失导致骨骼肌肌生成基因集的上调，这表明与表达全长融合的细胞相比，TDU和AD1结构域的缺失促进了肌肉分化。总体而言，我们的研究结果表明，VGLL2::NCOA2依赖于TDU和AD1结构域来支持致瘤活性，靶向这些结构域或其相互作用的蛋白伙伴代表了潜在的治疗机会。引文格式：Chinmay S. Sankhe, Delia Calderon, Cenny Taslim, Melissa Sammons, Lindsay Ryan, Amy C. Gross, Joanna Cyrta, Olivier Delattre, Ryan D. Roberts, Genevieve C. Kendall。VGLL2::NCOA2在婴儿横纹肌肉瘤中的结构域特异性致癌功能[摘要]。AACR癌症研究特别会议论文集：融合阳性癌症：从发现到治疗；2026年1月13-15日；宾夕法尼亚州的费城费城（PA）： AACR；巨蟹座Res 2026；86(1_Suppl): nr PR002。
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Pub Date : 2026-01-13DOI: 10.1158/1538-7445.fusionpositive26-a023
Miwa Tanaka, Takuro Nakamura
Prompt trafficking of growth factors and cytokines to the cytoplasmic membrane is essential to provide growth stimuli during cell-cell communication. Also, efficient trafficking of surface receptors is required for their renewal upon the binding with their specific ligands. The RAB27/SYTL/Myosin V/actin axis plays a central role in trafficking of cytoplasmic vesicles and surface receptors toward the plasma membrane. Abnormal enhancement of this pathway induces excessive intercellular signaling exchange in cancer, resulting in significant modifications of tumor microenvironment. Our previous study identified SYTL1, a binding partner of RAB27B, as a transcriptional target of MEIS1 that promotes homing and engraftment of leukemia stem cells in the hematopoietic niche by facilitating membrane trafficking of CXCR4 and FLT3. Alveolar soft part sarcoma (ASPS) is a rare neoplasm that affects adolescents and young adults with an invariable ASPSCR1::TFE3 (AT3) fusion. ASPS is characterized by the abundant vascular network forming the alveolus around tumor cell nests that causes the highly metastatic activity of the tumor. ChIP-seq analysis revealed that AT3 binding peaks are enriched at angiogenesis-associated enhancers, and inhibition of enhancer activity by the BRD4 inhibitor JQ1 suppressed angiogenesis and tumor growth in vivo. Subsequent in vivo epigenomic CRISPR/dCas9-KRAB screening identified RAB27A and SYTL2 as key molecules of angiogenesis in ASPS. Upregulation of the RAB27A/SYTL2 axis enhanced secretion of angiogenic factors including PDGFB, VWF, GPNMB, and ANGPTL2, promoting migration and proliferation of pericytes and endothelial cells to form the highly integrated vascular network characteristic of ASPS. A similar pathway activation is observed in translocation renal cell carcinoma (tRCC) harboring TFE3 rearrangements, generating a comparable vascular architecture. We have reconstructed vascular mimics in vitro using ASPS and tRCC cells in 3D microfluidic devices. We are currently exploring novel inhibitors targeting the protein-protein interaction (PPI) between RAB27A and SYTL2. To perform high throughput screening (HTS) of candidate inhibitors we constructed the cell-based Fluoppi and cell-free AlphaLISA systems. During our first HTS Compound A was identified as a specific inhibitor of RAB27A and SYTL2 PPI. This compound inhibited the secretion of pro-angiogenic factors and significantly suppressed angiogenesis and tumor growth in vivo. We are currently optimizing Compound A to enhance its PPI inhibitory activity and safety profile. Citation Format: Miwa Tanaka, Takuro Nakamura. ASPSCR1::TFE3 promotes angiogenesis via RAB27A/SYTL2 upregulation in alveolar soft part sarcoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Fusion-Positive Cancer: From Discovery to Therapy; 2026 Jan 13-15; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(1_Suppl): nr A023.
生长因子和细胞因子的迅速运输到细胞质膜是在细胞间通讯过程中提供生长刺激所必需的。此外，表面受体的有效运输是它们在与特定配体结合时更新所必需的。RAB27/SYTL/Myosin V/actin轴在细胞质囊泡和表面受体向质膜的运输中起核心作用。该通路的异常增强可诱导肿瘤细胞间过度信号交换，导致肿瘤微环境发生显著改变。我们之前的研究发现RAB27B的结合伙伴SYTL1作为MEIS1的转录靶点，通过促进CXCR4和FLT3的膜运输，促进白血病干细胞在造血生态位的归巢和植入。肺泡软部肉瘤（Alveolar soft part sarcoma， ASPS）是一种罕见的肿瘤，多发于青少年和年轻人，伴有不变的ASPSCR1::TFE3 （AT3）融合。ASPS的特点是肿瘤细胞巢周围有丰富的血管网络形成肺泡，引起肿瘤的高度转移活性。ChIP-seq分析显示，AT3结合峰在血管生成相关增强子上富集，BRD4抑制剂JQ1抑制增强子活性可抑制体内血管生成和肿瘤生长。随后的体内表观基因组CRISPR/dCas9-KRAB筛选鉴定出RAB27A和SYTL2是ASPS血管生成的关键分子。RAB27A/SYTL2轴上调可增强PDGFB、VWF、GPNMB、ANGPTL2等血管生成因子的分泌，促进周细胞和内皮细胞的迁移和增殖，形成高度整合的血管网络。在易位性肾细胞癌（tRCC）中观察到类似的途径激活，其中包含TFE3重排，产生类似的血管结构。我们在体外用ASPS和tRCC细胞在三维微流体装置中重建了血管模拟物。我们目前正在探索针对RAB27A和SYTL2之间蛋白蛋白相互作用（PPI）的新型抑制剂。为了进行候选抑制剂的高通量筛选（HTS），我们构建了基于细胞的Fluoppi和无细胞的AlphaLISA系统。在我们的第一个HTS中，化合物A被确定为RAB27A和SYTL2 PPI的特异性抑制剂。该化合物抑制促血管生成因子的分泌，显著抑制体内血管生成和肿瘤生长。我们目前正在优化化合物A，以增强其PPI抑制活性和安全性。引用格式：Miwa Tanaka， Takuro Nakamura。ASPSCR1::TFE3通过上调RAB27A/SYTL2促进肺泡软组织肉瘤血管生成[摘要]。AACR癌症研究特别会议论文集：融合阳性癌症：从发现到治疗；2026年1月13-15日；宾夕法尼亚州的费城费城（PA）： AACR；巨蟹座Res 2026；86(1_Suppl): no A023。
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Pub Date : 2026-01-13DOI: 10.1158/1538-7445.fusionpositive26-b026
Sean Misek, Anna Borgenvik, Daniel Christen, Gloria Kyrila, Alexander Zhang, Sarah Reel, Michelle Boisvert, Kelly Cai, Kevin Zhou, Elizabeth Gonzales, Lorena Lazo de la Vega, Timothy Ragnoni, Nicole Persky, Tanaz Abid, Esteban Miglietta, Sergey Vakhrushev, Michael Stumpe, Jacquelyn Jones, Seth Malinowski, Lobna Elsadek, Aaron Fultineer, Kira Tang, Antonio Maldera, Hyesung Jeon, Sangita Pal, Todd Golub, William Hahn, Eric Fischer, Jesse Boehm, Jörn Dengjel, Henrik Clausen, Nada Jabado, Till Milde, Anne Carpenter, Beth Cimini, Keith Ligon, Katherine Janeway, Michael Eck, David Root, David Jones, Timothy Phoenix, Rameen Beroukhim, Hiren Jitendra Joshi, Tilman Tilman, Adnan Halim, Pratiti Bandopadhayay
The most common fusion oncoprotein in the most common pediatric solid tumor, pediatric low-grade glioma (pLGG), is KIAA1549::BRAF. Although MAPK inhibitors show early promise, they often fail to achieve durable cures, highlighting the need to develop new therapeutics for KIAA1549::BRAF-driven tumors. In this study we leverage genome-scale anti-transformation CRISPR screens to uncover KIAA1549::BRAF-specific genetic vulnerabilities. Across all genes, POMT1 and POMT2, the two members of the heterodimeric Protein O-mannosyltransferase (POMT) complex emerge as the strongest KIAA1549::BRAF-specific dependencies. We demonstrate that KIAA1549 is a direct substrate of this complex, and that glycosylation of KIAA1549::BRAF by POMT is necessary for its maturation through the secretory pathway and subsequent oncogenic signaling. These data highlight for the first time a new route to directly target KIAA1549::BRAF independent of the MAPK pathway. This work also uncovered an unexpected and previously unrecognized role for KIAA1549 in driving KIAA1549::BRAF oncogenic signaling. The prevailing dogma has been that BRAF fusions exert their transforming activity through truncation and removal of N-terminal regulatory domains, thereby rendering the BRAF kinase domain constitutively active. We demonstrate that BRAF fusion partners, including KIAA1549, contain domains that facilitate membrane localization, thereby enhancing BRAF signaling. These findings challenge the traditional view of BRAF fusion biology and establish a role for fusion partners in shaping oncogenic potential. Citation Format: Sean Misek, Anna Borgenvik, Daniel Christen, Gloria Kyrila, Alexander Zhang, Sarah Reel, Michelle Boisvert, Kelly Cai, Kevin Zhou, Elizabeth Gonzales, Lorena Lazo de la Vega, Timothy Ragnoni, Nicole Persky, Tanaz Abid, Esteban Miglietta, Sergey Vakhrushev, Michael Stumpe, Jacquelyn Jones, Seth Malinowski, Lobna Elsadek, Aaron Fultineer, Kira Tang, Antonio Maldera, Hyesung Jeon, Sangita Pal, Todd Golub, William Hahn, Eric Fischer, Jesse Boehm, Jörn Dengjel, Henrik Clausen, Nada Jabado, Till Milde, Anne Carpenter, Beth Cimini, Keith Ligon, Katherine Janeway, Michael Eck, David Root, David Jones, Timothy Phoenix, Rameen Beroukhim, Hiren Jitendra Joshi, Tilman Tilman, Adnan Halim, Pratiti Bandopadhayay. O-mannosylation and protein maturation checkpoints represent therapeutic opportunities in BRAF fusion protein oncogenesis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Fusion-Positive Cancer: From Discovery to Therapy; 2026 Jan 13-15; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(1_Suppl): nr B026.
在最常见的儿童实体肿瘤——儿童低级别胶质瘤（pLGG）中，最常见的融合癌蛋白是KIAA1549::BRAF。尽管MAPK抑制剂显示出早期的希望，但它们往往无法实现持久的治疗，这突出了开发新的治疗KIAA1549:: braf驱动肿瘤的方法的必要性。在这项研究中，我们利用基因组规模的抗转化CRISPR筛选来发现KIAA1549:: brf特异性遗传脆弱性。在所有基因中，异二聚体蛋白o -甘露糖基转移酶（POMT）复合体的两个成员POMT1和POMT2表现出最强的KIAA1549:: braf特异性依赖。我们证明KIAA1549是该复合物的直接底物，并且POMT对KIAA1549::BRAF的糖基化是其通过分泌途径成熟和随后的致癌信号传导所必需的。这些数据首次突出了独立于MAPK通路直接靶向KIAA1549::BRAF的新途径。这项工作还发现了KIAA1549在驱动KIAA1549::BRAF致癌信号传导中的一个意想不到的和以前未被认识到的作用。普遍的观点认为，BRAF融合通过截断和去除n端调控结构域来发挥其转化活性，从而使BRAF激酶结构域具有组成性活性。我们证明BRAF融合伙伴，包括KIAA1549，包含促进膜定位的结构域，从而增强BRAF信号传导。这些发现挑战了BRAF融合生物学的传统观点，并确立了融合伙伴在形成致癌潜能中的作用。引文格式:肖恩·米塞克、安娜·博尔根维克、丹尼尔·克里斯腾、格洛丽亚·基里拉、亚历山大·张、莎拉·里尔、米歇尔·布瓦维尔、凯利·蔡、凯文·周、伊丽莎白·冈萨雷斯、洛雷纳·拉佐·德拉·维加、蒂莫西·拉格诺尼、妮可·波斯基、塔娜·阿比德、埃斯特班·米格列塔、谢尔盖·瓦赫鲁舍夫、迈克尔·斯坦普、杰奎琳·琼斯、塞思·马林诺夫斯基、洛布娜·埃尔萨德克、亚伦·富尔廷纳、唐吉娜、安东尼奥·马尔德拉、全Hyesung、桑吉塔·帕尔、托德·戈拉布、威廉·哈恩、埃里克·菲舍尔、杰西·博姆、Jörn邓杰尔、亨里克·克劳森、纳达·贾巴多、Till Milde, Anne Carpenter, Beth Cimini, Keith Ligon, Katherine Janeway, Michael Eck, David Root, David Jones, Timothy Phoenix, Rameen Beroukhim, Hiren Jitendra Joshi, Tilman Tilman, Adnan Halim, Pratiti Bandopadhayay。o -甘露糖基化和蛋白质成熟检查点代表了BRAF融合蛋白肿瘤发生的治疗机会[摘要]。AACR癌症研究特别会议论文集：融合阳性癌症：从发现到治疗；2026年1月13-15日；宾夕法尼亚州的费城费城（PA）： AACR；巨蟹座Res 2026；86(1_Suppl): nr B026。
{"title":"Abstract B026: O-mannosylation and protein maturation checkpoints represent therapeutic opportunities in BRAF fusion protein oncogenesis","authors":"Sean Misek, Anna Borgenvik, Daniel Christen, Gloria Kyrila, Alexander Zhang, Sarah Reel, Michelle Boisvert, Kelly Cai, Kevin Zhou, Elizabeth Gonzales, Lorena Lazo de la Vega, Timothy Ragnoni, Nicole Persky, Tanaz Abid, Esteban Miglietta, Sergey Vakhrushev, Michael Stumpe, Jacquelyn Jones, Seth Malinowski, Lobna Elsadek, Aaron Fultineer, Kira Tang, Antonio Maldera, Hyesung Jeon, Sangita Pal, Todd Golub, William Hahn, Eric Fischer, Jesse Boehm, Jörn Dengjel, Henrik Clausen, Nada Jabado, Till Milde, Anne Carpenter, Beth Cimini, Keith Ligon, Katherine Janeway, Michael Eck, David Root, David Jones, Timothy Phoenix, Rameen Beroukhim, Hiren Jitendra Joshi, Tilman Tilman, Adnan Halim, Pratiti Bandopadhayay","doi":"10.1158/1538-7445.fusionpositive26-b026","DOIUrl":"https://doi.org/10.1158/1538-7445.fusionpositive26-b026","url":null,"abstract":"The most common fusion oncoprotein in the most common pediatric solid tumor, pediatric low-grade glioma (pLGG), is KIAA1549::BRAF. Although MAPK inhibitors show early promise, they often fail to achieve durable cures, highlighting the need to develop new therapeutics for KIAA1549::BRAF-driven tumors. In this study we leverage genome-scale anti-transformation CRISPR screens to uncover KIAA1549::BRAF-specific genetic vulnerabilities. Across all genes, POMT1 and POMT2, the two members of the heterodimeric Protein O-mannosyltransferase (POMT) complex emerge as the strongest KIAA1549::BRAF-specific dependencies. We demonstrate that KIAA1549 is a direct substrate of this complex, and that glycosylation of KIAA1549::BRAF by POMT is necessary for its maturation through the secretory pathway and subsequent oncogenic signaling. These data highlight for the first time a new route to directly target KIAA1549::BRAF independent of the MAPK pathway. This work also uncovered an unexpected and previously unrecognized role for KIAA1549 in driving KIAA1549::BRAF oncogenic signaling. The prevailing dogma has been that BRAF fusions exert their transforming activity through truncation and removal of N-terminal regulatory domains, thereby rendering the BRAF kinase domain constitutively active. We demonstrate that BRAF fusion partners, including KIAA1549, contain domains that facilitate membrane localization, thereby enhancing BRAF signaling. These findings challenge the traditional view of BRAF fusion biology and establish a role for fusion partners in shaping oncogenic potential. Citation Format: Sean Misek, Anna Borgenvik, Daniel Christen, Gloria Kyrila, Alexander Zhang, Sarah Reel, Michelle Boisvert, Kelly Cai, Kevin Zhou, Elizabeth Gonzales, Lorena Lazo de la Vega, Timothy Ragnoni, Nicole Persky, Tanaz Abid, Esteban Miglietta, Sergey Vakhrushev, Michael Stumpe, Jacquelyn Jones, Seth Malinowski, Lobna Elsadek, Aaron Fultineer, Kira Tang, Antonio Maldera, Hyesung Jeon, Sangita Pal, Todd Golub, William Hahn, Eric Fischer, Jesse Boehm, Jörn Dengjel, Henrik Clausen, Nada Jabado, Till Milde, Anne Carpenter, Beth Cimini, Keith Ligon, Katherine Janeway, Michael Eck, David Root, David Jones, Timothy Phoenix, Rameen Beroukhim, Hiren Jitendra Joshi, Tilman Tilman, Adnan Halim, Pratiti Bandopadhayay. O-mannosylation and protein maturation checkpoints represent therapeutic opportunities in BRAF fusion protein oncogenesis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Fusion-Positive Cancer: From Discovery to Therapy; 2026 Jan 13-15; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(1_Suppl): nr B026.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"53 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145962069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-13DOI: 10.1158/1538-7445.fusionpositive26-a022
Debleena Basu, Hella Bolck, Dorothea Rutishauser, Peter Leary, Daniela C. Garcia (s), Abdullah Kahraman, Niels Rupp, Chantal Pauli, Holger Moch
TFE3 rearranged renal cell carcinoma (TFE3-tRCC) is a rare subtype of renal cell carcinoma (RCC) harboring gene fusions that trigger oncogenic activation of TFE3 transcription factor. The frequency of this rare tumor is surprisingly high in children and young adults (20% to 75% of childhood RCCs) compared to older adults (ranges between 1% and 5%). Importantly, TFE3-tRCC can show aggressive behavior with rapid progression and little to no response to drugs commonly used for renal cancer treatment. In this project we aim to define gene expression programs of distinct TFE3 fusions to uncover molecular events driven by chimeric TFE3 and delineate their consequences for important cancer phenotypes. By identifying fusion-specific pathway alterations, we seek to propose novel therapeutic strategies tailored to the patients with these fusions. Using a cohort of 31 patients with suspected diagnosis of TFE3-tRCC, we have employed a novel customized RNA-based targeted Next generation Sequencing (NGS) panel to determine putative fusion partners of TFE3. Next, high throughput technologies like short read and long read RNA sequencing and ChIP sequencing were used to characterize the molecular landscape downstream of different fusion events. Finally, to explore the influence of the transcriptional diversity on therapeutic decisions, we aim to perform molecularly informed drug screening in our in vitro models followed by in vivo validation. With our newly developed targeted NGS panel, we have characterized our patient cohort and identified 7 distinct TFE3 fusion partners in 25 cases out of 31. The putative partners are ASPSCR1, LUC7L3, MED15, NonO, PRCC, RBM10, and SFPQ. Certain partners confer unique tumor morphologies, e.g., MED15::TFE3 fusion associates with cystic features. Our transcriptomic analysis shows tumors with same fusion tend to cluster together, driven by shared pathway upregulation (OXPHOS, lysosomal pathway, autophagy, proteasome etc.). Differential upregulation of pathways such as immune response, metabolic pathways, mitophagy, RNA splicing etc. highlight fusion specific identity, informing fusion driven molecular characteristics. Preliminary in vitro chromatin accessibility data suggests the potential involvement of the chimeric TFE3 protein in alternative splicing regulation, which is further consistent with splicing enrichment observed in our transcriptomic analysis. Different fusion partners for TFE3 likely impact the dysregulation of the chimeric protein and drives tumorigenesis. However, our limited understanding of the molecular landscape and clinical consequences of the different TFE3 fusions presents as the major obstacle towards development of targeted therapeutic strategies for this disease. In this scenario of unmet clinical needs, we seek to define the molecular features of TFE3-tRCC, thereby uncovering specific vulnerabilities of tumor cells that prompt the development of new targeted therapeutic strategies. Citation Format: Debl
TFE3重排肾细胞癌（TFE3- trcc）是一种罕见的肾细胞癌（RCC）亚型，其基因融合可触发TFE3转录因子的致癌激活。与老年人（1%至5%）相比，这种罕见肿瘤在儿童和年轻人中的发病率惊人地高（占儿童rcc的20%至75%）。重要的是，TFE3-tRCC可表现出侵袭性行为，进展迅速，对常用的肾癌治疗药物几乎没有反应。在本项目中，我们旨在定义不同TFE3融合的基因表达程序，以揭示嵌合TFE3驱动的分子事件，并描述其对重要癌症表型的影响。通过识别融合特异性通路改变，我们寻求针对这些融合患者提出新的治疗策略。在31名疑似诊断为TFE3- trcc的患者中，我们采用了一种新的定制的基于rna的靶向下一代测序（NGS）面板来确定TFE3的推定融合伴侣。接下来，利用高通量技术，如短读和长读RNA测序和ChIP测序来表征不同融合事件下游的分子景观。最后，为了探索转录多样性对治疗决策的影响，我们的目标是在体外模型中进行分子知情的药物筛选，然后进行体内验证。通过我们新开发的靶向NGS小组，我们对患者队列进行了表征，并在31例患者中的25例中确定了7种不同的TFE3融合伙伴。可能的合作伙伴是ASPSCR1、LUC7L3、MED15、NonO、PRCC、RBM10和SFPQ。某些伴发者具有独特的肿瘤形态，例如，MED15::TFE3融合与囊性特征相关。我们的转录组学分析显示，具有相同融合的肿瘤倾向于聚集在一起，这是由共同的途径上调驱动的（OXPHOS，溶酶体途径，自噬，蛋白酶体等）。免疫反应、代谢途径、有丝分裂、RNA剪接等途径的差异上调凸显了融合的特异性，揭示了融合驱动的分子特征。初步的体外染色质可及性数据表明嵌合TFE3蛋白可能参与选择性剪接调节，这与我们在转录组学分析中观察到的剪接富集进一步一致。TFE3的不同融合伙伴可能影响嵌合蛋白的失调并驱动肿瘤发生。然而，我们对不同TFE3融合的分子景观和临床后果的了解有限，这是开发针对该疾病的靶向治疗策略的主要障碍。在这种未满足临床需求的情况下，我们试图确定TFE3-tRCC的分子特征，从而揭示肿瘤细胞的特定脆弱性，从而促进新的靶向治疗策略的发展。引文格式：Debleena Basu， Hella Bolck, Dorothea Rutishauser, Peter Leary, Daniela C. Garcia (s), Abdullah Kahraman, Niels Rupp, Chantal Pauli, Holger Moch。tfe3重排肾细胞癌的机制理解和新治疗策略的发展[摘要]。AACR癌症研究特别会议论文集：融合阳性癌症：从发现到治疗；2026年1月13-15日；宾夕法尼亚州的费城费城（PA）： AACR；巨蟹座Res 2026；86(1_supl): no A022。
{"title":"Abstract A022: Development of a mechanistic understanding and novel therapeutic strategies for TFE3-rearranged renal cell carcinoma","authors":"Debleena Basu, Hella Bolck, Dorothea Rutishauser, Peter Leary, Daniela C. Garcia (s), Abdullah Kahraman, Niels Rupp, Chantal Pauli, Holger Moch","doi":"10.1158/1538-7445.fusionpositive26-a022","DOIUrl":"https://doi.org/10.1158/1538-7445.fusionpositive26-a022","url":null,"abstract":"TFE3 rearranged renal cell carcinoma (TFE3-tRCC) is a rare subtype of renal cell carcinoma (RCC) harboring gene fusions that trigger oncogenic activation of TFE3 transcription factor. The frequency of this rare tumor is surprisingly high in children and young adults (20% to 75% of childhood RCCs) compared to older adults (ranges between 1% and 5%). Importantly, TFE3-tRCC can show aggressive behavior with rapid progression and little to no response to drugs commonly used for renal cancer treatment. In this project we aim to define gene expression programs of distinct TFE3 fusions to uncover molecular events driven by chimeric TFE3 and delineate their consequences for important cancer phenotypes. By identifying fusion-specific pathway alterations, we seek to propose novel therapeutic strategies tailored to the patients with these fusions. Using a cohort of 31 patients with suspected diagnosis of TFE3-tRCC, we have employed a novel customized RNA-based targeted Next generation Sequencing (NGS) panel to determine putative fusion partners of TFE3. Next, high throughput technologies like short read and long read RNA sequencing and ChIP sequencing were used to characterize the molecular landscape downstream of different fusion events. Finally, to explore the influence of the transcriptional diversity on therapeutic decisions, we aim to perform molecularly informed drug screening in our in vitro models followed by in vivo validation. With our newly developed targeted NGS panel, we have characterized our patient cohort and identified 7 distinct TFE3 fusion partners in 25 cases out of 31. The putative partners are ASPSCR1, LUC7L3, MED15, NonO, PRCC, RBM10, and SFPQ. Certain partners confer unique tumor morphologies, e.g., MED15::TFE3 fusion associates with cystic features. Our transcriptomic analysis shows tumors with same fusion tend to cluster together, driven by shared pathway upregulation (OXPHOS, lysosomal pathway, autophagy, proteasome etc.). Differential upregulation of pathways such as immune response, metabolic pathways, mitophagy, RNA splicing etc. highlight fusion specific identity, informing fusion driven molecular characteristics. Preliminary in vitro chromatin accessibility data suggests the potential involvement of the chimeric TFE3 protein in alternative splicing regulation, which is further consistent with splicing enrichment observed in our transcriptomic analysis. Different fusion partners for TFE3 likely impact the dysregulation of the chimeric protein and drives tumorigenesis. However, our limited understanding of the molecular landscape and clinical consequences of the different TFE3 fusions presents as the major obstacle towards development of targeted therapeutic strategies for this disease. In this scenario of unmet clinical needs, we seek to define the molecular features of TFE3-tRCC, thereby uncovering specific vulnerabilities of tumor cells that prompt the development of new targeted therapeutic strategies. Citation Format: Debl","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"22 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145962072","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-13DOI: 10.1158/1538-7445.fusionpositive26-pr005
Gabriel E. Boyle, Alexander W. Ying, Lara Yao, Chao-Jen Wong, Liam Caven, Morgan Merrill, Farzane Sivandzade, Matthew Wither, Soheil Meshinchi, Rachel Rau, Shan Lin, Cigall Kadoch, Jay F. Sarthy
Background: Pediatric acute myeloid leukemias (AMLs) are driven by transcription factor (TF) fusions that reprogram the epigenome, creating fusion-specific subtypes with distinct biomarkers, prognoses, and vulnerabilities. Pediatric AMLs driven by the CBFA2T3::GLIS2 (C/G) fusion are among the highest-risk subtypes, with fewer than 15% patients surviving 60 months post-diagnosis. These dismal outcomes stem from an incomplete understanding of how C/G rewires chromatin to establish subtype-specific regulatory dependencies, limiting development of targeted therapies. Comprehensive, multi-omic dissection of oncofusion-driven gene regulation is essential to reveal druggable mechanistic vulnerabilities. Methods and Results: To detect C/G-interacting factors, we performed unbiased immunoprecipitation mass spectrometry (IP-MS) profiling of C/G in patient-derived AML cell lines. This revealed a novel interaction with mammalian SWI/SNF (SWItch/Sucrose Non-Fermentable) chromatin remodeling complexes, which normally guide hematopoietic differentiation. CRISPR-based viability assays showed that C/G cell survival relies on BRG1-containing mSWI/SNF, revealing a fusion-specific chromatin remodeling dependency. To investigate how this interaction reprograms myeloid cells, we compared C/G-transformed hematopoietic stem and progenitor cells (HSPCs) to non-transformed counterparts. CUT&RUN profiling of C/G-mSWI/SNF occupancy and histone modifications, integrated with RNA-seq, showed that C/G retargets mSWI/SNF to oncogenic regulatory elements, sustaining overexpression of cell cycle genes CCND2 and CDK6. This C/G-directed chromatin remodeling creates a clinically targetable mSWI/SNF-G1 regulatory axis. Pharmacologic inhibition of this axis using palbociclib, an FDA-approved CDK4/6 kinase inhibitor, reduced leukemic burden and extended survival by ∼56% in an aggressive C/G AML mouse model, highlighting a clinically actionable vulnerability. Conclusions: These findings reveal how the C/G oncofusion repurposes BRG1-containing mSWI/SNF complexes to drive cell cycle gene activation, establishing a chromatin–cell cycle regulatory circuit that is selectively targetable through G1 restriction. This mechanistic insight provides a rationale for repurposing CDK4/6 inhibitors for children with this otherwise lethal AML subtype. Citation Format: Gabriel E. Boyle, Alexander W. Ying, Lara Yao, Chao-Jen Wong, Liam Caven, Morgan Merrill, Farzane Sivandzade, Matthew Wither, Soheil Meshinchi, Rachel Rau, Shan Lin, Cigall Kadoch, Jay F. Sarthy. Targeting Chromatin–Cell Cycle Vulnerabilities in High-Risk Pediatric Acute Myeloid Leukemia [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Fusion-Positive Cancer: From Discovery to Therapy; 2026 Jan 13-15; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(1_Suppl): nr PR005.
背景：儿童急性髓性白血病（AMLs）是由转录因子（TF）融合驱动的，这种融合会对表观基因组进行重编程，产生具有不同生物标志物、预后和脆弱性的融合特异性亚型。由CBFA2T3::GLIS2 （C/G）融合驱动的儿童aml是风险最高的亚型之一，诊断后60个月存活的患者不到15%。这些令人沮丧的结果源于对C/G如何重新连接染色质以建立亚型特异性调节依赖性的不完整理解，限制了靶向治疗的发展。对混乱驱动的基因调控进行全面的多组学解剖是揭示可药物机制脆弱性的必要条件。方法和结果：为了检测C/G相互作用因素，我们对患者源性AML细胞系的C/G进行了无偏免疫沉淀质谱（IP-MS）分析。这揭示了与哺乳动物SWI/SNF（开关/蔗糖不可发酵）染色质重塑复合物之间的一种新的相互作用，这些染色质重塑复合物通常指导造血分化。基于crispr的活力测定显示，C/G细胞存活依赖于含有brg1的mSWI/SNF，揭示了融合特异性染色质重塑依赖性。为了研究这种相互作用如何重编程髓细胞，我们比较了C/ g转化的造血干细胞和祖细胞（HSPCs）与未转化的同类细胞。结合RNA-seq对C/G-mSWI/SNF占用和组蛋白修饰的CUT&；RUN分析显示，C/G将mSWI/SNF重定向到致癌调控元件，维持细胞周期基因CCND2和CDK6的过表达。这种C/ g定向的染色质重塑创造了临床可靶向的mSWI/SNF-G1调节轴。在侵袭性C/G AML小鼠模型中，使用经fda批准的CDK4/6激酶抑制剂palbociclib对该轴进行药理学抑制，可减少白血病负担并延长生存期约56%，突出了临床可操作的弱点。结论：这些发现揭示了C/G混淆如何重新利用含有brg1的mSWI/SNF复合物来驱动细胞周期基因激活，建立了一个可通过G1限制选择性靶向的染色质-细胞周期调控回路。这一机制见解为CDK4/6抑制剂用于儿童致命AML亚型提供了理论依据。引用格式：Gabriel E. Boyle, Alexander W. Ying, Lara Yao, Chao-Jen Wong, Liam Caven, Morgan Merrill, Farzane Sivandzade, Matthew Wither, Soheil Meshinchi, Rachel Rau, Shan Lin, Cigall Kadoch, Jay F. Sarthy靶向高危儿童急性髓性白血病染色质细胞周期脆弱性[摘要]。AACR癌症研究特别会议论文集：融合阳性癌症：从发现到治疗；2026年1月13-15日；宾夕法尼亚州的费城费城（PA）： AACR；巨蟹座Res 2026；86(1_Suppl): nr PR005。
{"title":"Abstract PR005: Targeting Chromatin–Cell Cycle Vulnerabilities in High-Risk Pediatric Acute Myeloid Leukemia","authors":"Gabriel E. Boyle, Alexander W. Ying, Lara Yao, Chao-Jen Wong, Liam Caven, Morgan Merrill, Farzane Sivandzade, Matthew Wither, Soheil Meshinchi, Rachel Rau, Shan Lin, Cigall Kadoch, Jay F. Sarthy","doi":"10.1158/1538-7445.fusionpositive26-pr005","DOIUrl":"https://doi.org/10.1158/1538-7445.fusionpositive26-pr005","url":null,"abstract":"Background: Pediatric acute myeloid leukemias (AMLs) are driven by transcription factor (TF) fusions that reprogram the epigenome, creating fusion-specific subtypes with distinct biomarkers, prognoses, and vulnerabilities. Pediatric AMLs driven by the CBFA2T3::GLIS2 (C/G) fusion are among the highest-risk subtypes, with fewer than 15% patients surviving 60 months post-diagnosis. These dismal outcomes stem from an incomplete understanding of how C/G rewires chromatin to establish subtype-specific regulatory dependencies, limiting development of targeted therapies. Comprehensive, multi-omic dissection of oncofusion-driven gene regulation is essential to reveal druggable mechanistic vulnerabilities. Methods and Results: To detect C/G-interacting factors, we performed unbiased immunoprecipitation mass spectrometry (IP-MS) profiling of C/G in patient-derived AML cell lines. This revealed a novel interaction with mammalian SWI/SNF (SWItch/Sucrose Non-Fermentable) chromatin remodeling complexes, which normally guide hematopoietic differentiation. CRISPR-based viability assays showed that C/G cell survival relies on BRG1-containing mSWI/SNF, revealing a fusion-specific chromatin remodeling dependency. To investigate how this interaction reprograms myeloid cells, we compared C/G-transformed hematopoietic stem and progenitor cells (HSPCs) to non-transformed counterparts. CUT&RUN profiling of C/G-mSWI/SNF occupancy and histone modifications, integrated with RNA-seq, showed that C/G retargets mSWI/SNF to oncogenic regulatory elements, sustaining overexpression of cell cycle genes CCND2 and CDK6. This C/G-directed chromatin remodeling creates a clinically targetable mSWI/SNF-G1 regulatory axis. Pharmacologic inhibition of this axis using palbociclib, an FDA-approved CDK4/6 kinase inhibitor, reduced leukemic burden and extended survival by ∼56% in an aggressive C/G AML mouse model, highlighting a clinically actionable vulnerability. Conclusions: These findings reveal how the C/G oncofusion repurposes BRG1-containing mSWI/SNF complexes to drive cell cycle gene activation, establishing a chromatin–cell cycle regulatory circuit that is selectively targetable through G1 restriction. This mechanistic insight provides a rationale for repurposing CDK4/6 inhibitors for children with this otherwise lethal AML subtype. Citation Format: Gabriel E. Boyle, Alexander W. Ying, Lara Yao, Chao-Jen Wong, Liam Caven, Morgan Merrill, Farzane Sivandzade, Matthew Wither, Soheil Meshinchi, Rachel Rau, Shan Lin, Cigall Kadoch, Jay F. Sarthy. Targeting Chromatin–Cell Cycle Vulnerabilities in High-Risk Pediatric Acute Myeloid Leukemia [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Fusion-Positive Cancer: From Discovery to Therapy; 2026 Jan 13-15; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(1_Suppl): nr PR005.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"265 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145962412","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Targeted protein degradation (TPD) approaches, including molecular glue degraders (MGDs) and proteolysis targeting chimeras (PROTACs), overcome traditional occupancy-based inhibitor limitations and facilitate therapeutic development against "undruggable" disease-causing proteins. However, resistance to TPD is common, highlighting the need to further understand the driving mechanisms to improve treatment efficacy. Here, we identified a critical role of mTOR signaling in regulating PROTAC and MGD efficacy in vitro and in vivo. Activation or inhibition of mTOR respectively diminished or enhanced degradation efficacy of all proteasome-dependent TPD modalities tested. Mechanistically, mTOR inhibition suppressed de novo protein synthesis, thus creating a synthetic vulnerability by depleting replenishment of proteins targeted by PROTACs or MGDs. When applied to myeloma, mTOR inhibitors restored sensitivity to pomalidomide, one of the best characterized MGDs, in resistant cell lines and reduced malignant plasma cells in relapsed/refractory patients. This study reveals a clinically translatable strategy combining approved mTOR inhibitors with MGDs or PROTACs to enhance the therapeutic index of targeted protein degradation.
{"title":"Inhibition of mTOR Enhances the Efficacy of Proteasome-Dependent Targeted Protein Degradation Approaches.","authors":"Yang Liu,Yifeng Sun,Tian-Yu Song,Si-Yuan Ni,Yi-Sheng Pu,Yuan-Chen Chang,Wenrong Zhou,Zhen-Gang Peng,Jiajia Liu,Jun Shi,Wei Lu,Yong Cang","doi":"10.1158/0008-5472.can-25-3941","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-3941","url":null,"abstract":"Targeted protein degradation (TPD) approaches, including molecular glue degraders (MGDs) and proteolysis targeting chimeras (PROTACs), overcome traditional occupancy-based inhibitor limitations and facilitate therapeutic development against \"undruggable\" disease-causing proteins. However, resistance to TPD is common, highlighting the need to further understand the driving mechanisms to improve treatment efficacy. Here, we identified a critical role of mTOR signaling in regulating PROTAC and MGD efficacy in vitro and in vivo. Activation or inhibition of mTOR respectively diminished or enhanced degradation efficacy of all proteasome-dependent TPD modalities tested. Mechanistically, mTOR inhibition suppressed de novo protein synthesis, thus creating a synthetic vulnerability by depleting replenishment of proteins targeted by PROTACs or MGDs. When applied to myeloma, mTOR inhibitors restored sensitivity to pomalidomide, one of the best characterized MGDs, in resistant cell lines and reduced malignant plasma cells in relapsed/refractory patients. This study reveals a clinically translatable strategy combining approved mTOR inhibitors with MGDs or PROTACs to enhance the therapeutic index of targeted protein degradation.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"29 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145961328","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-13DOI: 10.1158/1538-7445.fusionpositive26-b019
Ruo-Wen Chen, John E. Tokarsky, Andrea K. Byrum, Megann A. Boone, Michael G. Poirier, Emily R. Theisen
Ewing sarcoma is the second most common childhood bone cancer. In approximately 85% of cases, the tumor is caused by expression of the fusion oncoprotein EWSR1::FLI1. EWSR1::FLI1 is generated from a chromosome translocation event between chromosomes 11 and 22. This combines the low complexity domain (LCD) of EWSR1 with the DNA-binding domain (DBD) of FLI1. Previous genomic studies have shown that EWSR1::FLI1 is a potent genome regulator at GGAA microsatellites. However, due to the technical difficulty in purifying the full-length EWSR1::FLI1, there has been a lack of biochemical studies characterizing the properties of the fusion protein. In this study, we successfully purified the full-length EWSR1::FLI1 and conducted a series of in vitro biochemical and fluorescence-based experiments to investigate its interaction with DNA and nucleosomes. We found that truncated EWSR1::FLI1 shows pioneering activities, and an alpha-helix in the FLI1 DBD further facilitates its binding to nucleosomes. Surprisingly, we observed that the DNA-binding sequence preference differs between full-length and truncated proteins. This suggests that the EWSR1 LCD might also be involved in regulating sequence-specific DNA binding. Our findings provide new insights into how EWSR1::FLI1 binds to DNA and nucleosomes as a pioneer factor to alter genome regulation in Ewing sarcoma. Citation Format: Ruo-Wen Chen, John E. Tokarsky, Andrea K. Byrum, Megann A. Boone, Michael G. Poirier, Emily R. Theisen. Full-length EWSR1::FLI1 reveals low-complexity domain regulation of DNA and nucleosome binding [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Fusion-Positive Cancer: From Discovery to Therapy; 2026 Jan 13-15; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(1_Suppl): nr B019.
尤文氏肉瘤是第二常见的儿童骨癌。在大约85%的病例中，肿瘤是由融合癌蛋白EWSR1::FLI1的表达引起的。EWSR1::FLI1是由11号和22号染色体之间的染色体易位事件产生的。这将EWSR1的低复杂性结构域（LCD）与FLI1的dna结合结构域（DBD）结合在一起。先前的基因组研究表明，EWSR1::FLI1在GGAA微卫星上是一个有效的基因组调控因子。然而，由于全长EWSR1::FLI1的纯化技术困难，缺乏表征融合蛋白特性的生化研究。在本研究中，我们成功纯化了全长EWSR1::FLI1，并进行了一系列体外生化和荧光实验来研究其与DNA和核小体的相互作用。我们发现截断的EWSR1::FLI1显示出开创性的活性，并且FLI1 DBD中的α -螺旋进一步促进其与核小体的结合。令人惊讶的是，我们观察到dna结合序列偏好在全长和截断的蛋白质之间是不同的。这表明EWSR1 LCD也可能参与调控序列特异性DNA结合。我们的研究结果为EWSR1::FLI1如何结合DNA和核小体作为改变尤文氏肉瘤基因组调控的先驱因子提供了新的见解。引文格式：陈若文，John E. Tokarsky, Andrea K. Byrum, Megann A. Boone, Michael G. Poirier, Emily R. Theisen。全长EWSR1::FLI1揭示了DNA和核小体结合的低复杂性结构域调控[摘要]。AACR癌症研究特别会议论文集：融合阳性癌症：从发现到治疗；2026年1月13-15日；宾夕法尼亚州的费城费城（PA）： AACR；巨蟹座Res 2026；86(1_Suppl): no B019。
{"title":"Abstract B019: Full-length EWSR1::FLI1 reveals low-complexity domain regulation of DNA and nucleosome binding","authors":"Ruo-Wen Chen, John E. Tokarsky, Andrea K. Byrum, Megann A. Boone, Michael G. Poirier, Emily R. Theisen","doi":"10.1158/1538-7445.fusionpositive26-b019","DOIUrl":"https://doi.org/10.1158/1538-7445.fusionpositive26-b019","url":null,"abstract":"Ewing sarcoma is the second most common childhood bone cancer. In approximately 85% of cases, the tumor is caused by expression of the fusion oncoprotein EWSR1::FLI1. EWSR1::FLI1 is generated from a chromosome translocation event between chromosomes 11 and 22. This combines the low complexity domain (LCD) of EWSR1 with the DNA-binding domain (DBD) of FLI1. Previous genomic studies have shown that EWSR1::FLI1 is a potent genome regulator at GGAA microsatellites. However, due to the technical difficulty in purifying the full-length EWSR1::FLI1, there has been a lack of biochemical studies characterizing the properties of the fusion protein. In this study, we successfully purified the full-length EWSR1::FLI1 and conducted a series of in vitro biochemical and fluorescence-based experiments to investigate its interaction with DNA and nucleosomes. We found that truncated EWSR1::FLI1 shows pioneering activities, and an alpha-helix in the FLI1 DBD further facilitates its binding to nucleosomes. Surprisingly, we observed that the DNA-binding sequence preference differs between full-length and truncated proteins. This suggests that the EWSR1 LCD might also be involved in regulating sequence-specific DNA binding. Our findings provide new insights into how EWSR1::FLI1 binds to DNA and nucleosomes as a pioneer factor to alter genome regulation in Ewing sarcoma. Citation Format: Ruo-Wen Chen, John E. Tokarsky, Andrea K. Byrum, Megann A. Boone, Michael G. Poirier, Emily R. Theisen. Full-length EWSR1::FLI1 reveals low-complexity domain regulation of DNA and nucleosome binding [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Fusion-Positive Cancer: From Discovery to Therapy; 2026 Jan 13-15; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(1_Suppl): nr B019.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"218 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145961981","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-13DOI: 10.1158/1538-7445.fusionpositive26-a016
MaKenna R. Browne, Peter G. Hendrickson, David G. Kirsch
Objective: CIC::DUX4 sarcoma (CDS) is a rare and aggressive sub-type of sarcoma with no effective treatment options currently available. A significant barrier to identifying alternative therapeutic approaches is the lack of robust pre-clinical models. We previously generated 3 genetically engineered mouse models of CDS, however, all 3 models spontaneously formed tumors in the absence of Cre-recombinase. Accordingly, we developed a novel dural-recombinase FLEx-switch model (dFLEx CDS). In this study we show the dFLEx CDS model is leak-proof, spatially and temporally controllable, and recapitulates human CDS. Methods: The dFLEx CDS allele features a stop cassette proceeded by an inverted exon 1, and exon 2. Cre-mediated recombination inverts the first exon into frame and removes the upstream stop cassette while FLP-mediated recombination inverts exon 2 into frame. Both Cre and FLP-mediated recombination are required for CIC::DUX4 expression. To induce recombination, two approaches were used: (1) injection of Adeno-Cre-2A-FLP and (2) electroporation of pCAG-Cre and pCAG-FLPE plasmids. Additionally, dFLEx CDS mice were crossed with R26-FlpO deleter or R26-Cre mice to remove 1 of the 2 FLEx switches (sFLEx CDS). Results: Injection of AdCre-2A-FLP resulted in tumors within 60 days with 100% penetrance; however, tumor formation was not restricted to the injected hindlimb. Conversely, electroporation of separate pCAG-Cre and pCAG-FLPE plasmids resulted in spatially and temporally restricted tumors that express the CIC::DUX4 fusion and known CIC::DUX4 target genes. Interestingly, sFLEx CDS mice were less viable and suffered from spontaneous tumor formation, similar to our previous CDS GEMMs. Conclusion: dFLEx CDS is the first temporally and spatially controllable mouse model that recapitulates human CDS tumors. sFLEx CDS mice develop spontaneous tumors, further highlighting the potency of the CIC::DUX4 oncogene and need for multiple layers of recombination protection. The use of two FLEx systems minimizes unintended tumor development, providing a reliable platform for mechanistic insight and robust preclinical drug testing for CDS. Citation Format: MaKenna R. Browne, Peter G. Hendrickson, David G. Kirsch. Overcoming Promiscuous Tumor Formation: A Controlled Genetically Engineered Mouse Model of CIC::DUX4 Sarcoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Fusion-Positive Cancer: From Discovery to Therapy; 2026 Jan 13-15; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(1_Suppl): nr A016.
目的：CIC: DUX4肉瘤（CDS）是一种罕见的侵袭性亚型肉瘤，目前尚无有效的治疗方案。确定替代治疗方法的一个重要障碍是缺乏健全的临床前模型。我们之前建立了3个CDS的基因工程小鼠模型，然而，所有3个模型在缺乏cre -重组酶的情况下自发形成肿瘤。因此，我们开发了一种新的硬膜重组酶弹性开关模型（dFLEx CDS）。在这项研究中，我们证明了dFLEx CDS模型是防泄漏的，空间和时间可控的，并概括了人类CDS。方法：dFLEx CDS等位基因具有由倒置的外显子1和外显子2进行的停止盒。cre介导的重组将第一个外显子倒置为框架并去除上游停止盒，而flp介导的重组将外显子2倒置为框架。CIC::DUX4的表达需要Cre和flp介导的重组。为了诱导重组，采用了两种方法：(1)注射Adeno-Cre-2A-FLP；(2)电穿孔pCAG-Cre和pCAG-FLPE质粒。此外，将dFLEx CDS小鼠与R26-FlpO deleter或R26-Cre小鼠杂交，去除2个FLEx开关（sFLEx CDS）中的1个。结果：注射AdCre-2A-FLP后60天内形成肿瘤，外显率100%；然而，肿瘤的形成并不局限于注射后肢。相反，单独的pCAG-Cre和pCAG-FLPE质粒电穿孔导致表达CIC::DUX4融合和已知CIC::DUX4靶基因的肿瘤在空间和时间上受到限制。有趣的是，sFLEx CDS小鼠的存活率较低，并出现自发肿瘤形成，与我们之前的CDS gem相似。结论：dFLEx是第一个能再现人类CDS肿瘤的时间和空间可控小鼠模型。sFLEx CDS小鼠发生自发性肿瘤，进一步突出了CIC::DUX4癌基因的效力，需要多层重组保护。两个FLEx系统的使用最大限度地减少了意外肿瘤的发展，为CDS的机制洞察和强大的临床前药物测试提供了可靠的平台。引文格式：MaKenna R. Browne, Peter G. Hendrickson, David G. Kirsch。克服混杂肿瘤形成：CIC::DUX4肉瘤的控制基因工程小鼠模型[摘要]。AACR癌症研究特别会议论文集：融合阳性癌症：从发现到治疗；2026年1月13-15日；宾夕法尼亚州的费城费城（PA）： AACR；巨蟹座Res 2026；86(1_supl): no A016。
{"title":"Abstract A016: Overcoming Promiscuous Tumor Formation: A Controlled Genetically Engineered Mouse Model of CIC::DUX4 Sarcoma","authors":"MaKenna R. Browne, Peter G. Hendrickson, David G. Kirsch","doi":"10.1158/1538-7445.fusionpositive26-a016","DOIUrl":"https://doi.org/10.1158/1538-7445.fusionpositive26-a016","url":null,"abstract":"Objective: CIC::DUX4 sarcoma (CDS) is a rare and aggressive sub-type of sarcoma with no effective treatment options currently available. A significant barrier to identifying alternative therapeutic approaches is the lack of robust pre-clinical models. We previously generated 3 genetically engineered mouse models of CDS, however, all 3 models spontaneously formed tumors in the absence of Cre-recombinase. Accordingly, we developed a novel dural-recombinase FLEx-switch model (dFLEx CDS). In this study we show the dFLEx CDS model is leak-proof, spatially and temporally controllable, and recapitulates human CDS. Methods: The dFLEx CDS allele features a stop cassette proceeded by an inverted exon 1, and exon 2. Cre-mediated recombination inverts the first exon into frame and removes the upstream stop cassette while FLP-mediated recombination inverts exon 2 into frame. Both Cre and FLP-mediated recombination are required for CIC::DUX4 expression. To induce recombination, two approaches were used: (1) injection of Adeno-Cre-2A-FLP and (2) electroporation of pCAG-Cre and pCAG-FLPE plasmids. Additionally, dFLEx CDS mice were crossed with R26-FlpO deleter or R26-Cre mice to remove 1 of the 2 FLEx switches (sFLEx CDS). Results: Injection of AdCre-2A-FLP resulted in tumors within 60 days with 100% penetrance; however, tumor formation was not restricted to the injected hindlimb. Conversely, electroporation of separate pCAG-Cre and pCAG-FLPE plasmids resulted in spatially and temporally restricted tumors that express the CIC::DUX4 fusion and known CIC::DUX4 target genes. Interestingly, sFLEx CDS mice were less viable and suffered from spontaneous tumor formation, similar to our previous CDS GEMMs. Conclusion: dFLEx CDS is the first temporally and spatially controllable mouse model that recapitulates human CDS tumors. sFLEx CDS mice develop spontaneous tumors, further highlighting the potency of the CIC::DUX4 oncogene and need for multiple layers of recombination protection. The use of two FLEx systems minimizes unintended tumor development, providing a reliable platform for mechanistic insight and robust preclinical drug testing for CDS. Citation Format: MaKenna R. Browne, Peter G. Hendrickson, David G. Kirsch. Overcoming Promiscuous Tumor Formation: A Controlled Genetically Engineered Mouse Model of CIC::DUX4 Sarcoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Fusion-Positive Cancer: From Discovery to Therapy; 2026 Jan 13-15; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(1_Suppl): nr A016.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"243 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145962076","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-13DOI: 10.1158/1538-7445.fusionpositive26-ia002
Jolanta Grembecka
The protein-protein interaction between menin and Lysine Methyltransferase 2A (KMT2A; also known as Mixed Lineage Leukemia 1, MLL1) plays a critical role in various acute leukemia subtypes, including those driven by oncogenic fusion proteins such as KMT2A and NUP98 fusions. Our group pioneered the development of small-molecule inhibitors targeting the menin-KMT2A interaction, leading to ziftomenib (co-developed with Kura Oncology), which recently received FDA approval for AML treatment. Our efforts focused on the discovery and development of ziftomenib and its activity in fusion protein driven leukemias, both as a single agent and in combination therapies, will be discussed. Furthermore, we will also address ziftomenib’s activity against drug-induced menin mutations identified in AML patients that confer resistance. Finally, we will present our recent work on a new generation of menin inhibitors that block the most frequent drug-resistant menin mutans found in AML patients, providing a promising strategy to overcome resistance to current menin inhibitors. Citation Format: Jolanta Grembecka. Targeted menin inhibition to disrupt leukemia fusion oncoproteins: from discovery to therapeutic applications [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Fusion-Positive Cancer: From Discovery to Therapy; 2026 Jan 13-15; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(1_Suppl): nr IA002.
menin和赖氨酸甲基转移酶2A （KMT2A，也称为混合谱系白血病1，MLL1）之间的蛋白-蛋白相互作用在各种急性白血病亚型中起关键作用，包括那些由致癌融合蛋白驱动的白血病亚型，如KMT2A和NUP98融合。我们的团队率先开发了靶向menin-KMT2A相互作用的小分子抑制剂，导致ziftomenib（与Kura Oncology共同开发）最近获得FDA批准用于AML治疗。我们的工作重点是发现和开发ziftomenib及其在融合蛋白驱动的白血病中的活性，无论是作为单一药物还是联合治疗，都将被讨论。此外，我们还将研究ziftomenib对AML患者中发现的药物诱导的脑膜蛋白突变的活性。最后，我们将介绍我们最近在新一代menin抑制剂方面的工作，该抑制剂可阻断AML患者中最常见的耐药menin突变体，为克服对当前menin抑制剂的耐药性提供了一种有希望的策略。引文格式：Jolanta Grembecka。靶向menin抑制破坏白血病融合癌蛋白：从发现到治疗应用[摘要]。AACR癌症研究特别会议论文集：融合阳性癌症：从发现到治疗；2026年1月13-15日；宾夕法尼亚州的费城费城（PA）： AACR；巨蟹座Res 2026；86(1_supl): nr IA002。
{"title":"Abstract IA002: Targeted menin inhibition to disrupt leukemia fusion oncoproteins: from discovery to therapeutic applications","authors":"Jolanta Grembecka","doi":"10.1158/1538-7445.fusionpositive26-ia002","DOIUrl":"https://doi.org/10.1158/1538-7445.fusionpositive26-ia002","url":null,"abstract":"The protein-protein interaction between menin and Lysine Methyltransferase 2A (KMT2A; also known as Mixed Lineage Leukemia 1, MLL1) plays a critical role in various acute leukemia subtypes, including those driven by oncogenic fusion proteins such as KMT2A and NUP98 fusions. Our group pioneered the development of small-molecule inhibitors targeting the menin-KMT2A interaction, leading to ziftomenib (co-developed with Kura Oncology), which recently received FDA approval for AML treatment. Our efforts focused on the discovery and development of ziftomenib and its activity in fusion protein driven leukemias, both as a single agent and in combination therapies, will be discussed. Furthermore, we will also address ziftomenib’s activity against drug-induced menin mutations identified in AML patients that confer resistance. Finally, we will present our recent work on a new generation of menin inhibitors that block the most frequent drug-resistant menin mutans found in AML patients, providing a promising strategy to overcome resistance to current menin inhibitors. Citation Format: Jolanta Grembecka. Targeted menin inhibition to disrupt leukemia fusion oncoproteins: from discovery to therapeutic applications [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Fusion-Positive Cancer: From Discovery to Therapy; 2026 Jan 13-15; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(1_Suppl): nr IA002.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"5 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145962410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cancer-associated fibroblasts (CAFs) are abundant stromal cells in the tumor microenvironment (TME) that play a vital role in promoting tumor progression and drug resistance. The mechanisms regulating heterogeneity of CAFs in the renal cell carcinoma (RCC) could represent potential targets for reprogramming the TME. In this study, we conducted single-cell RNA sequence and flow cytometry analyses that identified a CAF subset overexpressing ApoE, which was correlated with poor survival in RCC patients. Mechanistically, NRF1 activation in CAFs induced formation of ApoEhigh CAFs and secretion of NRG1. ApoEhigh CAFs potentiated stemness properties in the surrounding RCC cells by secreting NRG1 and subsequently activating the HER2/NF-κB pathway. Interfering with NRG1 expression or inhibiting NF-κB signaling reduced ApoEhigh CAF-induced stemness of RCC cells. Furthermore, neutralizing NRG1 enhanced the efficacy of sunitinib in RCC models in vivo. Together, these findings highlight targeting the tumor-promoting functions of ApoEhigh CAFs as a promising approach for treating advanced RCC.
{"title":"NRF1 Induces ApoEhigh Cancer-Associated Fibroblasts to Promote Stemness of Renal Cell Carcinoma.","authors":"Ying Zhang,Zhouting Tuo,Yuan Lin,Senmao Li,Zhiwei Jiang,Chao Jiang,Huming Wang,Fang Dai,Xin Chen,Guangzheng Lin,Xianchao Sun,Zhaojie Lyu,Liangkuan Bi","doi":"10.1158/0008-5472.can-25-0959","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-0959","url":null,"abstract":"Cancer-associated fibroblasts (CAFs) are abundant stromal cells in the tumor microenvironment (TME) that play a vital role in promoting tumor progression and drug resistance. The mechanisms regulating heterogeneity of CAFs in the renal cell carcinoma (RCC) could represent potential targets for reprogramming the TME. In this study, we conducted single-cell RNA sequence and flow cytometry analyses that identified a CAF subset overexpressing ApoE, which was correlated with poor survival in RCC patients. Mechanistically, NRF1 activation in CAFs induced formation of ApoEhigh CAFs and secretion of NRG1. ApoEhigh CAFs potentiated stemness properties in the surrounding RCC cells by secreting NRG1 and subsequently activating the HER2/NF-κB pathway. Interfering with NRG1 expression or inhibiting NF-κB signaling reduced ApoEhigh CAF-induced stemness of RCC cells. Furthermore, neutralizing NRG1 enhanced the efficacy of sunitinib in RCC models in vivo. Together, these findings highlight targeting the tumor-promoting functions of ApoEhigh CAFs as a promising approach for treating advanced RCC.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"68 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145961326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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