JCI insightPub Date : 2024-11-08DOI: 10.1172/jci.insight.181067
Mohadeseh Hasanpourghadi, Mikhail Novikov, Robert Ambrose, Arezki Chekaoui, Dakota Newman, ZhiQuan Xiang, Andrew D Luber, Sue L Currie, XiangYang Zhou, Hildegund Cj Ertl
{"title":"A therapeutic HBV vaccine containing a checkpoint modifier enhances CD8+ T cell and antiviral responses.","authors":"Mohadeseh Hasanpourghadi, Mikhail Novikov, Robert Ambrose, Arezki Chekaoui, Dakota Newman, ZhiQuan Xiang, Andrew D Luber, Sue L Currie, XiangYang Zhou, Hildegund Cj Ertl","doi":"10.1172/jci.insight.181067","DOIUrl":"10.1172/jci.insight.181067","url":null,"abstract":"<p><p>In patients who progress from acute hepatitis B virus (HBV) infection to a chronic HBV (CHB) infection, CD8+ T cells fail to eliminate the virus and become impaired. A functional cure of CHB likely requires CD8+ T cell responses different from those induced by the infection. Here we report preclinical immunogenicity and efficacy of an HBV therapeutic vaccine that includes herpes simplex virus (HSV) glycoprotein D (gD), a checkpoint modifier of early T cell activation, that augments CD8+ T cell responses. The vaccine is based on a chimpanzee adenovirus serotype 6 (AdC6) vector, called AdC6-gDHBV2, which targets conserved and highly immunogenic regions of the viral polymerase and core antigens fused to HSV gD. The vaccine was tested with and without gD in mice for immunogenicity, and in an AAV8-1.3HBV vector model of antiviral efficacy. The vaccine encoding the HBV antigens within gD stimulates potent and broad CD8+ T cell responses. In a surrogate model of HBV infection, a single intramuscular injection achieved pronounced and sustained declines of circulating HBV DNA copies and HBV surface antigen; both inversely correlated with HBV-specific CD8+ T cell frequencies in spleen and liver.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142125761","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}
JCI insightPub Date : 2024-11-08DOI: 10.1172/jci.insight.164762
Chandra M Menendez, Jonathan Zuccolo, Susan E Swedo, Sean Reim, Brian Richmand, Hilla Ben-Pazi, Abraham Kovoor, Madeleine W Cunningham
{"title":"Dopamine receptor autoantibody signaling in infectious sequelae differentiates movement versus neuropsychiatric disorders.","authors":"Chandra M Menendez, Jonathan Zuccolo, Susan E Swedo, Sean Reim, Brian Richmand, Hilla Ben-Pazi, Abraham Kovoor, Madeleine W Cunningham","doi":"10.1172/jci.insight.164762","DOIUrl":"10.1172/jci.insight.164762","url":null,"abstract":"<p><p>Despite growing recognition, neuropsychiatric diseases associated with infections are a major unsolved problem worldwide. Group A streptococcal (GAS) infections can cause autoimmune sequelae characterized by movement disorders, such as Sydenham chorea, and neuropsychiatric disorders. The molecular mechanisms underlying these diseases are not fully understood. Our previous work demonstrates that autoantibodies (AAbs) can target dopaminergic neurons and increase dopamine D2 receptor (D2R) signaling. However, AAb influence on dopamine D1 receptor (D1R) activity is underexplored. We found evidence that suggests GAS-induced cross-reactive AAbs promote autoimmune encephalitis of the basal ganglia, a region of high dopamine receptor density. Here, we report a mechanism whereby neuropsychiatric syndromes are distinguished from movement disorders by differences in D1R and D2R AAb titers, signaling, receiver operating characteristic curves, and immunoreactivity with D1R and D2R autoreactive epitopes. D1R AAb signaling was observed through patient serum AAbs and novel patient-derived monoclonal antibodies (mAbs), which induced both D1R G protein- and β-arrestin-transduced signals. Furthermore, patient AAbs and mAbs enhanced D1R signaling mechanisms mediated by the neurotransmitter dopamine. Our findings suggest that AAb-mediated D1R signaling may contribute to the pathogenesis of neuropsychiatric sequelae and inform new options for diagnosis and treatment of GAS sequelae and related disorders.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142346970","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}
JCI insightPub Date : 2024-11-08DOI: 10.1172/jci.insight.183400
Ye Chen, Maogen Chen, Yu Liu, Qiang Li, Youqiu Xue, Liu Liu, Rongzhen Liang, Yiding Xiong, Jun Zhao, Jingrong Chen, Weidong Lin, Julie Wang, Yun Feng Pan, William Stohl, Song Guo Zheng
{"title":"BAFF promotes follicular helper T cell development and germinal center formation through BR3 signal.","authors":"Ye Chen, Maogen Chen, Yu Liu, Qiang Li, Youqiu Xue, Liu Liu, Rongzhen Liang, Yiding Xiong, Jun Zhao, Jingrong Chen, Weidong Lin, Julie Wang, Yun Feng Pan, William Stohl, Song Guo Zheng","doi":"10.1172/jci.insight.183400","DOIUrl":"10.1172/jci.insight.183400","url":null,"abstract":"<p><p>T follicular helper (Tfh) cells represent an important subset of CD4+ T cells that is crucial to the maturation and differentiation of B cells and the production of high-affinity antibodies. Because B cell activating-factor (BAFF), a vital B cell survival factor, is also crucial to B cell maturation and differentiation, we assessed the effects of BAFF on Tfh cell development and function. We demonstrated that deficiency of BAFF, but not of APRIL, markedly inhibited Tfh cell development, germinal center (GC) formation, and antigen-specific antibody production. The promoting effect of BAFF on Tfh cell development was dependent on expression of BR3 on T cells, and its promoting effect on GC formation was dependent on expression of BR3 on both T cells and B cells. BAFF directly promoted expression of the Tfh cell-characteristic genes via NF-κB signaling. This effect did need BR3 expression. Thus, BAFF not only has direct effects on B cells, but it also has direct effects on Tfh cell differentiation via engagement of BR3, which collectively promoted GC formation and production of high-affinity antibodies. This dual effect of BAFF on B cells and Tfh cells may help explain the clinical utility of BAFF antagonists in the management of certain autoimmune diseases.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142346969","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}
JCI insightPub Date : 2024-11-08DOI: 10.1172/jci.insight.182766
Sophia Y Chen, Heng-Chung Kung, Birginia Espinoza, India Washington, Kai Chen, Jianxin Wang, Haley Zlomke, Michael Loycano, Rulin Wang, Michael Pickup, William R Burns, Juan Fu, William L Hwang, Lei Zheng
{"title":"Targeting heterogeneous tumor microenvironments in pancreatic cancer mouse models of metastasis by TGF-β depletion.","authors":"Sophia Y Chen, Heng-Chung Kung, Birginia Espinoza, India Washington, Kai Chen, Jianxin Wang, Haley Zlomke, Michael Loycano, Rulin Wang, Michael Pickup, William R Burns, Juan Fu, William L Hwang, Lei Zheng","doi":"10.1172/jci.insight.182766","DOIUrl":"10.1172/jci.insight.182766","url":null,"abstract":"<p><p>The dual tumor-suppressive and -promoting functions of TGF-β signaling has made its targeting challenging. We examined the effects of TGF-β depletion by AVID200/BMS-986416 (TGF-β-TRAP), a TGF-β ligand trap, on the tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC) murine models with different organ-specific metastasis. Our study demonstrated that TGF-β-TRAP potentiates the efficacy of anti-programmed cell death 1 (anti-PD-1) in a PDAC orthotopic murine model with liver metastasis tropism, significantly reducing liver metastases. We further demonstrated the heterogeneous response of cytotoxic effector T cells to combination TGF-β-TRAP and anti-PD-1 treatment across several tumor models. Single-nuclear RNA sequencing suggested that TGF-β-TRAP modulates cancer-associated fibroblast (CAF) heterogeneity and suppresses neutrophil degranulation and CD4+ T cell response to neutrophil degranulation. Ligand-receptor analysis indicated that TGF-β-TRAP may modulate the CCL5/CCR5 axis as well as costimulatory and checkpoint signaling from CAFs and myeloid cells. Notably, the most highly expressed ligands of CCR5 shifted from the immunosuppressive CCL5 to CCL7 and CCL8, which may mediate the immune agonist activity of CCR5 following TGF-β-TRAP and anti-PD-1 combination treatment. This study suggested that TGF-β depletion modulates CAF heterogeneity and potentially reprograms CAFs and myeloid cells into antitumor immune agonists in PDAC, supporting the validation of such effects in human specimens.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142287567","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}
JCI insightPub Date : 2024-11-08DOI: 10.1172/jci.insight.177789
Bingjie Zheng, Xuyang Zhang, Xiangxi Kong, Jie Li, Bao Huang, Hui Li, Zhongyin Ji, Xiaoan Wei, Siyue Tao, Zhi Shan, Zemin Ling, Junhui Liu, Jian Chen, Fengdong Zhao
{"title":"S1P regulates intervertebral disc aging by mediating endoplasmic reticulum-mitochondrial calcium ion homeostasis.","authors":"Bingjie Zheng, Xuyang Zhang, Xiangxi Kong, Jie Li, Bao Huang, Hui Li, Zhongyin Ji, Xiaoan Wei, Siyue Tao, Zhi Shan, Zemin Ling, Junhui Liu, Jian Chen, Fengdong Zhao","doi":"10.1172/jci.insight.177789","DOIUrl":"10.1172/jci.insight.177789","url":null,"abstract":"<p><p>As the aging process progresses, age-related intervertebral disc degeneration (IVDD) is becoming an emerging public health issue. Site-1 protease (S1P) has recently been found to be associated with abnormal spinal development in patients with mutations and has multiple biological functions. Here, we discovered a reduction of S1P in degenerated and aging intervertebral discs, primarily regulated by DNA methylation. Furthermore, through drug treatment and siRNA-mediated S1P knockdown, nucleus pulposus cells were more prone to exhibit degenerative and aging phenotypes. Conditional KO of S1P in mice resulted in spinal developmental abnormalities and premature aging. Mechanistically, S1P deficiency impeded COP II-mediated transport vesicle formation, which leads to protein retention in the endoplasmic reticulum (ER) and subsequently ER distension. ER distension increased the contact between the ER and mitochondria, disrupting ER-to-mitochondria calcium flow and resulting in mitochondrial dysfunction and energy metabolism disturbance. Finally, using 2-APB to inhibit calcium ion channels and the senolytic drug dasatinib and quercetin (D + Q) partially rescued the aging and degenerative phenotypes caused by S1P deficiency. In conclusion, our findings suggest that S1P is a critical factor in causing IVDD in the process of aging and highlight the potential of targeting S1P as a therapeutic approach for age-related IVDD.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142346984","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}
JCI insightPub Date : 2024-11-08DOI: 10.1172/jci.insight.184138
Emily A Nelson, Anna L Tyler, Taylor Lakusta-Wong, Karolyn G Lahue, Katherine C Hankes, Cory Teuscher, Rachel M Lynch, Martin T Ferris, J Matthew Mahoney, Dimitry N Krementsov
{"title":"Analysis of CNS autoimmunity in genetically diverse mice reveals unique phenotypes and mechanisms.","authors":"Emily A Nelson, Anna L Tyler, Taylor Lakusta-Wong, Karolyn G Lahue, Katherine C Hankes, Cory Teuscher, Rachel M Lynch, Martin T Ferris, J Matthew Mahoney, Dimitry N Krementsov","doi":"10.1172/jci.insight.184138","DOIUrl":"10.1172/jci.insight.184138","url":null,"abstract":"<p><p>Multiple sclerosis (MS) is a complex disease with significant heterogeneity in disease course and progression. Genetic studies have identified numerous loci associated with MS risk, but the genetic basis of disease progression remains elusive. To address this, we leveraged the Collaborative Cross (CC), a genetically diverse mouse strain panel, and experimental autoimmune encephalomyelitis (EAE). The 32 CC strains studied captured a wide spectrum of EAE severity, trajectory, and presentation, including severe-progressive, monophasic, relapsing remitting, and axial rotary-EAE (AR-EAE), accompanied by distinct immunopathology. Sex differences in EAE severity were observed in 6 strains. Quantitative trait locus analysis revealed distinct genetic linkage patterns for different EAE phenotypes, including EAE severity and incidence of AR-EAE. Machine learning-based approaches prioritized candidate genes for loci underlying EAE severity (Abcc4 and Gpc6) and AR-EAE (Yap1 and Dync2h1). This work expands the EAE phenotypic repertoire and identifies potentially novel loci controlling unique EAE phenotypes, supporting the hypothesis that heterogeneity in MS disease course is driven by genetic variation.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142346968","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}
JCI insightPub Date : 2024-11-08DOI: 10.1172/jci.insight.180239
Justin Sui, Hanxi Xiao, Ugonna Mbaekwe, Nai-Chun Ting, Kaley Murday, Qianjiang Hu, Alyssa D Gregory, Theodore S Kapellos, Ali Öender Yildirim, Melanie Königshoff, Yingze Zhang, Frank Sciurba, Jishnu Das, Corrine R Kliment
{"title":"Interpretable machine learning uncovers epithelial transcriptional rewiring and a role for Gelsolin in COPD.","authors":"Justin Sui, Hanxi Xiao, Ugonna Mbaekwe, Nai-Chun Ting, Kaley Murday, Qianjiang Hu, Alyssa D Gregory, Theodore S Kapellos, Ali Öender Yildirim, Melanie Königshoff, Yingze Zhang, Frank Sciurba, Jishnu Das, Corrine R Kliment","doi":"10.1172/jci.insight.180239","DOIUrl":"10.1172/jci.insight.180239","url":null,"abstract":"<p><p>Transcriptomic analyses have advanced the understanding of complex disease pathophysiology including chronic obstructive pulmonary disease (COPD). However, identifying relevant biologic causative factors has been limited by the integration of high dimensionality data. COPD is characterized by lung destruction and inflammation, with smoke exposure being a major risk factor. To define previously unknown biological mechanisms in COPD, we utilized unsupervised and supervised interpretable machine learning analyses of single-cell RNA-Seq data from the mouse smoke-exposure model to identify significant latent factors (context-specific coexpression modules) impacting pathophysiology. The machine learning transcriptomic signatures coupled to protein networks uncovered a reduction in network complexity and new biological alterations in actin-associated gelsolin (GSN), which was transcriptionally linked to disease state. GSN was altered in airway epithelial cells in the mouse model and in human COPD. GSN was increased in plasma from patients with COPD, and smoke exposure resulted in enhanced GSN release from airway cells from patients with COPD. This method provides insights into rewiring of transcriptional networks that are associated with COPD pathogenesis and provides a translational analytical platform for other diseases.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142346983","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}
JCI insightPub Date : 2024-11-08DOI: 10.1172/jci.insight.174725
Mauricio Torres, Brent Pederson, Hui Wang, Liangguang Leo Lin, Huilun Helen Wang, Amara Bugarin-Lapuz, Zhen Zhao, Ling Qi
{"title":"Purkinje cell-specific deficiency in SEL1L-hrd1 endoplasmic reticulum-associated degradation causes progressive cerebellar ataxia in mice.","authors":"Mauricio Torres, Brent Pederson, Hui Wang, Liangguang Leo Lin, Huilun Helen Wang, Amara Bugarin-Lapuz, Zhen Zhao, Ling Qi","doi":"10.1172/jci.insight.174725","DOIUrl":"10.1172/jci.insight.174725","url":null,"abstract":"<p><p>Recent studies have identified multiple genetic variants of SEL1L-HRD1 endoplasmic reticulum-associated degradation (ERAD) in humans with neurodevelopmental disorders and locomotor dysfunctions, including ataxia. However, the relevance and importance of SEL1L-HRD1 ERAD in the pathogenesis of ataxia remain unexplored. Here, we showed that SEL1L deficiency in Purkinje cells leads to early-onset progressive cerebellar ataxia with progressive loss of Purkinje cells with age. Mice with Purkinje cell-specific deletion of SEL1L (Sel1LPcp2Cre) exhibited motor dysfunction beginning around 9 weeks of age. Transmission electron microscopy analysis revealed dilated ER and fragmented nuclei in Purkinje cells of adult Sel1LPcp2Cre mice, indicative of altered ER homeostasis and cell death. Finally, loss of Purkinje cells was associated with a secondary neurodegeneration of granular cells, as well as robust activation of astrocytes and proliferation of microglia, in the cerebellums of Sel1LPcp2Cre mice. These data demonstrate the pathophysiological importance of SEL1L-HRD1 ERAD in Purkinje cells in the pathogenesis of cerebellar ataxia.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142365271","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}
JCI insightPub Date : 2024-11-05DOI: 10.1172/jci.insight.178159
Zhiquan Liu, Siyu Chen, Chien-Hui Lo, Qing Wang, Yang Sun
{"title":"All-in-one AAV-mediated Nrl gene inactivation rescues retinal degeneration in Pde6a mice.","authors":"Zhiquan Liu, Siyu Chen, Chien-Hui Lo, Qing Wang, Yang Sun","doi":"10.1172/jci.insight.178159","DOIUrl":"https://doi.org/10.1172/jci.insight.178159","url":null,"abstract":"<p><p>Retinitis pigmentosa (RP) is a complex group of inherited retinal diseases characterized by progressive death of photoreceptor cells and eventual blindness. Pde6a, which encodes a cGMP-specific phosphodiesterase, is a crucial pathogenic gene for autosomal recessive RP (RP43); there is no effective therapy for this form of RP. The compact CRISPR/SaCas9 system, which can be packaged into a single adeno-associated virus, holds promise for simplifying effective gene therapy. Here, we demonstrated that all-in-one AAV-SaCas9-mediated Nrl gene inactivation can efficiently prevent retinal degeneration in a RP mouse model with Pde6anmf363/nmf363 mutation. We screened single guide RNAs (sgRNAs) capable of efficiently editing mouse Nrl gene in N2a cells and then achieved effective gene editing by using a single AAV to co-deliver SaCas9 and an optimal Nrl-sg2 into the mouse retina. Excitingly, in vivo inactivation of Nrl improved photoreceptor cell survival and rescued retinal function in treated Pde6a deficient mice. Thus, we showed that a practical, gene-independent method, AAV-SaCas9-mediated Nrl inactivation, holds promise for future therapeutic applications in patients with RP.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142583245","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}
JCI insightPub Date : 2024-11-05DOI: 10.1172/jci.insight.183889
Christopher Ag Booth, Juliette M Bouyssou, Katsuhiro Togami, Olivier Armand, Hembly G Rivas, Kezhi Yan, Siobhan Rice, Shuyuan Cheng, Emily M Lachtara, Jean-Pierre Bourquin, Alex Kentsis, Esther Rheinbay, James A DeCaprio, Andrew A Lane
{"title":"BPDCN MYB fusions regulate cell cycle genes, impair differentiation and induce myeloid-dendritic cell leukemia.","authors":"Christopher Ag Booth, Juliette M Bouyssou, Katsuhiro Togami, Olivier Armand, Hembly G Rivas, Kezhi Yan, Siobhan Rice, Shuyuan Cheng, Emily M Lachtara, Jean-Pierre Bourquin, Alex Kentsis, Esther Rheinbay, James A DeCaprio, Andrew A Lane","doi":"10.1172/jci.insight.183889","DOIUrl":"https://doi.org/10.1172/jci.insight.183889","url":null,"abstract":"<p><p>MYB fusions are recurrently found in select cancers, including blastic plasmacytoid dendritic cell neoplasm (BPDCN), an acute leukemia with poor prognosis. They are markedly enriched in BPDCN compared to other blood cancers, and in some patients are the only obvious somatic mutation detected. This suggests they may alone be sufficient to drive dendritic cell transformation. MYB fusions are hypothesized to alter the normal transcription factor activity of MYB, but mechanistically how they promote leukemogenesis is poorly understood. Using CUT&RUN chromatin profiling, we found that in BPDCN leukemogenesis, MYB switches from being a regulator of dendritic cell lineage genes to aberrantly regulating G2/M cell cycle control genes. MYB fusions found in BPDCN patients increased the magnitude of DNA binding at these locations, and this was linked to BPDCN-associated gene expression changes. Furthermore, expression of MYB fusions in vivo impaired dendritic cell differentiation and induced transformation to generate a mouse model of myeloid-dendritic acute leukemia. Therapeutically, we present evidence that all-trans retinoic acid (ATRA) may cause loss of MYB protein and cell death in BPDCN.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142583249","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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