Cell Death & Disease最新文献_第5页

Inhibition of furin in CAR macrophages directs them toward a proinflammatory phenotype and enhances their antitumor activities.

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2024-12-04 DOI: 10.1038/s41419-024-07267-4

Lydia Ziane-Chaouche, Antonella Raffo-Romero, Nawale Hajjaji, Firas Kobeissy, Donna Pinheiro, Soulaimane Aboulouard, Adeline Cozzani, Suman Mitra, Isabelle Fournier, Dasa Cizkova, Michel Salzet, Marie Duhamel

{"title":"Inhibition of furin in CAR macrophages directs them toward a proinflammatory phenotype and enhances their antitumor activities.","authors":"Lydia Ziane-Chaouche, Antonella Raffo-Romero, Nawale Hajjaji, Firas Kobeissy, Donna Pinheiro, Soulaimane Aboulouard, Adeline Cozzani, Suman Mitra, Isabelle Fournier, Dasa Cizkova, Michel Salzet, Marie Duhamel","doi":"10.1038/s41419-024-07267-4","DOIUrl":"10.1038/s41419-024-07267-4","url":null,"abstract":"Chimeric antigen receptor (CAR)-T-cell therapy has revolutionized cellular immunotherapy, demonstrating remarkable efficacy in hematological cancers. However, its application in solid tumors faces significant challenges, including limited T-cell infiltration and tumor-induced immunosuppression. Given the prominent role of macrophages in the tumor microenvironment, their phenotypic plasticity and inherent antitumor properties, such as phagocytosis, offer a promising avenue for therapeutic intervention. This study focuses on the development of a second generation of CAR macrophages (CAR-Ms). We elucidated the role of the proprotein convertase furin in macrophages, demonstrating its overexpression in the presence of tumor cells. Importantly, furin inhibition maintains a proinflammatory macrophage phenotype, potentially redirecting them towards an antitumor state. Compared to furin-expressing counterparts, furin-inhibited CAR-Ms exhibited heightened antitumor phagocytic activity against breast cancer cells and ex vivo patient-derived tumoroids. Notably, they sustained a persistent proinflammatory profile, indicative of enhanced tumoricidal potential. Additionally, furin-inhibited CAR-Ms secreted factors that promote T-cell activation, offering a means to modulate the tumor microenvironment. In summary, our work highlights the translational potential of furin-inhibited CAR-Ms as a potent cellular therapy to mitigate macrophage exhaustion within the tumor environment. By capitalizing on macrophage-mediated antitumor responses, these findings pave the way for the development of second-generation CAR-M therapeutic strategies tailored for solid tumors.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"15 12","pages":"879"},"PeriodicalIF":8.1,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11618602/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142779505","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Colorectal cancer patients-derived immunity-organoid platform unveils cancer-specific tissue markers associated with immunotherapy resistance.

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2024-12-04 DOI: 10.1038/s41419-024-07266-5

A Esposito, A Agostini, G Quero, G Piro, L Priori, A Caggiano, G Scaglione, A Battaglia, M A Calegari, L Salvatore, M Bensi, M G Maratta, A Ceccarelli, G Trovato, G Genovese, E Gurreri, S Ascrizzi, M Martini, C Fiorillo, A Fattorossi, F De Sanctis, S Ugel, V Corbo, S Alfieri, G Tortora, C Carbone

{"title":"Colorectal cancer patients-derived immunity-organoid platform unveils cancer-specific tissue markers associated with immunotherapy resistance.","authors":"A Esposito, A Agostini, G Quero, G Piro, L Priori, A Caggiano, G Scaglione, A Battaglia, M A Calegari, L Salvatore, M Bensi, M G Maratta, A Ceccarelli, G Trovato, G Genovese, E Gurreri, S Ascrizzi, M Martini, C Fiorillo, A Fattorossi, F De Sanctis, S Ugel, V Corbo, S Alfieri, G Tortora, C Carbone","doi":"10.1038/s41419-024-07266-5","DOIUrl":"10.1038/s41419-024-07266-5","url":null,"abstract":"Colorectal cancer (CRC) is a devastating disease, ranking as the second leading cause of cancer-related deaths worldwide. Immune checkpoint inhibitors (ICIs) have emerged as promising treatments; however, their efficacy is largely restricted to a subgroup of microsatellite instable (MSI) CRCs. In contrast, microsatellite stable (MSS) CRCs, which account for the majority of cases, exhibit variable and generally weaker response to ICIs, with only a subset demonstrating exceptional responsiveness. Identifying novel cancer-specific tissue (CST) markers predictive of immunotherapy response is crucial for refining patient selection and overcoming treatment resistance. In this study, we developed clinically relevant CRC organoids and autologous immune system interaction platforms to model ICI response. We conducted a comprehensive molecular characterization of both responder and non-responder models, identifying CST markers that predict ICI response. Validation of these findings was performed using an independent cohort of patient specimens through multiplex immunofluorescence. Furthermore, we demonstrated that knocking out a key gene from the identified predictive signature in resistant organoids restored immune sensitivity and induced T-cell-mediated apoptosis. Overall, our results provide novel insights into the mechanisms underlying immunotherapy resistance and suggest new markers for enhancing patient selection. These findings may pave the way for new therapeutic options in MSS patients, potentially broadening the cohort of individuals eligible for immunotherapy.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"15 12","pages":"878"},"PeriodicalIF":8.1,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11618451/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142779500","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

TIP60 enhances cisplatin resistance via regulating ΔNp63α acetylation in SCC.

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2024-12-03 DOI: 10.1038/s41419-024-07265-6

Akshay Hira, Jin Zhang, Madhavi P Kadakia

{"title":"TIP60 enhances cisplatin resistance via regulating ΔNp63α acetylation in SCC.","authors":"Akshay Hira, Jin Zhang, Madhavi P Kadakia","doi":"10.1038/s41419-024-07265-6","DOIUrl":"10.1038/s41419-024-07265-6","url":null,"abstract":"Non-melanoma skin cancer, including basal and squamous cell carcinoma, is the most common form of cancer worldwide, with approximately 5.4 million new cases diagnosed each year in the United States. While the chemotherapeutic drug cisplatin is often used to treat squamous cell carcinoma (SCC) patients, low response rates and disease recurrence are common. In this study, we show that TIP60 and ΔNp63α levels correlate with cisplatin resistance in SCC cell lines, suggesting that TIP60 contributes to the failure of platinum-based drugs in SCC by regulating the stability and transcriptional activity of ΔNp63α. Depletion of endogenous TIP60 or pharmacological inhibition of TIP60 led to a decrease in ΔNp63α protein and acetylation levels in multiple SCC cell lines. We showed that TIP60 upregulates ΔNp63α protein levels in cisplatin-resistant SCC cell lines by protecting it from cisplatin-mediated degradation and increasing its protein stability. Stable expression of TIP60 or ΔNp63α individually promoted resistance to cisplatin and reduced cell death, while loss of either TIP60 or ΔNp63α induced G2/M arrest, increased cell death, and sensitized cells to cisplatin. Moreover, pharmacological inhibition of TIP60 reduced acetylation of ΔNp63α and sensitized resistant cells to cisplatin. Taken together, our study indicates that TIP60-mediated stabilization of ΔNp63α increases cisplatin resistance and provides critical insights into the mechanisms by which ΔNp63α confers cisplatin resistance by promoting cell proliferation and inhibiting apoptosis. Furthermore, our data suggests that inhibition of TIP60 may be therapeutically advantageous in overcoming cisplatin resistance in SCC and other epithelial cancers.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"15 12","pages":"877"},"PeriodicalIF":8.1,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11615348/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142766369","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Correction: Long non-coding RNA Myd88 promotes growth and metastasis in hepatocellular carcinoma via regulating Myd88 expression through H3K27 modification.

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2024-12-03 DOI: 10.1038/s41419-024-07101-x

Xiaoliang Xu, Yin Yin, Junwei Tang, Yu Xie, Zhuo Han, Xudong Zhang, Qiaoyu Liu, Xihu Qin, Xinli Huang, Beicheng Sun

引用次数: 0

Correction: Serum apolipoprotein H determines ferroptosis resistance by modulating cellular lipid composition.

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2024-12-03 DOI: 10.1038/s41419-024-07181-9

Xiang He, Jiahui Zhang, Masha Huang, Jie Wang, Simin Yang, Xiang Yu, Yingjie Xu, Wen Yang

引用次数: 0

β-Hydroxybutyrate suppresses M1 macrophage polarization through β-hydroxybutyrylation of the STAT1 protein.

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2024-12-03 DOI: 10.1038/s41419-024-07268-3

Ya-Ping Bai, Yu-Jie Xing, Tao Ma, Kai Li, Teng Zhang, De-Guo Wang, Shu-Jun Wan, Cui-Wei Zhang, Yue Sun, Meng-Yan Wang, Guo-Dong Wang, Wen-Jun Pei, Kun Lv, Yan Zhang, Xiang Kong

{"title":"β-Hydroxybutyrate suppresses M1 macrophage polarization through β-hydroxybutyrylation of the STAT1 protein.","authors":"Ya-Ping Bai, Yu-Jie Xing, Tao Ma, Kai Li, Teng Zhang, De-Guo Wang, Shu-Jun Wan, Cui-Wei Zhang, Yue Sun, Meng-Yan Wang, Guo-Dong Wang, Wen-Jun Pei, Kun Lv, Yan Zhang, Xiang Kong","doi":"10.1038/s41419-024-07268-3","DOIUrl":"10.1038/s41419-024-07268-3","url":null,"abstract":"β-Hydroxybutyrate (β-OHB), the primary ketone body, is a bioactive metabolite that acts as both an energy substrate and a signaling molecule. Recent studies found that β-OHB inhibits the production of pro-inflammatory cytokines in macrophages, but its underlying molecular mechanisms have not yet been fully elucidated. Lysine β-hydroxybutyrylation (Kbhb), a post-translational modification mediated by β-OHB, plays a key role in regulating the expression and activity of modified proteins. However, whether macrophages undergo protein Kbhb and whether Kbhb modification regulates macrophage polarization remains largely unknown. In this study, treatment with β-OHB and ketone ester significantly decreased the lipopolysaccharide (LPS)-induced enhancement of the M1 phenotype of mouse bone marrow-derived macrophages (BMDMs), RAW264.7 cells, and peritoneal macrophages (PMs) in vitro and in vivo. Moreover, β-OHB treatment induced global protein Kbhb, which is associated with the regulation of macrophage M1 polarization. Proteome-wide Kbhb analysis in β-OHB-treated BMDMs revealed 3469 Kbhb modification sites within 1549 proteins, among which interleukin-12-responding proteins were significantly upregulated. Our results indicated that β-OHB regulated M1 macrophage polarization by inducing Kbhb modification of the signal transducer and activator of transcription 1 (STAT1) K679 site, which inhibited its LPS-induced phosphorylation and transcription. Altogether, our study demonstrated the presence of a widespread Kbhb landscape in the β-OHB-treated macrophages and provided novel insights into the anti-inflammatory effects of β-OHB.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"15 12","pages":"874"},"PeriodicalIF":8.1,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11615246/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142766373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The USP11/Nrf2 positive feedback loop promotes colorectal cancer progression by inhibiting mitochondrial apoptosis.

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2024-12-01 DOI: 10.1038/s41419-024-07188-2

Yuanyuan Lu, Wanhui Wei, Mengting Li, Danyang Chen, Wenjie Li, Qian Hu, Shouquan Dong, Lan Liu, Qiu Zhao

{"title":"The USP11/Nrf2 positive feedback loop promotes colorectal cancer progression by inhibiting mitochondrial apoptosis.","authors":"Yuanyuan Lu, Wanhui Wei, Mengting Li, Danyang Chen, Wenjie Li, Qian Hu, Shouquan Dong, Lan Liu, Qiu Zhao","doi":"10.1038/s41419-024-07188-2","DOIUrl":"https://doi.org/10.1038/s41419-024-07188-2","url":null,"abstract":"Abnormal antioxidant capacity of cancer is closely related to tumor malignancy. Modulation of oxidative stress status is a novel anticancer therapeutic target. Nrf2 is a key regulator of various antioxidant enzymes, but the mechanism of its deubiquitination remains largely unclear. This study unveiled that Nrf2 received post-transcriptional regulation from a proteasome-associated deubiquitinating enzyme, USP11, in colorectal cancer (CRC). It was found that USP11 was overexpressed in CRC tissues acting as an oncogene by inhibiting mitochondrial apoptosis, and USP11 managed to maintain balance in the production and elimination of reactive oxygen species (ROS). Mechanistically, we identified a feedback loop between USP11 and Nrf2 maintaining the redox homeostasis. USP11 stabilized Nrf2 by deubiquitinating and protecting it from proteasome-mediated degradation. Interestingly, we also map that Nrf2 could bind to the antioxidant reaction element (ARE) in the USP11 promoter to promote its transcription. Hence, USP11/Nrf2 positive feedback loop inhibited mitochondrial apoptosis of CRC cells by activating Nrf2/ARE signaling pathway, thus promoting CRC progression. Schematic diagram of the mechanism by which USP11/Nrf2 positive feedback loop inhibited mitochondrial apoptosis in CRC cells. This study found that USP11 was highly expressed in colorectal cancer (CRC) tissue and was associated with poor prognosis. In CRC, the inhibition of USP11 expression could promote the ubiquitination degradation of Nrf2, thereby inhibiting the Nrf2/ARE signaling pathway. This led to an increase in reactive oxygen species in the cell, causing mitochondrial apoptosis. In addition, Nrf2 could bind to the promoter region of USP11 to promote its transcription, both of which formed positive feedback loop.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"15 12","pages":"873"},"PeriodicalIF":8.1,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11609304/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142766366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Stabilization of SQLE mRNA by WTAP/FTO/IGF2BP3-dependent manner in HGSOC: implications for metabolism, stemness, and progression.

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2024-12-01 DOI: 10.1038/s41419-024-07257-6

Rui Hou, Xinrui Sun, Shiyao Cao, Yadong Wang, Luo Jiang

{"title":"Stabilization of SQLE mRNA by WTAP/FTO/IGF2BP3-dependent manner in HGSOC: implications for metabolism, stemness, and progression.","authors":"Rui Hou, Xinrui Sun, Shiyao Cao, Yadong Wang, Luo Jiang","doi":"10.1038/s41419-024-07257-6","DOIUrl":"https://doi.org/10.1038/s41419-024-07257-6","url":null,"abstract":"The metabolic reprogramming in high-grade serous ovarian carcinoma (HGSOC) affects the tumor stemness, which mediates tumor recurrence and progression. Knowledge of the stemness and metabolic characteristics of HGSOC is insufficient. Squalene epoxidase (SQLE), a key enzyme in cholesterol metabolism, was significantly upregulated in HGSOC samples with a fold change of about 4 in the RNA sequencing analysis. SQLE was positively related to peritoneal metastasis and poor prognosis of HGSOC patients. Functionally, SQLE drove cancer cell proliferation and inhibited apoptosis to accelerate HGSOC growth. SQLE was highly expressed in ALDH+CD133+ FACS-sorted cells derived from HGSOC cells and ovarian cancer stem cells (OCSCs)-enriched tumorspheres. SQLE overexpression resulted in enhanced CSC-like properties, including increased tumorsphere formation and stemness markers expression. In vivo, SQLE not only promoted cell line-derived xenografts growth but extended the OCSCs subpopulation of single-cell suspension. Moreover, non-targeted metabolomics profiling from UPLC-MS/MS system identified 90 differential metabolites responding to SQLE overexpression in HGSOC cells. Among them, the dysfunctional metabolisms of cholesterol and glutathione were involved in the maintenance of HGSOC stemness. Previous studies showed the alteration of N6-Methyladenosine (m6A) modification in HGSOC development. Herein, the m6A modification in the 3'UTR and CDS regions of SQLE mRNA was increased due to upregulated methyltransferases WTAP and downregulated demethylases FTO, which was recognized by m6A-binding proteins IGF2BP3, rather than IGF2BP1 or IGF2BP2, thereby stabilizing the SQLE mRNA. These results suggested that SQLE was a novel potential clinical marker for predicting the HGSOC development and prognosis, as well as a potential therapeutic target of HGSOC.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"15 12","pages":"872"},"PeriodicalIF":8.1,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11609299/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142766356","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

DOCK8 gene mutation alters cell subsets, BCR signaling, and cell metabolism in B cells.

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2024-12-01 DOI: 10.1038/s41419-024-07180-w

Heng Gu, Miaomiao Xie, Siyu Zhao, Xi Luo, Yanmei Huang, Lu Yang, Fei Guan, Jiahui Lei, Chaohong Liu

{"title":"DOCK8 gene mutation alters cell subsets, BCR signaling, and cell metabolism in B cells.","authors":"Heng Gu, Miaomiao Xie, Siyu Zhao, Xi Luo, Yanmei Huang, Lu Yang, Fei Guan, Jiahui Lei, Chaohong Liu","doi":"10.1038/s41419-024-07180-w","DOIUrl":"https://doi.org/10.1038/s41419-024-07180-w","url":null,"abstract":"DOCK8 deficiency has been shown to affect the migration, function, and survival of immune cells in innate and adaptive immune responses. The immunological mechanisms underlying autosomal recessive (AR) hyper-IgE syndrome (AR-HIES) caused by DOCK8 mutations remain unclear, leading to a lack of specific therapeutic options. In this study, we used CRISPR/Cas9 technology to develop a mouse model with a specific DOCK8 point mutation in exon 45 (c.5846C>A), which is observed in patients with AR-HIES. We then investigated the effect of this mutation on B cell development, cell metabolism, and function in a mouse model with Dock8 gene mutation. The results demonstrated that Dock8 gene mutation inhibited splenic MZ and GC B cell development and crippled BCR signaling. In addition, it resulted in enhanced glycolysis in B cells. Mechanistically, the reduced BCR signaling was related to decreased B cell spreading, BCR clustering, and signalosomes, mediated by inhibited activation of WASP. Furthermore, the DOCK8 mutation led to increased expression of c-Myc in B cells, which plays an important role in glycolysis. As such, GC B cells' formation and immune responses were disturbed in LCMV-infected mice. These findings will provide new insights into the immunological pathogenesis of primary immunodeficiency disorder caused by DOCK8 mutation.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"15 11","pages":"871"},"PeriodicalIF":8.1,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11608328/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142766516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

High iASPP (PPP1R13L) expression is an independent predictor of adverse clinical outcome in acute myeloid leukemia (AML).

IF 8.1 1区生物学

Cell Death & Disease Pub Date : 2024-11-30 DOI: 10.1038/s41419-024-07190-8

Mihada Bajrami Saipi, Alessia Ruiba, Marcus Matthias Schittenhelm, Gunnar Blumenstock, Balázs Győrffy, Serena Fazio, Marlon Hafner, Anna-Lena Ahrens, Lara Aldinger, Vanessa Aellig, François G Kavelaars, César Nombela-Arrieta, Falko Fend, Peter J M Valk, Driessen Christoph, Kerstin Maria Kampa-Schittenhelm

{"title":"High iASPP (PPP1R13L) expression is an independent predictor of adverse clinical outcome in acute myeloid leukemia (AML).","authors":"Mihada Bajrami Saipi, Alessia Ruiba, Marcus Matthias Schittenhelm, Gunnar Blumenstock, Balázs Győrffy, Serena Fazio, Marlon Hafner, Anna-Lena Ahrens, Lara Aldinger, Vanessa Aellig, François G Kavelaars, César Nombela-Arrieta, Falko Fend, Peter J M Valk, Driessen Christoph, Kerstin Maria Kampa-Schittenhelm","doi":"10.1038/s41419-024-07190-8","DOIUrl":"https://doi.org/10.1038/s41419-024-07190-8","url":null,"abstract":"Apoptosis-stimulating proteins of p53 (ASPPs) are a family of proteins that modulate key tumor suppressor pathways via direct interaction with p53. Deregulation of these proteins promotes cancer development and impairs sensitivity to systemic (chemo)therapy and radiation. In this study, we describe that the inhibitor of ASPP (iASPP) is frequently highly expressed in acute myeloid leukemia (AML) and that overexpression correlates with a poor clinical outcome. Four independent patient cohorts comprising about 1500 patient samples were analysed and consistently confirm an association of high iASPP expression with unfavourable clinical characteristics and shorter survival. Notably, the predictive role of iASPP is independent of, and adds information to, the European LeukemiaNET (ELN) risk classification. iASPP-interference cell models were developed to investigate the underlying functional aspects of iASPP in AML biology. Attenuation of iASPP expression resulted in reduced proliferation rates of leukemic blasts and rendered cells more susceptible towards induction of apoptosis in response to cytotoxic therapy. In line, independent NSG xenograft mouse experiments demonstrate that attenuation of iASPP results in a significant delay of disease onset and tumor burden and this translates to longer overall survival of mice. In conclusion, deregulation of iASPP has direct functional consequences in AML. Determination of iASPP expression levels provides valuable additional information as a predictive marker in AML and may guide treatment decisions.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"15 11","pages":"869"},"PeriodicalIF":8.1,"publicationDate":"2024-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11608330/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142765889","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0