Leukemia最新文献

{"title":"YTHDC1 is a therapeutic target for B-cell acute lymphoblastic leukemia by attenuating DNA damage response through the KMT2C-H3K4me1/me3 epigenetic axis.","authors":"Xinxin Li, Minhua Zheng, Shoubao Ma, Fengze Nie, Zhiqiang Yin, Yanan Liang, Xianchun Yan, Weihong Wen, Jianhua Yu, Yingmin Liang, Siyong Huang, Hua Han","doi":"10.1038/s41375-024-02451-z","DOIUrl":"https://doi.org/10.1038/s41375-024-02451-z","url":null,"abstract":"<p><p>B-cell acute lymphoblastic leukemia (B-ALL) is an aggressive malignancy characterized by the aberrant accumulation of immature and dysfunctional B cells in bone marrow (BM). Although chemotherapy and other therapies have been widely applied, some patients such as relapsed or drug-refractory (R/R) B-ALL patients exhibit limited response. YT521-B homologous domain-containing protein 1 (YTHDC1) is a nuclear reader of N⁶-methyladenosine (m⁶A) RNA modification, which has been implicated in different malignancies including leukemia. In the current study, we show that YTHDC1 is highly expressed in B-ALL cells. YTHDC1 knockdown attenuated B-ALL cell proliferation and cell cycle progression in vitro, and prolonged survival of mice in the human B-ALL xenograft model in vivo attributable to compromised leukemogenesis. Mechanistically, YTHDC1 knockdown significantly increased the accumulation of endogenous and chemotherapeutic agents-induced DNA damage in B-ALL cells. Furthermore, we identified that YTHDC1 binds to and stabilizes m⁶A-modified KMT2C mRNA. KMT2C is a key enzyme catalyzing histone H3K4 methylation required for the expression of DNA damage response (DDR)-related genes, implying that YTHDC1 inhibitors might improve chemotherapy by attenuating DDR via reducing KMT2C. Indeed, with molecular docking and biochemical experiments, we identified EPZ-5676 as a YTHDC1 inhibitor, and combination of EPZ-5676 with Cytarabine (Ara-c) significantly improved the efficacy of chemotherapy in B-ALL mouse models using YTHDC1^high primary and lined B-ALL cells. Collectively, YTHDC1 is required for DDR in B-ALL cells by upregulating DDR-related gene expression via stabilizing m⁶A-modified KMT2C mRNA, thereby leading to increased histone H3K4 methylation, and targeted inhibition of YTHDC1 is a potentially new therapeutic strategy against B-ALL, especially YTHDC1^high B-ALL.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":" ","pages":""},"PeriodicalIF":12.8,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582999","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}

{"title":"Transcriptional regulatory program controlled by MYB in T-cell acute lymphoblastic leukemia","authors":"Xiaoman Shao,&nbsp;Rui Yokomori,&nbsp;Jolynn Zu Lin Ong,&nbsp;Haoqing Shen,&nbsp;Dennis Kappei,&nbsp;Leilei Chen,&nbsp;Allen Eng Juh Yeoh,&nbsp;Shi Hao Tan,&nbsp;Takaomi Sanda","doi":"10.1038/s41375-024-02455-9","DOIUrl":"10.1038/s41375-024-02455-9","url":null,"abstract":"The transcription factor MYB is frequently upregulated in T-cell acute lymphoblastic leukemia (T-ALL), a hematological malignancy originating from T-cell precursors. Here, we demonstrate that MYB plays a crucial role by regulating genes essential for T-ALL pathogenesis. Integrative analysis reveals a long MYB isoform, ENST00000367814.8, which is dominantly expressed and confers a proliferative advantage in T-ALL cells. Rapid depletion of MYB via dTAG-mediated protein degradation affects a large number of genes, which can be classified into early response or late response genes based on their kinetics. Early response genes include many genes involved in hematopoiesis, such as TAL1, RUNX1, GATA3, IKZF2, and CXCR4. Their expression can be recovered at later time-points, suggesting the presence of a negative feedback loop mechanism. In contrast, late response genes, which are continuously downregulated after MYB depletion, includes many genes involved in cell proliferation as well as TAL1 targets, thereby affecting the cellular phenotype.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"38 12","pages":"2573-2584"},"PeriodicalIF":12.8,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02455-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Post-transplant cyclophosphamide separates graft-versus host disease and graft versus leukemia effects after HLA-matched stem-cell transplantation for acute myeloid leukemia.","authors":"Avichai Shimoni, Christophe Peczynski, Myriam Labopin, Alexander Kulagin, Ellen Meijer, Jan Cornelissen, Goda Choi, Jaime Sanz, Montserrat Rovira, Gwendolyn Van Gorkom, Nicolaus Kröger, Yener Koc, Jan Vydra, J L Diez-Martin, Carlos Solano, Amit Patel, Patrizia Chiusolo, Fabio Ciceri, Arnon Nagler, Mohamad Mohty","doi":"10.1038/s41375-024-02445-x","DOIUrl":"https://doi.org/10.1038/s41375-024-02445-x","url":null,"abstract":"<p><p>The association of graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effects after allogeneic stem-cell transplantation (SCT) is well-established but was not confirmed in the modern era and following post-transplant cyclophosphamide (PTCy). We assessed GVHD/ GVL association in AML patients following HLA-matched SCT with standard calcineurin-based (n = 12,653, 57% with additional in-vivo T-cell depletion) or PTCy-based (n = 508) GVHD prophylaxis. Following standard prophylaxis, acute GVHD grade II-IV and III-IV, chronic GVHD, and extensive chronic GVHD rates were 23.8%, 7.5%, 37.0%, and 16.3%, respectively. Acute GVHD grade II and III-IV were associated with lower relapse [hazard-ratio (HR) 0.85, P = 0.002; HR 0.76, P = 0.003, respectively)], higher non-relapse mortality (NRM) (HR 1.5, P < 0.001; HR 6.21, P < 0.001) and lower overall survival (OS) (HR 1.49, P < 0.001; HR 6.1, P < 0.001). Extensive chronic GVHD predicted lower relapse (HR 0.69, P < 0.001), higher NRM (HR 2.83, P < 0.001), and lower OS (HR 2.74, P < 0.001). Following PTCy, GVHD rates were 22.8%, 6.2%, 35.5%, and 17.7%, respectively. Acute GVHD was not associated with relapse (HR 1.37, P = 0.15) but predicted higher NRM (HR 3.34, P < 0.001) and lower OS (HR 1.92, P = 0.001). Chronic GVHD was not prognostic for these outcomes. In conclusion, GVHD and GVL are strongly associated with contemporary SCT. However, following PTCy, GVHD is not associated with reduced relapse.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":" ","pages":""},"PeriodicalIF":12.8,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142558192","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}

{"title":"The dynamic evolution of lineage switch under CD19 CAR-T treatment in non-KMT2A rearranged B-ALL patients","authors":"Shaowei Qiu, Yihan Mei, Runxia Gu, Yu Liu, Manling Chen, Haiyan Xing, Kejing Tang, Zheng Tian, Qing Rao, Donglin Yang, Aiming Pang, Shuning Wei, Yujiao Jia, Huijun Wang, Sizhou Feng, Hui Wei, Ping Zhu, Min Wang, Ying Wang, Wenbing Liu, Jianxiang Wang","doi":"10.1038/s41375-024-02449-7","DOIUrl":"https://doi.org/10.1038/s41375-024-02449-7","url":null,"abstract":"<p>Reconstructing the clonal evolution paradigm helps us understand the process of lineage switching [6]. Therefore, we depicted the clonal evolution pattern of patient 1 (P01) through single-cell targeted DNA sequencing (Supplementary Table 3). Through single-cell genomic sequencing and quality control, we obtained a total of 6566 high-quality cells with related gene mutations (<i>FLT3, BCORL1</i>, and <i>STAG2</i>) at the four time points for clone structure inference (Fig. 1B, Supplementary Table 4). The Tapestri insights analysis (Fig. 1B) revealed that the <i>FLT3-ITD</i> mutation consistently persisted at four different time points (83.3%, 69.4%, 98.8%, 9.0%). Pre-existing <i>BCORL1</i> mutation rapidly expanded after the initiation of myeloid relapse, while <i>STAG2</i> mutation occurred with the presence of <i>BCORL1</i> mutation (16.1%, 4.3%, 96.1%, 0.0%). Compared with the T1_Pre_CART time point, we found that the <i>BCORL1</i> mutation burden (Fig. 1C) increased at the T3_Relapse time point. Moreover, the single-cell membrane protein data (Supplementary Fig. 1A–D, Supplementary Table 5) showed that B-ALL blast cells expressed typical B-ALL-associated markers CD19 and CD10, along with co-expression of myeloid-associated markers CD33 and CD123 at the T1_Pre_CART time point and the blast cells lost the expression of lymphoid marker CD19 at relapse, confirming the phenomenon of lineage switch.</p><p>Moreover, the clonal evolution structure of patient 2 (P02) was reconstructed through whole exon sequencing and targeted sequencing (Fig. 1D, Supplementary Table 6). Throughout the treatment course of P02, the expression of fusion gene <i>EP300::ZNF384</i> persisted, the <i>IKZF2</i> mutated clone disappeared after CD19 CAR-T therapy, and the <i>BCOR</i> gene mutated clone emerged upon myeloid lineage relapse. Through BCR sequencing, we observed the presence of identical immunoglobulin sequences at the T2_Relapse time point as those in the T1_Pre_CART time point (Fig. 1E, Supplementary Table 7), and we could also observe that the clonal frequency of immunoglobulin sequences increased during relapse, suggesting their enrichment in the myeloid reprogramming process. This result suggested that the origin of myeloid progenitor cells was reprogrammed from B-ALL cells [7].</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"239 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142555985","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}

{"title":"Comparative small molecule screening of primary human acute leukemias, engineered human leukemia and leukemia cell lines","authors":"Safia Safa-Tahar-Henni, Karla Páez Martinez, Verena Gress, Nayeli Esparza, Élodie Roques, Florence Bonnet-Magnaval, Mélanie Bilodeau, Valérie Gagné, Eva Bresson, Sophie Cardin, Nehme El-Hachem, Isabella Iasenza, Gabriel Alzial, Isabel Boivin, Naoto Nakamichi, Anne-Cécile Soufflet, Cristina Mirela Pascariu, Jean Duchaine, Simon Mathien, Éric Bonneil, Kolja Eppert, Anne Marinier, Guy Sauvageau, Geneviève Deblois, Pierre Thibault, Josée Hébert, Connie J. Eaves, Sonia Cellot, Frédéric Barabé, Brian T. Wilhelm","doi":"10.1038/s41375-024-02400-w","DOIUrl":"https://doi.org/10.1038/s41375-024-02400-w","url":null,"abstract":"<p>Targeted therapeutics for high-risk cancers remain an unmet medical need. Here we report the results of a large-scale screen of over 11,000 molecules for their ability to inhibit the survival and growth in vitro of human leukemic cells from multiple sources including patient samples, de novo generated human leukemia models, and established human leukemic cell lines. The responses of cells from de novo models were most similar to those of patient samples, both of which showed striking differences from the cell-line responses. Analysis of differences in subtype-specific therapeutic vulnerabilities made possible by the scale of this screen enabled the identification of new specific modulators of apoptosis, while also highlighting the complex polypharmacology of anti-leukemic small molecules such as shikonin. These findings introduce a new platform for uncovering new therapeutic options for high-risk human leukemia, in addition to reinforcing the importance of the test sample choice for effective drug discovery.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"14 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142536551","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}

{"title":"Validation and refinement of the 2022 European LeukaemiaNet genetic risk classification of acute myeloid leukaemia patients receiving allogeneic haematopoietic cell transplantation","authors":"Weihao Chen,&nbsp;Lieguang Chen,&nbsp;Yang Cao,&nbsp;Chuanhe Jiang,&nbsp;Yi Luo,&nbsp;Guifang Ouyang,&nbsp;Jian Yu,&nbsp;Yamin Tan,&nbsp;Xiaoyu Lai,&nbsp;Lizhen Liu,&nbsp;Huarui Fu,&nbsp;Yishan Ye,&nbsp;Luxin Yang,&nbsp;Congxiao Zhang,&nbsp;Jimin Shi,&nbsp;Xiaoxia Hu,&nbsp;He Huang,&nbsp;Yanmin Zhao","doi":"10.1038/s41375-024-02440-2","DOIUrl":"10.1038/s41375-024-02440-2","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"38 12","pages":"2712-2716"},"PeriodicalIF":12.8,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142519309","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}

{"title":"Antibody blockade of the PSGL-1 immune checkpoint enhances T-cell responses to B-cell lymphoma","authors":"João L. Pereira, Liliana Arede, Francisca Ferreira, Andreia Matos, Dulcineia Pereira, Rita F. Santos, Alexandre M. Carmo, Maria J. Oliveira, José C. Machado, Delfim Duarte, Nuno R. dos Santos","doi":"10.1038/s41375-024-02446-w","DOIUrl":"https://doi.org/10.1038/s41375-024-02446-w","url":null,"abstract":"<p>Despite advancements in cancer immunotherapy, most lymphomas remain unresponsive to checkpoint inhibitors. P-selectin glycoprotein ligand-1 (PSGL-1), recently identified as a promoter of T-cell exhaustion in murine melanoma models, has emerged as a novel immune checkpoint protein and promising immunotherapeutic target. In this study, we investigated the potential of PSGL-1 antibody targeting in B-cell lymphoma. Using allogeneic co-culture systems, we demonstrated that targeted antibody interventions against human PSGL-1 enhanced T-cell activation and effector cytokine production in response to lymphoma cells. Moreover, in vitro treatment of primary lymphoma cell suspensions with PSGL-1 antibody resulted in increased activation of autologous lymphoma-infiltrating T cells. Using the A20 syngeneic B-cell lymphoma mouse model, we found that PSGL-1 antibody treatment significantly slowed tumor development and reduced the endpoint tumor burden. This antitumoral effect was accompanied by augmented tumor infiltration of CD4⁺ and CD8⁺ T cells and reduced infiltration of regulatory T cells. Finally, anti-PSGL-1 administration enhanced the expansion of CAR T cells previously transferred to mice bearing the aggressive Eμ-<i>Myc</i> lymphoma cells and improved disease control. These results demonstrate that PSGL-1 antibody blockade bolsters T-cell activity against B-cell lymphoma, suggesting a potential novel immunotherapeutic approach for treating these malignancies.</p><figure></figure>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"194 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142490304","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}

{"title":"Leveraging CRISPR gene editing technology to optimize the efficacy, safety and accessibility of CAR T-cell therapy","authors":"Tao Lei,&nbsp;Yazhuo Wang,&nbsp;Yuchen Zhang,&nbsp;Yufei Yang,&nbsp;Jiaying Cao,&nbsp;Jiansong Huang,&nbsp;Jiali Chen,&nbsp;Huajing Chen,&nbsp;Jiayi Zhang,&nbsp;Luzheng Wang,&nbsp;Xinjie Xu,&nbsp;Robert Peter Gale,&nbsp;Liang Wang","doi":"10.1038/s41375-024-02444-y","DOIUrl":"10.1038/s41375-024-02444-y","url":null,"abstract":"Chimeric Antigen Receptor (CAR)-T-cell therapy has revolutionized cancer immune therapy. However, challenges remain including increasing efficacy, reducing adverse events and increasing accessibility. Use of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) technology can effectively perform various functions such as precise integration, multi-gene editing, and genome-wide functional regulation. Additionally, CRISPR screening using large-scale guide RNA (gRNA) genetic perturbation provides an unbiased approach to understanding mechanisms underlying anti-cancer efficacy of CAR T-cells. Several emerging CRISPR tools with high specificity, controllability and efficiency are useful to modify CAR T-cells and identify new targets. In this review we summarize potential uses of the CRISPR system to improve results of CAR T-cells therapy including optimizing efficacy and safety and, developing universal CAR T-cells. We discuss challenges facing CRISPR gene editing and propose solutions highlighting future research directions in CAR T-cell therapy.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"38 12","pages":"2517-2543"},"PeriodicalIF":12.8,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02444-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142490306","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aberrant BCAT1 expression augments MTOR activity and accelerates disease progression in chronic lymphocytic leukemia","authors":"Qiangqiang Shao, Jedrzej Wykretowicz, Nan Hu, Karan Bedi, Mohamed Rizk, Isabella A. Malek, Surinder Kumar, David B. Lombard, Kerby Shedden, David Scott, Sami N. Malek","doi":"10.1038/s41375-024-02448-8","DOIUrl":"https://doi.org/10.1038/s41375-024-02448-8","url":null,"abstract":"<p>We performed gene expression profiling of mRNA/cDNA isolated from <i>N</i> = 117 flow sorted CLL. We detected aberrant expression of the metabolic enzyme branched chain amino acid transferase (BCAT1) in CLL with del17p/<i>TP53</i>mut. Through extensive validation, we confirmed the highly preferential expression of BCAT1 in CLL with del17p/<i>TP53</i>mut (66%) or trisomy 12 (77%). BCAT1 was not expressed in B cells isolated from normal human lymph nodes. The products of the bidirectional BCAT1 reaction, including leucine, acetyl-CoA, and alpha-ketoglutarate are known activators of MTOR. We measured an ~two-fold higher MTOR activity via normalized p-S6K levels in primary CLL with BCAT1 high versus absent expression before and after sIgM crosslinking. Through steady state metabolomics and heavy isotope metabolic tracing in primary CLL cells, we demonstrate that CLL cells are avid consumers of branched chain amino acids (BCAAs) and that BCAT1 in CLL engages in bidirectional substrate reactions. Of additional interest, CLL with aberrant BCAT1 expression were less sensitive to Venetoclax-induced apoptosis. Biologically, three CLL-derived cell lines with disruption of <i>BCAT1</i> had substantially reduced growth ex vivo. Clinically, the expression of any detectable BCAT1 protein in CLL independently associated with shorter median survival (125 months versus 296 months; <i>p</i> &lt; 0.0001), even after exclusion of del17p/<i>TP53</i>mut cases.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"41 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142490301","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}

{"title":"Apoliprotein E-mediated ferroptosis controls cellular proliferation in chronic lymphocytic leukemia","authors":"Federica Nardi, Rosita Del Prete, Roberta Drago, Anthea Di Rita, Francesco Edoardo Vallone, Sara Ciofini, Margherita Malchiodi, Laura Pezzella, Laura Tinti, Vittoria Cicaloni, Laura Salvini, Danilo Licastro, Aidan T. Pezacki, Christopher J. Chang, Giuseppe Marotta, Antonella Naldini, Silvia Deaglio, Tiziana Vaisitti, Alessandro Gozzetti, Monica Bocchia, Anna Kabanova","doi":"10.1038/s41375-024-02442-0","DOIUrl":"https://doi.org/10.1038/s41375-024-02442-0","url":null,"abstract":"<p>Unraveling vulnerabilities in chronic lymphocytic leukemia (CLL) represents a key approach to understand molecular basis for its indolence and a path toward developing tailored therapeutic approaches. In this study, we found that CLL cells are particularly sensitive to the inhibitory action of abundant serum protein, apolipoprotein E (ApoE). Physiological concentrations of ApoE affect CLL cell viability and inhibit CD40-driven proliferation. Transcriptomics of ApoE-treated CLL cells revealed a signature of redox and metal disbalance which prompted us to explore the underlying mechanism of cell death. We discover, on one hand, that ApoE treatment of CLL cells induces lipid peroxidation and ferroptosis. On the other hand, we find that ApoE is a copper-binding protein and that intracellular copper regulates ApoE toxicity. ApoE regulation tends to be lost in aggressive CLL. CLL cells from patients with high leukocyte counts are less sensitive to ApoE inhibition, while resistance to ApoE is possible in transformed CLL cells from patients with Richter syndrome (RS). Nevertheless, both aggressive CLL and RS cells maintain sensitivity to drug-induced ferroptosis. Our findings suggest a natural suppression axis that mediates ferroptotic disruption of CLL cell proliferation, building up the rationale for choosing ferroptosis as a therapeutic target in CLL and RS.</p><figure></figure>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"30 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142488327","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}