Pub Date : 2024-11-06DOI: 10.1038/s41375-024-02436-y
Rachel M. Hendricks, Jung Kim, Jeremy S. Haley, Mark Louie Ramos, Uyenlinh L. Mirshahi, David J. Carey, Douglas R. Stewart, Lisa J. McReynolds
It is estimated that 10% of individuals with a myeloid malignancy carry a germline susceptibility. Using the genome-first approach, in which individuals were ascertained on genotype alone, rather than clinical phenotype, we quantified the prevalence and penetrance of pathogenic germline variants in eight myeloid malignancy predisposition (gMMP) genes. ANKRD26, CEBPA, DDX41, MECOM, SRP72, ETV6, RUNX1 and GATA2, were analyzed from the Geisinger MyCode DiscovEHR (n = 170,503) and the United Kingdom Biobank (UKBB, n = 469,595). We identified a high risk of myeloid malignancies (MM) (odds ratio[OR] all genes: DiscovEHR, 4.6 [95% confidential interval (CI) 2.1–9.7], p < 0.0001; UKBB, 6.0 [95% CI 4.3–8.2], p = 3.1 × 10-27), and decreased overall survival (hazard ratio [HR] DiscovEHR, 1.8 [95% CI 1.3–2.6], p = 0.00049; UKBB, 1.4 [95% CI 1.2–1.8], p = 8.4 × 10-5) amongst heterozygotes. Pathogenic DDX41 variants were the most commonly identified, and in UKBB showed a significantly increased risk of MM (OR 5.7 [95% CI 3.9–8.3], p = 6.0 × 10-20) and increased all-cause mortality (HR 1.35 [95% CI 1.1–1.7], p = 0.0063). Through a genome-first approach, this study genetically ascertained individuals with a gMMP and determined their MM risk and survival.
据估计，10% 的髓系恶性肿瘤患者携带种系易感性。采用基因组优先方法，即仅根据基因型而非临床表型确定个体，我们量化了八个髓系恶性肿瘤易感基因（gMMP）中致病性种系变异的流行率和渗透率。我们对 Geisinger MyCode DiscovEHR（n = 170,503）和英国生物库（UKBB，n = 469,595）中的 ANKRD26、CEBPA、DDX41、MECOM、SRP72、ETV6、RUNX1 和 GATA2 进行了分析。我们发现罹患骨髓恶性肿瘤（MM）的风险很高（所有基因的几率比[OR]：DiscovEHR，4.6 [95% 保密区间 (CI) 2.1-9.7]，p -27），杂合子的总生存率降低（危险比 [HR] DiscovEHR，1.8 [95% CI 1.3-2.6]，p = 0.00049；UKBB，1.4 [95% CI 1.2-1.8]，p = 8.4 × 10-5）。致病性 DDX41 变体是最常见的变体，在 UKBB 中显示 MM 风险显著增加（OR 5.7 [95% CI 3.9-8.3]，p = 6.0 × 10-20），全因死亡率增加（HR 1.35 [95% CI 1.1-1.7]，p = 0.0063）。本研究通过基因组优先的方法，从基因上确定了具有 gMMP 的个体，并确定了他们的 MM 风险和存活率。
{"title":"Genome-first determination of the prevalence and penetrance of eight germline myeloid malignancy predisposition genes: a study of two population-based cohorts","authors":"Rachel M. Hendricks, Jung Kim, Jeremy S. Haley, Mark Louie Ramos, Uyenlinh L. Mirshahi, David J. Carey, Douglas R. Stewart, Lisa J. McReynolds","doi":"10.1038/s41375-024-02436-y","DOIUrl":"10.1038/s41375-024-02436-y","url":null,"abstract":"It is estimated that 10% of individuals with a myeloid malignancy carry a germline susceptibility. Using the genome-first approach, in which individuals were ascertained on genotype alone, rather than clinical phenotype, we quantified the prevalence and penetrance of pathogenic germline variants in eight myeloid malignancy predisposition (gMMP) genes. ANKRD26, CEBPA, DDX41, MECOM, SRP72, ETV6, RUNX1 and GATA2, were analyzed from the Geisinger MyCode DiscovEHR (n = 170,503) and the United Kingdom Biobank (UKBB, n = 469,595). We identified a high risk of myeloid malignancies (MM) (odds ratio[OR] all genes: DiscovEHR, 4.6 [95% confidential interval (CI) 2.1–9.7], p < 0.0001; UKBB, 6.0 [95% CI 4.3–8.2], p = 3.1 × 10-27), and decreased overall survival (hazard ratio [HR] DiscovEHR, 1.8 [95% CI 1.3–2.6], p = 0.00049; UKBB, 1.4 [95% CI 1.2–1.8], p = 8.4 × 10-5) amongst heterozygotes. Pathogenic DDX41 variants were the most commonly identified, and in UKBB showed a significantly increased risk of MM (OR 5.7 [95% CI 3.9–8.3], p = 6.0 × 10-20) and increased all-cause mortality (HR 1.35 [95% CI 1.1–1.7], p = 0.0063). Through a genome-first approach, this study genetically ascertained individuals with a gMMP and determined their MM risk and survival.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 2","pages":"400-411"},"PeriodicalIF":12.8,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02436-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582994","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}
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 YTHDC1high 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 YTHDC1high B-ALL.
{"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":"10.1038/s41375-024-02451-z","url":null,"abstract":"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 YTHDC1high 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 YTHDC1high B-ALL.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 2","pages":"308-322"},"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}
Pub Date : 2024-11-05DOI: 10.1038/s41375-024-02458-6
Firas El Chaer, Anthony J. Perissinotti, Sanam Loghavi, Amer M. Zeidan
The use of measurable residual disease (MRD) as a biomarker for prognostication, risk stratification, and therapeutic decision-making in acute myeloid leukemia (AML) is gaining prominence. MRD monitoring for NPM1-mutated and core-binding factor AML using PCR techniques is well-established for assessing disease after intensive chemotherapy. AML with persistent FLT3-ITD MRD post-intensive chemotherapy and pre-allogeneic hematopoietic cell transplantation (pre-allo-HCT) is associated with an increased risk of relapse and lower survival. Pre-allo-HCT MRD is an independent risk factor for post-allo-HCT outcomes, including relapse and death. Therefore, preemptive interventions on the natural history of MRD positivity are an active area of research beyond its initial prognostic function. Targeting MRD in AML with innovative treatment strategies can improve patient outcomes.
{"title":"Pre-emptive therapeutic decisions based on measurable residual disease status in acute myeloid leukemia: ready for prime time?","authors":"Firas El Chaer, Anthony J. Perissinotti, Sanam Loghavi, Amer M. Zeidan","doi":"10.1038/s41375-024-02458-6","DOIUrl":"10.1038/s41375-024-02458-6","url":null,"abstract":"The use of measurable residual disease (MRD) as a biomarker for prognostication, risk stratification, and therapeutic decision-making in acute myeloid leukemia (AML) is gaining prominence. MRD monitoring for NPM1-mutated and core-binding factor AML using PCR techniques is well-established for assessing disease after intensive chemotherapy. AML with persistent FLT3-ITD MRD post-intensive chemotherapy and pre-allogeneic hematopoietic cell transplantation (pre-allo-HCT) is associated with an increased risk of relapse and lower survival. Pre-allo-HCT MRD is an independent risk factor for post-allo-HCT outcomes, including relapse and death. Therefore, preemptive interventions on the natural history of MRD positivity are an active area of research beyond its initial prognostic function. Targeting MRD in AML with innovative treatment strategies can improve patient outcomes.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 1","pages":"1-7"},"PeriodicalIF":12.8,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02458-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142576366","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}
Pub Date : 2024-11-02DOI: 10.1038/s41375-024-02455-9
Xiaoman Shao, Rui Yokomori, Jolynn Zu Lin Ong, Haoqing Shen, Dennis Kappei, Leilei Chen, Allen Eng Juh Yeoh, Shi Hao Tan, Takaomi Sanda
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.
{"title":"Transcriptional regulatory program controlled by MYB in T-cell acute lymphoblastic leukemia","authors":"Xiaoman Shao, Rui Yokomori, Jolynn Zu Lin Ong, Haoqing Shen, Dennis Kappei, Leilei Chen, Allen Eng Juh Yeoh, Shi Hao Tan, 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}
Pub Date : 2024-10-31DOI: 10.1038/s41375-024-02445-x
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
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.
{"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":"10.1038/s41375-024-02445-x","url":null,"abstract":"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.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 1","pages":"222-228"},"PeriodicalIF":12.8,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02445-x.pdf","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-29DOI: 10.1038/s41375-024-02400-w
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
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.
{"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":"10.1038/s41375-024-02400-w","url":null,"abstract":"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.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 1","pages":"29-41"},"PeriodicalIF":12.8,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02400-w.pdf","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-25DOI: 10.1038/s41375-024-02446-w
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
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-Myc 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.
尽管癌症免疫疗法取得了进展，但大多数淋巴瘤对检查点抑制剂仍无反应。P-选择素糖蛋白配体-1（P-selectin glycoprotein ligand-1，PSGL-1）最近被确定为小鼠黑色素瘤模型中T细胞衰竭的促进因子，它已成为一种新型免疫检查点蛋白和有希望的免疫治疗靶点。在这项研究中，我们探讨了 PSGL-1 抗体靶向治疗 B 细胞淋巴瘤的潜力。利用异体共培养系统，我们证明了针对人 PSGL-1 的靶向抗体干预能增强 T 细胞的活化和效应细胞因子的产生，以应对淋巴瘤细胞。此外，用 PSGL-1 抗体体外处理原代淋巴瘤细胞悬浮液可增强自体淋巴瘤浸润 T 细胞的活化。通过使用 A20 合成 B 细胞淋巴瘤小鼠模型，我们发现 PSGL-1 抗体治疗能显著减缓肿瘤的发展并减少终点肿瘤负荷。这种抗肿瘤效应伴随着 CD4+ 和 CD8+ T 细胞的肿瘤浸润增加和调节性 T 细胞浸润的减少。最后，服用抗 PSGL-1 能增强先前转移到携带侵袭性 Eμ-Myc 淋巴瘤细胞小鼠体内的 CAR T 细胞的扩增，并改善疾病控制。这些结果表明，PSGL-1 抗体阻断增强了 T 细胞对抗 B 细胞淋巴瘤的活性，为治疗这些恶性肿瘤提供了一种潜在的新型免疫治疗方法。
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Pub Date : 2024-10-25DOI: 10.1038/s41375-024-02444-y
Tao Lei, Yazhuo Wang, Yuchen Zhang, Yufei Yang, Jiaying Cao, Jiansong Huang, Jiali Chen, Huajing Chen, Jiayi Zhang, Luzheng Wang, Xinjie Xu, Robert Peter Gale, Liang Wang
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.
嵌合抗原受体（CAR）-T 细胞疗法彻底改变了癌症免疫疗法。然而，提高疗效、减少不良反应和增加可及性等挑战依然存在。使用簇状正则间隔短回文重复序列（CRISPR）技术可有效实现精确整合、多基因编辑和全基因组功能调控等多种功能。此外，利用大规模向导 RNA（gRNA）遗传扰动进行 CRISPR 筛选为了解 CAR T 细胞抗癌功效的内在机制提供了一种无偏见的方法。几种新兴的 CRISPR 工具具有高特异性、可控性和高效性，可用于改造 CAR T 细胞和鉴定新靶点。在这篇综述中，我们总结了 CRISPR 系统在改善 CAR T 细胞疗法效果方面的潜在用途，包括优化疗效和安全性以及开发通用 CAR T 细胞。我们讨论了 CRISPR 基因编辑面临的挑战，并提出了解决方案，强调了 CAR T 细胞疗法的未来研究方向。
{"title":"Leveraging CRISPR gene editing technology to optimize the efficacy, safety and accessibility of CAR T-cell therapy","authors":"Tao Lei, Yazhuo Wang, Yuchen Zhang, Yufei Yang, Jiaying Cao, Jiansong Huang, Jiali Chen, Huajing Chen, Jiayi Zhang, Luzheng Wang, Xinjie Xu, Robert Peter Gale, 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}
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