Pub Date : 2024-09-02DOI: 10.1038/s41375-024-02385-6
Elias Jabbour, Jane Apperley, Jorge Cortes, Delphine Rea, Michael Deininger, Elisabetta Abruzzese, Charles Chuah, Daniel J. DeAngelo, Andreas Hochhaus, Jeffrey H. Lipton, Michael Mauro, Franck Nicolini, Javier Pinilla-Ibarz, Gianantonio Rosti, Philippe Rousselot, Neil P. Shah, Moshe Talpaz, Alexander Vorog, Xiaowei Ren, Hagop Kantarjian
{"title":"Correction: Dose modification dynamics of ponatinib in patients with chronic-phase chronic myeloid leukemia (CP-CML) from the PACE and OPTIC trials","authors":"Elias Jabbour, Jane Apperley, Jorge Cortes, Delphine Rea, Michael Deininger, Elisabetta Abruzzese, Charles Chuah, Daniel J. DeAngelo, Andreas Hochhaus, Jeffrey H. Lipton, Michael Mauro, Franck Nicolini, Javier Pinilla-Ibarz, Gianantonio Rosti, Philippe Rousselot, Neil P. Shah, Moshe Talpaz, Alexander Vorog, Xiaowei Ren, Hagop Kantarjian","doi":"10.1038/s41375-024-02385-6","DOIUrl":"10.1038/s41375-024-02385-6","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"38 10","pages":"2291-2291"},"PeriodicalIF":12.8,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02385-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142120205","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 : 2024-09-02DOI: 10.1038/s41375-024-02396-3
Simon Husby, Morten Tulstrup, Mads Harsløf, Christian Nielsen, Eva Haastrup, Lene Hyldahl Ebbesen, Mette Klarskov Andersen, Maroulio Pertesi, Christian Brieghel, Carsten U. Niemann, Björn Nilsson, Agoston Gyula Szabo, Niels Frost Andersen, Niels Abildgaard, Annette Vangsted, Kirsten Grønbæk
Mosaic chromosomal alterations (mCAs) in hematopoietic cells increase mortality and risk of hematological cancers and infections. We investigated the landscape of mCAs and their clinical consequences in 976 patients with multiple myeloma undergoing high-dose chemotherapy and autologous stem cell support (ASCT) with median 6.4 years of follow-up. mCAs were detected in the stem cell harvest product of 158 patients (16.2%). Autosomal aberrations were found in 60 patients (6.1%) and affected all chromosomes. Loss of chromosome X was found in 51 females (12.7%) and loss of chromosome Y in 55 males (9.6%). Overall survival and progression were similar between carriers of autosomal mCAs and non-carriers. In contrast, female patients with loss of the X chromosome had longer overall survival (age-adjusted[a.a.] HR 0.54, 95% CI 0.32–0.93, p = 0.02), lower risk of progression (a.a. HR 0.55, 95% CI 0.35–0.87; p = 0.01), and better post-transplant response (higher degree of complete response (CR) or very good partial response (VGPR)). The reason for this substantial effect is unknown. Additionally, myeloma clones in the stem cell product was confirmed by mCA analysis in the few patients with multiple mCAs (n = 12 patients). Multiple mCAs conferred inferior overall survival (a.a. HR 2.0, 95% CI 1.02–3.84; p = 0.04) and higher risk of myeloma progression (a.a. HR 3.36, 95% CI 1.67–6.81; p < 0.001), which is presumed to be driven by suspected myeloma contaminants.
造血细胞中的镶嵌染色体改变（mCAs）会增加死亡率以及罹患血癌和感染的风险。我们调查了976名接受大剂量化疗和自体干细胞支持（ASCT）的多发性骨髓瘤患者的mCAs情况及其临床后果，中位随访时间为6.4年。60名患者（6.1%）发现常染色体畸变，影响所有染色体。51名女性（12.7%）发现X染色体缺失，55名男性（9.6%）发现Y染色体缺失。常染色体 mCAs 携带者与非携带者的总体生存期和病情进展相似。相比之下，X 染色体缺失的女性患者总生存期更长（年龄调整[a.a.] HR 0.54，95% CI 0.32-0.93，p = 0.02），病情进展风险更低（a.a.HR 0.55，95% CI 0.35-0.87；p = 0.01），移植后反应更好（完全反应（CR）或非常好的部分反应（VGPR）程度更高）。这种实质性影响的原因尚不清楚。此外，干细胞产物中的骨髓瘤克隆在少数有多个mCA的患者（12人）中通过mCA分析得到证实。多发性mCA导致总生存率降低（a.a. HR 2.0, 95% CI 1.02-3.84; p = 0.04）和骨髓瘤进展风险升高（a.a. HR 3.36, 95% CI 1.67-6.81; p = 0.04）。
{"title":"Mosaic chromosomal alterations in hematopoietic cells and clinical outcomes in patients with multiple myeloma","authors":"Simon Husby, Morten Tulstrup, Mads Harsløf, Christian Nielsen, Eva Haastrup, Lene Hyldahl Ebbesen, Mette Klarskov Andersen, Maroulio Pertesi, Christian Brieghel, Carsten U. Niemann, Björn Nilsson, Agoston Gyula Szabo, Niels Frost Andersen, Niels Abildgaard, Annette Vangsted, Kirsten Grønbæk","doi":"10.1038/s41375-024-02396-3","DOIUrl":"10.1038/s41375-024-02396-3","url":null,"abstract":"Mosaic chromosomal alterations (mCAs) in hematopoietic cells increase mortality and risk of hematological cancers and infections. We investigated the landscape of mCAs and their clinical consequences in 976 patients with multiple myeloma undergoing high-dose chemotherapy and autologous stem cell support (ASCT) with median 6.4 years of follow-up. mCAs were detected in the stem cell harvest product of 158 patients (16.2%). Autosomal aberrations were found in 60 patients (6.1%) and affected all chromosomes. Loss of chromosome X was found in 51 females (12.7%) and loss of chromosome Y in 55 males (9.6%). Overall survival and progression were similar between carriers of autosomal mCAs and non-carriers. In contrast, female patients with loss of the X chromosome had longer overall survival (age-adjusted[a.a.] HR 0.54, 95% CI 0.32–0.93, p = 0.02), lower risk of progression (a.a. HR 0.55, 95% CI 0.35–0.87; p = 0.01), and better post-transplant response (higher degree of complete response (CR) or very good partial response (VGPR)). The reason for this substantial effect is unknown. Additionally, myeloma clones in the stem cell product was confirmed by mCA analysis in the few patients with multiple mCAs (n = 12 patients). Multiple mCAs conferred inferior overall survival (a.a. HR 2.0, 95% CI 1.02–3.84; p = 0.04) and higher risk of myeloma progression (a.a. HR 3.36, 95% CI 1.67–6.81; p < 0.001), which is presumed to be driven by suspected myeloma contaminants.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"38 11","pages":"2456-2465"},"PeriodicalIF":12.8,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02396-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142120206","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 : 2024-09-02DOI: 10.1038/s41375-024-02369-6
Monika M. Toma, Tomasz Skorski
Leukemia, although most likely starts as a monoclonal genetic/epigenetic anomaly, is a polyclonal disease at manifestation. This polyclonal nature results from ongoing evolutionary changes in the genome/epigenome of leukemia cells to promote their survival and proliferation advantages. We discuss here how genetic and/or epigenetic aberrations alter intracellular microenvironment in individual leukemia clones and how extracellular microenvironment selects the best fitted clones. This dynamic polyclonal composition of leukemia makes designing an effective therapy a challenging task especially because individual leukemia clones often display substantial differences in response to treatment. Here, we discuss novel therapeutic approach employing single cell multiomics to identify and eradicate all individual clones in a patient.
{"title":"Star wars against leukemia: attacking the clones","authors":"Monika M. Toma, Tomasz Skorski","doi":"10.1038/s41375-024-02369-6","DOIUrl":"10.1038/s41375-024-02369-6","url":null,"abstract":"Leukemia, although most likely starts as a monoclonal genetic/epigenetic anomaly, is a polyclonal disease at manifestation. This polyclonal nature results from ongoing evolutionary changes in the genome/epigenome of leukemia cells to promote their survival and proliferation advantages. We discuss here how genetic and/or epigenetic aberrations alter intracellular microenvironment in individual leukemia clones and how extracellular microenvironment selects the best fitted clones. This dynamic polyclonal composition of leukemia makes designing an effective therapy a challenging task especially because individual leukemia clones often display substantial differences in response to treatment. Here, we discuss novel therapeutic approach employing single cell multiomics to identify and eradicate all individual clones in a patient.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"38 11","pages":"2293-2302"},"PeriodicalIF":12.8,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02369-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142118056","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 : 2024-08-30DOI: 10.1038/s41375-024-02389-2
Irene Pastor-Galán, Arturo Pereira, Eduardo Arellano-Rodrigo, Iván Martín, Adrián Mosquera-Orgueira, María-Teresa Gómez-Casares, Alberto Hernández-Sánchez, Francisca Ferrer-Marín, Elvira Mora, Patricia Velez, Rosa Ayala, Anna Angona, Natalia de las Heras, Elena Magro, María-Isabel Mata-Vázquez, María-Laura Fox, Sonia González de Villambrosía, María-José Ramírez, Ana García, Valentín García-Gutiérrez, Amparo Cáceres, María-Antonia Durán, María-Alicia Senín, José-María Raya, José Antonio González, Beatriz Cuevas, Blanca Xicoy, Marta Garrote, Blanca Ferrer, Manuel Pérez-Encinas, Jesús María Hernández-Rivas, Beatriz Bellosillo, Alberto Álvarez-Larrán, Juan Carlos Hernández-Boluda
{"title":"Impact of somatic gene mutations on the risk of thrombosis in myelofibrosis","authors":"Irene Pastor-Galán, Arturo Pereira, Eduardo Arellano-Rodrigo, Iván Martín, Adrián Mosquera-Orgueira, María-Teresa Gómez-Casares, Alberto Hernández-Sánchez, Francisca Ferrer-Marín, Elvira Mora, Patricia Velez, Rosa Ayala, Anna Angona, Natalia de las Heras, Elena Magro, María-Isabel Mata-Vázquez, María-Laura Fox, Sonia González de Villambrosía, María-José Ramírez, Ana García, Valentín García-Gutiérrez, Amparo Cáceres, María-Antonia Durán, María-Alicia Senín, José-María Raya, José Antonio González, Beatriz Cuevas, Blanca Xicoy, Marta Garrote, Blanca Ferrer, Manuel Pérez-Encinas, Jesús María Hernández-Rivas, Beatriz Bellosillo, Alberto Álvarez-Larrán, Juan Carlos Hernández-Boluda","doi":"10.1038/s41375-024-02389-2","DOIUrl":"10.1038/s41375-024-02389-2","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"38 11","pages":"2483-2486"},"PeriodicalIF":12.8,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142100840","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 : 2024-08-30DOI: 10.1038/s41375-024-02391-8
Jennifer Sun, Stefan Corradini, Feda Azab, Monica Shokeen, Barbara Muz, Katerina E. Miari, Mina Maksimos, Camila Diedrich, Obed Asare, Kinan Alhallak, Chaelee Park, Berit Lubben, Yixuan Chen, Ola Adebayo, Hannah Bash, Sarah Kelley, Mark Fiala, Diane E. Bender, Haibin Zhou, Shaomeng Wang, Ravi Vij, Mark T. S. Williams, Abdel Kareem Azab
Multiple myeloma (MM) is the cancer of plasma cells within the bone marrow and remains incurable. Tumor-associated macrophages (TAMs) within the tumor microenvironment often display a pro-tumor phenotype and correlate with tumor proliferation, survival, and therapy resistance. IL-10 is a key immunosuppressive cytokine that leads to recruitment and development of TAMs. In this study, we investigated the role of IL-10 in MM TAM development as well as the therapeutic application of IL-10/IL-10R/STAT3 signaling inhibition. We demonstrated that IL-10 is overexpressed in MM BM and mediates M2-like polarization of TAMs in patient BM, 3D co-cultures in vitro, and mouse models. In turn, TAMs promote MM proliferation and drug resistance, both in vitro and in vivo. Moreover, inhibition of IL-10/IL-10R/STAT3 axis using a blocking IL-10R monoclonal antibody and STAT3 protein degrader/PROTAC prevented M2 polarization of TAMs and the consequent TAM-induced proliferation of MM, and re-sensitized MM to therapy, in vitro and in vivo. Therefore, our findings suggest that inhibition of IL-10/IL-10R/STAT3 axis is a novel therapeutic strategy with monotherapy efficacy and can be further combined with current anti-MM therapy, such as immunomodulatory drugs, to overcome drug resistance. Future investigation is warranted to evaluate the potential of such therapy in MM patients.
多发性骨髓瘤（MM）是骨髓中浆细胞的癌症，至今仍无法治愈。肿瘤微环境中的肿瘤相关巨噬细胞（TAMs）通常表现出亲肿瘤表型，并与肿瘤增殖、存活和耐药性相关。IL-10 是一种关键的免疫抑制细胞因子，可导致 TAMs 的招募和发展。在这项研究中，我们探讨了IL-10在MM TAM发展中的作用以及抑制IL-10/IL-10R/STAT3信号传导的治疗应用。我们证实，IL-10在MM骨髓中过表达，并在患者骨髓、体外三维共培养和小鼠模型中介导TAMs的M2样极化。反过来，TAMs 在体外和体内都会促进 MM 的增殖和耐药性。此外，使用阻断IL-10R单克隆抗体和STAT3蛋白降解剂/PROTAC抑制IL-10/IL-10R/STAT3轴，可防止TAMs的M2极化和TAM诱导的MM增殖，并在体外和体内使MM对治疗重新敏感。因此，我们的研究结果表明，抑制IL-10/IL-10R/STAT3轴是一种新型治疗策略，具有单药疗效，并可进一步与当前的抗MM疗法（如免疫调节药物）相结合，以克服耐药性。未来有必要对这种疗法在 MM 患者中的潜力进行评估。
{"title":"IL-10R inhibition reprograms tumor-associated macrophages and reverses drug resistance in multiple myeloma","authors":"Jennifer Sun, Stefan Corradini, Feda Azab, Monica Shokeen, Barbara Muz, Katerina E. Miari, Mina Maksimos, Camila Diedrich, Obed Asare, Kinan Alhallak, Chaelee Park, Berit Lubben, Yixuan Chen, Ola Adebayo, Hannah Bash, Sarah Kelley, Mark Fiala, Diane E. Bender, Haibin Zhou, Shaomeng Wang, Ravi Vij, Mark T. S. Williams, Abdel Kareem Azab","doi":"10.1038/s41375-024-02391-8","DOIUrl":"10.1038/s41375-024-02391-8","url":null,"abstract":"Multiple myeloma (MM) is the cancer of plasma cells within the bone marrow and remains incurable. Tumor-associated macrophages (TAMs) within the tumor microenvironment often display a pro-tumor phenotype and correlate with tumor proliferation, survival, and therapy resistance. IL-10 is a key immunosuppressive cytokine that leads to recruitment and development of TAMs. In this study, we investigated the role of IL-10 in MM TAM development as well as the therapeutic application of IL-10/IL-10R/STAT3 signaling inhibition. We demonstrated that IL-10 is overexpressed in MM BM and mediates M2-like polarization of TAMs in patient BM, 3D co-cultures in vitro, and mouse models. In turn, TAMs promote MM proliferation and drug resistance, both in vitro and in vivo. Moreover, inhibition of IL-10/IL-10R/STAT3 axis using a blocking IL-10R monoclonal antibody and STAT3 protein degrader/PROTAC prevented M2 polarization of TAMs and the consequent TAM-induced proliferation of MM, and re-sensitized MM to therapy, in vitro and in vivo. Therefore, our findings suggest that inhibition of IL-10/IL-10R/STAT3 axis is a novel therapeutic strategy with monotherapy efficacy and can be further combined with current anti-MM therapy, such as immunomodulatory drugs, to overcome drug resistance. Future investigation is warranted to evaluate the potential of such therapy in MM patients.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"38 11","pages":"2355-2365"},"PeriodicalIF":12.8,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02391-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142100841","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 : 2024-08-28DOI: 10.1038/s41375-024-02393-6
Karan L. Chohan, Rajiv K. Pruthi, Saurabh Zanwar, Jonas Paludo, Ronald Go, Animesh Pardanani, Aneel Ashrani, Joselle M. Cook, Carrie A. Thompson, Asher Chanan-Khan, Sikander Ailawadhi, Thomas M. Habermann, Thomas E. Witzig, Morie A. Gertz, David Dingli, Fransis K. Buadi, Angela Dispenzieri, Nelson Leung, Shaji K. Kumar, Vincent Rajkumar, William L. Nichols, Robert A. Kyle, Stephen M. Ansell, Prashant Kapoor, Meera Sridharan, Jithma P. Abeykoon
{"title":"The clinical impact of acquired von Willebrand syndrome secondary to Waldenström macroglobulinemia: an underrecognized source of major bleeding events","authors":"Karan L. Chohan, Rajiv K. Pruthi, Saurabh Zanwar, Jonas Paludo, Ronald Go, Animesh Pardanani, Aneel Ashrani, Joselle M. Cook, Carrie A. Thompson, Asher Chanan-Khan, Sikander Ailawadhi, Thomas M. Habermann, Thomas E. Witzig, Morie A. Gertz, David Dingli, Fransis K. Buadi, Angela Dispenzieri, Nelson Leung, Shaji K. Kumar, Vincent Rajkumar, William L. Nichols, Robert A. Kyle, Stephen M. Ansell, Prashant Kapoor, Meera Sridharan, Jithma P. Abeykoon","doi":"10.1038/s41375-024-02393-6","DOIUrl":"10.1038/s41375-024-02393-6","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"38 11","pages":"2497-2500"},"PeriodicalIF":12.8,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142084724","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 : 2024-08-27DOI: 10.1038/s41375-024-02370-z
Agata Pastorczak, Zuzanna Urbanska, Borys Styka, Karolina Miarka-Walczyk, Lukasz Sedek, Kamila Wypyszczak, Anna Wakulinska, Zuzanna Nowicka, Tomasz Szczepański, Marcin Stańczak, Wojciech Fendler, Jerzy Kowalczyk, Wojciech Młynarski, Monika Lejman
Chromothripsis (cth) is a form of genomic instability leading to massive de novo structural chromosome rearrangements in a one-time catastrophic event. It can cause cancer-promoting alterations, such as loss of sequences for tumor-suppressor genes, formation of oncogenic fusions, and oncogene amplifications. We investigated the genetic background and clinical significance of cth in childhood T-cell acute lymphoblastic leukemia (T-ALL) patients. For this purpose, whole-genome copy number alterations were analyzed in 173 children with newly diagnosed T-ALL using high-density microarrays. Cth was identified in 10 T-ALL samples (5.78%). In six of them, cth occurred in a constitutional background of Nijmegen breakage syndrome (n = 5) or Li-Fraumeni syndrome (n = 1). Cth generated alterations, including deletions of CDKN2A/B (n = 4) and EZH2 (n = 4), amplifications of CDK6 (n = 2), and NUP214::ABL1 and TFG::GPR128 fusions. Cth-positive leukemias exhibited deletions involving the tumor-suppressor genes RB1 (n = 3), TP53 (n = 1) and MED12 (n = 2). Cth-positive T-ALL patients had a lower probability of 5-year overall survival (OS) [0.56 vs. 0.81; hazard ratio (HR) = 4.14 (1.42–12.02) p = 0.017] as did 5-year event-free survival [0.45 vs. 0.74; HR = 3.91 (1.52–10.08); p = 0.012]. Chromothripsis is an infrequent genomic phenomenon in pediatric T-ALL but is significantly associated with cancer-predisposing syndromes and may associate with inferior prognosis.
染色体重排（cth）是基因组不稳定的一种形式，在一次性的灾难性事件中导致大量新的染色体结构重排。它可导致促癌改变，如抑癌基因序列缺失、致癌融合的形成和癌基因扩增。我们研究了儿童 T 细胞急性淋巴细胞白血病（T-ALL）患者 cth 的遗传背景和临床意义。为此，我们使用高密度芯片分析了 173 名新确诊 T-ALL 儿童的全基因组拷贝数改变。在10个T-ALL样本（5.78%）中发现了Cth。其中6例样本的Cth发生在奈梅亨断裂综合征（5例）或李-弗劳米尼综合征（1例）的体质背景中。Cth产生的改变包括CDKN2A/B缺失（4例）和EZH2缺失（4例）、CDK6扩增（2例）以及NUP214::ABL1和TFG::GPR128融合。Cth阳性白血病表现出肿瘤抑制基因RB1（3例）、TP53（1例）和MED12（2例）的缺失。Cth阳性T-ALL患者的5年总生存率（OS）较低[0.56 vs. 0.81；危险比（HR）= 4.14 (1.42-12.02) p = 0.017]，5年无事件生存率也较低[0.45 vs. 0.74；HR = 3.91 (1.52-10.08); p = 0.012]。在小儿T-ALL中，染色体三体是一种并不常见的基因组现象，但它与癌症易感综合征密切相关，并可能与预后不良有关。
{"title":"Genetic hallmarks and clinical implications of chromothripsis in childhood T-cell acute lymphoblastic leukemia","authors":"Agata Pastorczak, Zuzanna Urbanska, Borys Styka, Karolina Miarka-Walczyk, Lukasz Sedek, Kamila Wypyszczak, Anna Wakulinska, Zuzanna Nowicka, Tomasz Szczepański, Marcin Stańczak, Wojciech Fendler, Jerzy Kowalczyk, Wojciech Młynarski, Monika Lejman","doi":"10.1038/s41375-024-02370-z","DOIUrl":"10.1038/s41375-024-02370-z","url":null,"abstract":"Chromothripsis (cth) is a form of genomic instability leading to massive de novo structural chromosome rearrangements in a one-time catastrophic event. It can cause cancer-promoting alterations, such as loss of sequences for tumor-suppressor genes, formation of oncogenic fusions, and oncogene amplifications. We investigated the genetic background and clinical significance of cth in childhood T-cell acute lymphoblastic leukemia (T-ALL) patients. For this purpose, whole-genome copy number alterations were analyzed in 173 children with newly diagnosed T-ALL using high-density microarrays. Cth was identified in 10 T-ALL samples (5.78%). In six of them, cth occurred in a constitutional background of Nijmegen breakage syndrome (n = 5) or Li-Fraumeni syndrome (n = 1). Cth generated alterations, including deletions of CDKN2A/B (n = 4) and EZH2 (n = 4), amplifications of CDK6 (n = 2), and NUP214::ABL1 and TFG::GPR128 fusions. Cth-positive leukemias exhibited deletions involving the tumor-suppressor genes RB1 (n = 3), TP53 (n = 1) and MED12 (n = 2). Cth-positive T-ALL patients had a lower probability of 5-year overall survival (OS) [0.56 vs. 0.81; hazard ratio (HR) = 4.14 (1.42–12.02) p = 0.017] as did 5-year event-free survival [0.45 vs. 0.74; HR = 3.91 (1.52–10.08); p = 0.012]. Chromothripsis is an infrequent genomic phenomenon in pediatric T-ALL but is significantly associated with cancer-predisposing syndromes and may associate with inferior prognosis.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"38 11","pages":"2344-2354"},"PeriodicalIF":12.8,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02370-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142080798","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 : 2024-08-27DOI: 10.1038/s41375-024-02392-7
Patrick Derigs, Maria-Luisa Schubert, Peter Dreger, Anita Schmitt, Schayan Yousefian, Simon Haas, Caroline Röthemeier, Brigitte Neuber, Angela Hückelhoven-Krauss, Monika Brüggemann, Helga Bernhard, Guido Kobbe, Albrecht Lindemann, Mathias Rummel, Birgit Michels, Felix Korell, Anthony D. Ho, Carsten Müller-Tidow, Michael Schmitt
Third-generation chimeric antigen receptor T cells (CARTs) for relapsed or refractory (r/r) chronic lymphocytic leukemia (CLL) may improve efficacy compared to second-generation CARTs due to their enhanced CAR design. We performed the first phase 1/2 investigator-initiated trial evaluating escalating doses of third-generation CARTs (HD-CAR-1) targeting CD19 in patients with r/r CLL and B-cell lymphoma. CLL eligibility criteria were failure to two therapy lines including at least one pathway inhibitor and/or allogeneic hematopoietic cell transplantation. Nine heavily pretreated patients received HD-CAR-1 at dose levels ranging from 1 × 106 to 200 × 106 CART/m2. In-house HD-CAR-1 manufacturing was successful for all patients. While neurotoxicity was absent, one case of grade 3 cytokine release syndrome was observed. By day 90, six patients (67%) attained a CR, five of these (83%) with undetectable MRD. With a median follow-up of 27 months, 2-year PFS and OS were 30% and 69%, respectively. HD-CAR-1 products of responders contained significantly more CD4 + T cells compared to non-responders. In non-responders, a strong enrichment of effector memory-like CD8 + T cells with high expression of CD39 and/or CD197 was observed. HD-CAR-1 demonstrated encouraging efficacy and exceptionally low treatment-specific toxicity, presenting new treatment options for patients with r/r CLL. Trial registration: #NCT03676504.
{"title":"Third-generation anti-CD19 CAR T cells for relapsed/refractory chronic lymphocytic leukemia: a phase 1/2 study","authors":"Patrick Derigs, Maria-Luisa Schubert, Peter Dreger, Anita Schmitt, Schayan Yousefian, Simon Haas, Caroline Röthemeier, Brigitte Neuber, Angela Hückelhoven-Krauss, Monika Brüggemann, Helga Bernhard, Guido Kobbe, Albrecht Lindemann, Mathias Rummel, Birgit Michels, Felix Korell, Anthony D. Ho, Carsten Müller-Tidow, Michael Schmitt","doi":"10.1038/s41375-024-02392-7","DOIUrl":"10.1038/s41375-024-02392-7","url":null,"abstract":"Third-generation chimeric antigen receptor T cells (CARTs) for relapsed or refractory (r/r) chronic lymphocytic leukemia (CLL) may improve efficacy compared to second-generation CARTs due to their enhanced CAR design. We performed the first phase 1/2 investigator-initiated trial evaluating escalating doses of third-generation CARTs (HD-CAR-1) targeting CD19 in patients with r/r CLL and B-cell lymphoma. CLL eligibility criteria were failure to two therapy lines including at least one pathway inhibitor and/or allogeneic hematopoietic cell transplantation. Nine heavily pretreated patients received HD-CAR-1 at dose levels ranging from 1 × 106 to 200 × 106 CART/m2. In-house HD-CAR-1 manufacturing was successful for all patients. While neurotoxicity was absent, one case of grade 3 cytokine release syndrome was observed. By day 90, six patients (67%) attained a CR, five of these (83%) with undetectable MRD. With a median follow-up of 27 months, 2-year PFS and OS were 30% and 69%, respectively. HD-CAR-1 products of responders contained significantly more CD4 + T cells compared to non-responders. In non-responders, a strong enrichment of effector memory-like CD8 + T cells with high expression of CD39 and/or CD197 was observed. HD-CAR-1 demonstrated encouraging efficacy and exceptionally low treatment-specific toxicity, presenting new treatment options for patients with r/r CLL. Trial registration: #NCT03676504.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"38 11","pages":"2419-2428"},"PeriodicalIF":12.8,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02392-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142080799","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 : 2024-08-26DOI: 10.1038/s41375-024-02390-9
Vilma Dembitz, Hannah Lawson, Richard Burt, Sirisha Natani, Céline Philippe, Sophie C. James, Samantha Atkinson, Jozef Durko, Lydia M. Wang, Joana Campos, Aoife M. S. Magee, Keith Woodley, Michael J. Austin, Ana Rio-Machin, Pedro Casado, Findlay Bewicke-Copley, Giovanny Rodriguez Blanco, Diego Pereira-Martins, Lieve Oudejans, Emeline Boet, Alex von Kriegsheim, Juerg Schwaller, Andrew J. Finch, Bela Patel, Jean-Emmanuel Sarry, Jerome Tamburini, Jan Jacob Schuringa, Lori Hazlehurst, John A. Copland III, Mariia Yuneva, Barrie Peck, Pedro Cutillas, Jude Fitzgibbon, Kevin Rouault-Pierre, Kamil Kranc, Paolo Gallipoli
Identification of specific and therapeutically actionable vulnerabilities, ideally present across multiple mutational backgrounds, is needed to improve acute myeloid leukemia (AML) patients’ outcomes. We identify stearoyl-CoA desaturase (SCD), the key enzyme in fatty acid (FA) desaturation, as prognostic of patients'' outcomes and, using the clinical-grade inhibitor SSI-4, show that SCD inhibition (SCDi) is a therapeutic vulnerability across multiple AML models in vitro and in vivo. Multiomic analysis demonstrates that SCDi causes lipotoxicity, which induces AML cell death via pleiotropic effects. Sensitivity to SCDi correlates with AML dependency on FA desaturation regardless of mutational profile and is modulated by FA biosynthesis activity. Finally, we show that lipotoxicity increases chemotherapy-induced DNA damage and standard chemotherapy further sensitizes AML cells to SCDi. Our work supports developing FA desaturase inhibitors in AML while stressing the importance of identifying predictive biomarkers of response and biologically validated combination therapies to realize their full therapeutic potential.
要改善急性髓性白血病（AML）患者的预后，就必须找出特定的、可治疗的弱点，这些弱点最好存在于多种突变背景中。我们发现脂肪酸（FA）去饱和的关键酶硬脂酰-CoA 去饱和酶（SCD）是影响患者预后的因素，并利用临床级抑制剂 SSI-4，证明 SCD 抑制（SCDi）是体外和体内多种急性髓性白血病模型的治疗漏洞。多组学分析表明，SCDi 会导致脂毒性，通过多效应诱导急性髓细胞性白血病细胞死亡。无论突变情况如何，对 SCDi 的敏感性都与急性髓细胞对 FA 去饱和的依赖性相关，并受 FA 生物合成活性的调节。最后，我们发现脂毒性会增加化疗诱导的 DNA 损伤，而标准化疗会进一步使 AML 细胞对 SCDi 敏感。我们的工作支持开发急性髓细胞性白血病的FA去饱和酶抑制剂，同时强调了确定反应的预测性生物标志物和生物验证的联合疗法以充分发挥其治疗潜力的重要性。
{"title":"Stearoyl-CoA desaturase inhibition is toxic to acute myeloid leukemia displaying high levels of the de novo fatty acid biosynthesis and desaturation","authors":"Vilma Dembitz, Hannah Lawson, Richard Burt, Sirisha Natani, Céline Philippe, Sophie C. James, Samantha Atkinson, Jozef Durko, Lydia M. Wang, Joana Campos, Aoife M. S. Magee, Keith Woodley, Michael J. Austin, Ana Rio-Machin, Pedro Casado, Findlay Bewicke-Copley, Giovanny Rodriguez Blanco, Diego Pereira-Martins, Lieve Oudejans, Emeline Boet, Alex von Kriegsheim, Juerg Schwaller, Andrew J. Finch, Bela Patel, Jean-Emmanuel Sarry, Jerome Tamburini, Jan Jacob Schuringa, Lori Hazlehurst, John A. Copland III, Mariia Yuneva, Barrie Peck, Pedro Cutillas, Jude Fitzgibbon, Kevin Rouault-Pierre, Kamil Kranc, Paolo Gallipoli","doi":"10.1038/s41375-024-02390-9","DOIUrl":"10.1038/s41375-024-02390-9","url":null,"abstract":"Identification of specific and therapeutically actionable vulnerabilities, ideally present across multiple mutational backgrounds, is needed to improve acute myeloid leukemia (AML) patients’ outcomes. We identify stearoyl-CoA desaturase (SCD), the key enzyme in fatty acid (FA) desaturation, as prognostic of patients'' outcomes and, using the clinical-grade inhibitor SSI-4, show that SCD inhibition (SCDi) is a therapeutic vulnerability across multiple AML models in vitro and in vivo. Multiomic analysis demonstrates that SCDi causes lipotoxicity, which induces AML cell death via pleiotropic effects. Sensitivity to SCDi correlates with AML dependency on FA desaturation regardless of mutational profile and is modulated by FA biosynthesis activity. Finally, we show that lipotoxicity increases chemotherapy-induced DNA damage and standard chemotherapy further sensitizes AML cells to SCDi. Our work supports developing FA desaturase inhibitors in AML while stressing the importance of identifying predictive biomarkers of response and biologically validated combination therapies to realize their full therapeutic potential.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"38 11","pages":"2395-2409"},"PeriodicalIF":12.8,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02390-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142073233","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 : 2024-08-26DOI: 10.1038/s41375-024-02381-w
Joost B. Koedijk, Inge van der Werf, Livius Penter, Marijn A. Vermeulen, Farnaz Barneh, Alicia Perzolli, Joyce I. Meesters-Ensing, Dennis S. Metselaar, Thanasis Margaritis, Marta Fiocco, Hester A. de Groot-Kruseman, Rubina Moeniralam, Kristina Bang Christensen, Billie Porter, Kathleen Pfaff, Jacqueline S. Garcia, Scott J. Rodig, Catherine J. Wu, Henrik Hasle, Stefan Nierkens, Mirjam E. Belderbos, C. Michel Zwaan, Olaf Heidenreich
Because of the low mutational burden and consequently, fewer potential neoantigens, children with acute myeloid leukemia (AML) are thought to have a T cell-depleted or ‘cold’ tumor microenvironment and may have a low likelihood of response to T cell-directed immunotherapies. Understanding the composition, phenotype, and spatial organization of T cells and other microenvironmental populations in the pediatric AML bone marrow (BM) is essential for informing future immunotherapeutic trials about targetable immune-evasion mechanisms specific to pediatric AML. Here, we conducted a multidimensional analysis of the tumor immune microenvironment in pediatric AML and non-leukemic controls. We demonstrated that nearly one-third of pediatric AML cases has an immune-infiltrated BM, which is characterized by a decreased ratio of M2- to M1-like macrophages. Furthermore, we detected the presence of large T cell networks, both with and without colocalizing B cells, in the BM and dissected the cellular composition of T- and B cell-rich aggregates using spatial transcriptomics. These analyses revealed that these aggregates are hotspots of CD8+ T cells, memory B cells, plasma cells and/or plasmablasts, and M1-like macrophages. Collectively, our study provides a multidimensional characterization of the BM immune microenvironment in pediatric AML and indicates starting points for further investigations into immunomodulatory mechanisms in this devastating disease.
由于突变负荷低，因此潜在的新抗原较少，急性髓性白血病（AML）患儿被认为具有T细胞贫乏或 "冷 "的肿瘤微环境，对T细胞导向的免疫疗法产生反应的可能性较低。了解小儿急性髓细胞性白血病骨髓（BM）中T细胞和其他微环境群体的组成、表型和空间组织对于未来的免疫治疗试验了解小儿急性髓细胞性白血病特有的可靶向免疫逃避机制至关重要。在这里，我们对小儿急性髓细胞白血病和非白血病对照组的肿瘤免疫微环境进行了多维分析。我们发现，近三分之一的小儿急性髓细胞性白血病病例具有免疫浸润性骨髓组织，其特征是 M2 型和 M1 型巨噬细胞的比例下降。此外，我们还检测到骨髓组织中存在大型 T 细胞网络，其中既有 B 细胞，也有不共聚焦的 B 细胞，并利用空间转录组学分析了富含 T 细胞和 B 细胞的聚集体的细胞组成。这些分析表明，这些聚集体是 CD8+ T 细胞、记忆性 B 细胞、浆细胞和/或浆细胞以及 M1 样巨噬细胞的热点。总之，我们的研究提供了小儿急性髓细胞白血病骨髓免疫微环境的多维特征，为进一步研究这种毁灭性疾病的免疫调节机制指明了起点。
{"title":"A multidimensional analysis reveals distinct immune phenotypes and the composition of immune aggregates in pediatric acute myeloid leukemia","authors":"Joost B. Koedijk, Inge van der Werf, Livius Penter, Marijn A. Vermeulen, Farnaz Barneh, Alicia Perzolli, Joyce I. Meesters-Ensing, Dennis S. Metselaar, Thanasis Margaritis, Marta Fiocco, Hester A. de Groot-Kruseman, Rubina Moeniralam, Kristina Bang Christensen, Billie Porter, Kathleen Pfaff, Jacqueline S. Garcia, Scott J. Rodig, Catherine J. Wu, Henrik Hasle, Stefan Nierkens, Mirjam E. Belderbos, C. Michel Zwaan, Olaf Heidenreich","doi":"10.1038/s41375-024-02381-w","DOIUrl":"10.1038/s41375-024-02381-w","url":null,"abstract":"Because of the low mutational burden and consequently, fewer potential neoantigens, children with acute myeloid leukemia (AML) are thought to have a T cell-depleted or ‘cold’ tumor microenvironment and may have a low likelihood of response to T cell-directed immunotherapies. Understanding the composition, phenotype, and spatial organization of T cells and other microenvironmental populations in the pediatric AML bone marrow (BM) is essential for informing future immunotherapeutic trials about targetable immune-evasion mechanisms specific to pediatric AML. Here, we conducted a multidimensional analysis of the tumor immune microenvironment in pediatric AML and non-leukemic controls. We demonstrated that nearly one-third of pediatric AML cases has an immune-infiltrated BM, which is characterized by a decreased ratio of M2- to M1-like macrophages. Furthermore, we detected the presence of large T cell networks, both with and without colocalizing B cells, in the BM and dissected the cellular composition of T- and B cell-rich aggregates using spatial transcriptomics. These analyses revealed that these aggregates are hotspots of CD8+ T cells, memory B cells, plasma cells and/or plasmablasts, and M1-like macrophages. Collectively, our study provides a multidimensional characterization of the BM immune microenvironment in pediatric AML and indicates starting points for further investigations into immunomodulatory mechanisms in this devastating disease.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"38 11","pages":"2332-2343"},"PeriodicalIF":12.8,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02381-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142073221","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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