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
Myelofibrosis (MF) is a chronic myeloproliferative neoplasm (MPN) characterized by clonal proliferation of hematopoietic progenitors, bone marrow fibrosis, and extramedullary hematopoiesis. Constitutive activation of JAK-STAT pathway signaling through mutations in the MPN driver genes (i.e., JAK2, CALR, and MPL) plays a fundamental role in its pathogenesis and progression, which can be influenced by mutations in other genes (non-MPN driver genes) [1].
Thrombotic complications increase morbidity and mortality in MF [2,3,4,5]. Around 20% of patients experience thrombosis before or at diagnosis, with 6–12% developing thrombotic events during follow-up. The main risk factors for thrombosis include older age, a prior history of thrombosis, and a JAK2 mutated genotype [2, 3]. While several studies have evaluated non-MPN driver gene mutations as risk factors for thrombosis in essential thrombocythemia (ET) [6, 7] and polycythemia vera (PV) [8, 9], their role in MF is less defined.
{"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":"https://doi.org/10.1038/s41375-024-02389-2","url":null,"abstract":"<p>Myelofibrosis (MF) is a chronic myeloproliferative neoplasm (MPN) characterized by clonal proliferation of hematopoietic progenitors, bone marrow fibrosis, and extramedullary hematopoiesis. Constitutive activation of JAK-STAT pathway signaling through mutations in the MPN driver genes (i.e., <i>JAK2</i>, <i>CALR</i>, and <i>MPL</i>) plays a fundamental role in its pathogenesis and progression, which can be influenced by mutations in other genes (non-MPN driver genes) [1].</p><p>Thrombotic complications increase morbidity and mortality in MF [2,3,4,5]. Around 20% of patients experience thrombosis before or at diagnosis, with 6–12% developing thrombotic events during follow-up. The main risk factors for thrombosis include older age, a prior history of thrombosis, and a <i>JAK2</i> mutated genotype [2, 3]. While several studies have evaluated non-MPN driver gene mutations as risk factors for thrombosis in essential thrombocythemia (ET) [6, 7] and polycythemia vera (PV) [8, 9], their role in MF is less defined.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":11.4,"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":"https://doi.org/10.1038/s41375-024-02391-8","url":null,"abstract":"<p>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.</p><figure></figure>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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
An under-recognized source of bleeding in Waldenström macroglobulinemia (WM) is the development of an acquired von Willebrand syndrome (AVWS) [1]. In WM, the von Willebrand Factor (vWF) glycoprotein can be degraded due to autoantibody destruction, increased shear stress due to hyperviscosity, or sequestered due to adsorption onto malignant cells, leading to the development of AVWS (AVWS-WM) [1, 2]. However, there is currently a paucity of published literature characterizing the clinical features associated with AVWS-WM and, specifically, the change in bleeding-related symptoms through treatment [3,4,5,6]. In this study, we assessed the prevalence of AVWS-WM in patients with WM treated in a tertiary care center and evaluated the associated clinical manifestations and outcomes of patients with AVWS-WM compared to those with WM and without AVWS.
This retrospective cohort study evaluated patients with active WM seen at Mayo Clinic and affiliated practices from January 2002 to January 2022. Patients were identified using the Mayo Clinic Data Explorer, and those who underwent vWF testing and had confirmed a diagnoses of WM and AVWS were included [7]. A matched control cohort (patients with WM and without AVWS) with a 5:1 ratio based on age, sex, and diagnosis date was also established. Detailed methodologies are available in the Supplementary Materials.
{"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":"https://doi.org/10.1038/s41375-024-02393-6","url":null,"abstract":"<p>An under-recognized source of bleeding in Waldenström macroglobulinemia (WM) is the development of an acquired von Willebrand syndrome (AVWS) [1]. In WM, the von Willebrand Factor (vWF) glycoprotein can be degraded due to autoantibody destruction, increased shear stress due to hyperviscosity, or sequestered due to adsorption onto malignant cells, leading to the development of AVWS (AVWS-WM) [1, 2]. However, there is currently a paucity of published literature characterizing the clinical features associated with AVWS-WM and, specifically, the change in bleeding-related symptoms through treatment [3,4,5,6]. In this study, we assessed the prevalence of AVWS-WM in patients with WM treated in a tertiary care center and evaluated the associated clinical manifestations and outcomes of patients with AVWS-WM compared to those with WM and without AVWS.</p><p>This retrospective cohort study evaluated patients with active WM seen at Mayo Clinic and affiliated practices from January 2002 to January 2022. Patients were identified using the Mayo Clinic Data Explorer, and those who underwent vWF testing and had confirmed a diagnoses of WM and AVWS were included [7]. A matched control cohort (patients with WM and without AVWS) with a 5:1 ratio based on age, sex, and diagnosis date was also established. Detailed methodologies are available in the Supplementary Materials.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":11.4,"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":"https://doi.org/10.1038/s41375-024-02370-z","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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":"https://doi.org/10.1038/s41375-024-02392-7","url":null,"abstract":"<p><p>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 × 10<sup>6</sup> to 200 × 10<sup>6</sup> CART/m<sup>2</sup>. 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.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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":"https://doi.org/10.1038/s41375-024-02390-9","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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":"<p><p>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<sup>+</sup> 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.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-23DOI: 10.1038/s41375-024-02368-7
Branko Cuglievan, Hagop Kantarjian, Jeffrey E. Rubnitz, Todd M. Cooper, C. Michel Zwaan, Jessica A. Pollard, Courtney D. DiNardo, Tapan M. Kadia, Erin Guest, Nicholas J. Short, David McCall, Naval Daver, Cesar Nunez, Fadi G. Haddad, Miriam Garcia, Kapil N. Bhalla, Abhishek Maiti, Samanta Catueno, Warren Fiskus, Bing Z. Carter, Amber Gibson, Michael Roth, Sajad Khazal, Priti Tewari, Hussein A. Abbas, Wallace Bourgeois, Michael Andreeff, Neerav N. Shukla, Danh D. Truong, Jeremy Connors, Joseph A. Ludwig, Janine Stutterheim, Elisabeth Salzer, Kristian L. Juul-Dam, Koji Sasaki, Kris M. Mahadeo, Sarah K. Tasian, Gautam Borthakur, Samantha Dickson, Nitin Jain, Elias Jabbour, Soheil Meshinchi, Guillermo Garcia-Manero, Farhad Ravandi, Eytan M. Stein, E. Anders Kolb, Ghayas C. Issa
Aberrant expression of HOX and MEIS1 family genes, as seen in KMT2A-rearranged, NUP98-rearranged, or NPM1-mutated leukemias leads to arrested differentiation and leukemia development. HOX family genes are essential gatekeepers of physiologic hematopoiesis, and their expression is regulated by the interaction between KMT2A and menin. Menin inhibitors block this interaction, downregulate the abnormal expression of MEIS1 and other transcription factors and thereby release the differentiation block. Menin inhibitors show significant clinical efficacy against KMT2A-rearranged and NPM1-mutated acute leukemias, with promising potential to address unmet needs in various pediatric leukemia subtypes. In this collaborative initiative, pediatric and adult hematologists/oncologists, and stem cell transplant physicians have united their expertise to explore the potential of menin inhibitors in pediatric leukemia treatment internationally. Our efforts aim to provide a comprehensive clinical overview of menin inhibitors, integrating preclinical evidence and insights from ongoing global clinical trials. Additionally, we propose future international, inclusive, and efficient clinical trial designs, integrating pediatric populations in adult trials, to ensure broad access to this promising therapy for all children and adolescents with menin-dependent leukemias.
{"title":"Menin inhibitors in pediatric acute leukemia: a comprehensive review and recommendations to accelerate progress in collaboration with adult leukemia and the international community","authors":"Branko Cuglievan, Hagop Kantarjian, Jeffrey E. Rubnitz, Todd M. Cooper, C. Michel Zwaan, Jessica A. Pollard, Courtney D. DiNardo, Tapan M. Kadia, Erin Guest, Nicholas J. Short, David McCall, Naval Daver, Cesar Nunez, Fadi G. Haddad, Miriam Garcia, Kapil N. Bhalla, Abhishek Maiti, Samanta Catueno, Warren Fiskus, Bing Z. Carter, Amber Gibson, Michael Roth, Sajad Khazal, Priti Tewari, Hussein A. Abbas, Wallace Bourgeois, Michael Andreeff, Neerav N. Shukla, Danh D. Truong, Jeremy Connors, Joseph A. Ludwig, Janine Stutterheim, Elisabeth Salzer, Kristian L. Juul-Dam, Koji Sasaki, Kris M. Mahadeo, Sarah K. Tasian, Gautam Borthakur, Samantha Dickson, Nitin Jain, Elias Jabbour, Soheil Meshinchi, Guillermo Garcia-Manero, Farhad Ravandi, Eytan M. Stein, E. Anders Kolb, Ghayas C. Issa","doi":"10.1038/s41375-024-02368-7","DOIUrl":"10.1038/s41375-024-02368-7","url":null,"abstract":"Aberrant expression of HOX and MEIS1 family genes, as seen in KMT2A-rearranged, NUP98-rearranged, or NPM1-mutated leukemias leads to arrested differentiation and leukemia development. HOX family genes are essential gatekeepers of physiologic hematopoiesis, and their expression is regulated by the interaction between KMT2A and menin. Menin inhibitors block this interaction, downregulate the abnormal expression of MEIS1 and other transcription factors and thereby release the differentiation block. Menin inhibitors show significant clinical efficacy against KMT2A-rearranged and NPM1-mutated acute leukemias, with promising potential to address unmet needs in various pediatric leukemia subtypes. In this collaborative initiative, pediatric and adult hematologists/oncologists, and stem cell transplant physicians have united their expertise to explore the potential of menin inhibitors in pediatric leukemia treatment internationally. Our efforts aim to provide a comprehensive clinical overview of menin inhibitors, integrating preclinical evidence and insights from ongoing global clinical trials. Additionally, we propose future international, inclusive, and efficient clinical trial designs, integrating pediatric populations in adult trials, to ensure broad access to this promising therapy for all children and adolescents with menin-dependent leukemias.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02368-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142042693","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 : 2024-08-23DOI: 10.1038/s41375-024-02383-8
Yue Sun, Yushuang Wu, Guozheng Pang, Jingru Huang, Mengyao Sheng, Jiaying Xie, Pingyue Chen, Yin Wang, Dongrui Yin, Guangjie Zhao, Stefan K. Bohlander, Jian Huang, Guo-Liang Xu, Hai Gao, Dan Zhou, Yuheng Shi
Even though acute myeloid leukemia (AML) patients with a RUNX1::RUNX1T1 (AE) fusion have a relatively favorable prognosis, approximately 50% relapse within 2.5 years and develop resistance to subsequent chemotherapy [1]. It is therefore imperative to identify novel therapeutic targets for AE leukemia to improve outcomes. In this study, we unveil that targeting STING effectively suppresses the growth of AE leukemia cells. Both genetic and pharmacological inhibition of STING lead to the diminish of AE leukemia cells. Importantly, in a mouse primary AE leukemia model, STING deletion significantly attenuates leukemogenesis and prolongs the animals’ lifespan. Blocking the downstream inflammatory pathway of STING yields similar effects to STING inhibition in AE leukemia cells, highlighting the pivotal role of STING-dependent inflammatory responses in sustaining the survival of AE leukemia cells. Moreover, through a genome-wide CRISPR screen, we identified fatty acid desaturase 2 (FADS2) as a non-canonical factor downstream of STING inhibition that mediates cell death. Inhibition of STING releases FADS2 activity, consequently inducing the synthesis of polyunsaturated fatty acids (PUFAs) and triggering lipid peroxidation-associated cell death [2]. Taken together, these findings reveal a critical function of STING in the survival of AE-positive AML cells and suggest STING to be a potential therapeutic target for clinical intervention in these patients.
{"title":"STING is crucial for the survival of RUNX1::RUNX1T1 leukemia cells","authors":"Yue Sun, Yushuang Wu, Guozheng Pang, Jingru Huang, Mengyao Sheng, Jiaying Xie, Pingyue Chen, Yin Wang, Dongrui Yin, Guangjie Zhao, Stefan K. Bohlander, Jian Huang, Guo-Liang Xu, Hai Gao, Dan Zhou, Yuheng Shi","doi":"10.1038/s41375-024-02383-8","DOIUrl":"10.1038/s41375-024-02383-8","url":null,"abstract":"Even though acute myeloid leukemia (AML) patients with a RUNX1::RUNX1T1 (AE) fusion have a relatively favorable prognosis, approximately 50% relapse within 2.5 years and develop resistance to subsequent chemotherapy [1]. It is therefore imperative to identify novel therapeutic targets for AE leukemia to improve outcomes. In this study, we unveil that targeting STING effectively suppresses the growth of AE leukemia cells. Both genetic and pharmacological inhibition of STING lead to the diminish of AE leukemia cells. Importantly, in a mouse primary AE leukemia model, STING deletion significantly attenuates leukemogenesis and prolongs the animals’ lifespan. Blocking the downstream inflammatory pathway of STING yields similar effects to STING inhibition in AE leukemia cells, highlighting the pivotal role of STING-dependent inflammatory responses in sustaining the survival of AE leukemia cells. Moreover, through a genome-wide CRISPR screen, we identified fatty acid desaturase 2 (FADS2) as a non-canonical factor downstream of STING inhibition that mediates cell death. Inhibition of STING releases FADS2 activity, consequently inducing the synthesis of polyunsaturated fatty acids (PUFAs) and triggering lipid peroxidation-associated cell death [2]. Taken together, these findings reveal a critical function of STING in the survival of AE-positive AML cells and suggest STING to be a potential therapeutic target for clinical intervention in these patients.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02383-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142042696","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 : 2024-08-23DOI: 10.1038/s41375-024-02373-w
Chiara Carretta, Sandra Parenti, Matteo Bertesi, Sebastiano Rontauroli, Filippo Badii, Lara Tavernari, Elena Genovese, Marica Malerba, Elisa Papa, Samantha Sperduti, Elena Enzo, Margherita Mirabile, Francesca Pedrazzi, Anita Neroni, Camilla Tombari, Barbara Mora, Margherita Maffioli, Marco Mondini, Marco Brociner, Monica Maccaferri, Elena Tenedini, Silvia Martinelli, Niccolò Bartalucci, Elisa Bianchi, Livio Casarini, Leonardo Potenza, Mario Luppi, Enrico Tagliafico, Paola Guglielmelli, Manuela Simoni, Francesco Passamonti, Ruggiero Norfo, Alessandro Maria Vannucchi, Rossella Manfredini, on behalf of MYNERVA (Myeloid NEoplasms Research Venture AIRC)
JAK2V617F is the most recurrent genetic mutation in Philadelphia-negative chronic Myeloproliferative Neoplasms (MPNs). Since the JAK2 locus is located on Chromosome 9, we hypothesized that Chromosome 9 copy number abnormalities may be a disease modifier in JAK2V617F-mutant MPN patients. In this study, we identified a subset of MPN patients with partial or complete Chromosome 9 trisomy (+9p patients), who differ from JAK2V617F-homozygous MPN patients as they carry three JAK2 alleles as well as three copies of all neighboring gene loci, including CD274, encoding immunosuppressive Programmed death-ligand 1 (PD-L1) protein. Investigation of the clonal hierarchy revealed that the JAK2V617F occurs first, followed by +9p. Functionally, CD34+ cells from +9p MPN patients demonstrated increased clonogenicity, generating a greater number of primitive colonies, due to high OCT4 and NANOG expression, with knock-down of these genes leading to a genotype-specific decrease in colony numbers. Moreover, our analysis revealed increased PD-L1 surface expression in malignant monocytes from +9p patients, while analysis of the T cell compartment unveiled elevated levels of exhausted cytotoxic T cells. Overall, here we identify a distinct novel subgroup of MPN patients, who feature a synergistic interplay between +9p and JAK2V617F that shapes immune escape characteristics and increased stemness in CD34+ cells.
{"title":"Chromosome 9p trisomy increases stem cells clonogenic potential and fosters T-cell exhaustion in JAK2-mutant myeloproliferative neoplasms","authors":"Chiara Carretta, Sandra Parenti, Matteo Bertesi, Sebastiano Rontauroli, Filippo Badii, Lara Tavernari, Elena Genovese, Marica Malerba, Elisa Papa, Samantha Sperduti, Elena Enzo, Margherita Mirabile, Francesca Pedrazzi, Anita Neroni, Camilla Tombari, Barbara Mora, Margherita Maffioli, Marco Mondini, Marco Brociner, Monica Maccaferri, Elena Tenedini, Silvia Martinelli, Niccolò Bartalucci, Elisa Bianchi, Livio Casarini, Leonardo Potenza, Mario Luppi, Enrico Tagliafico, Paola Guglielmelli, Manuela Simoni, Francesco Passamonti, Ruggiero Norfo, Alessandro Maria Vannucchi, Rossella Manfredini, on behalf of MYNERVA (Myeloid NEoplasms Research Venture AIRC)","doi":"10.1038/s41375-024-02373-w","DOIUrl":"10.1038/s41375-024-02373-w","url":null,"abstract":"JAK2V617F is the most recurrent genetic mutation in Philadelphia-negative chronic Myeloproliferative Neoplasms (MPNs). Since the JAK2 locus is located on Chromosome 9, we hypothesized that Chromosome 9 copy number abnormalities may be a disease modifier in JAK2V617F-mutant MPN patients. In this study, we identified a subset of MPN patients with partial or complete Chromosome 9 trisomy (+9p patients), who differ from JAK2V617F-homozygous MPN patients as they carry three JAK2 alleles as well as three copies of all neighboring gene loci, including CD274, encoding immunosuppressive Programmed death-ligand 1 (PD-L1) protein. Investigation of the clonal hierarchy revealed that the JAK2V617F occurs first, followed by +9p. Functionally, CD34+ cells from +9p MPN patients demonstrated increased clonogenicity, generating a greater number of primitive colonies, due to high OCT4 and NANOG expression, with knock-down of these genes leading to a genotype-specific decrease in colony numbers. Moreover, our analysis revealed increased PD-L1 surface expression in malignant monocytes from +9p patients, while analysis of the T cell compartment unveiled elevated levels of exhausted cytotoxic T cells. Overall, here we identify a distinct novel subgroup of MPN patients, who feature a synergistic interplay between +9p and JAK2V617F that shapes immune escape characteristics and increased stemness in CD34+ cells.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02373-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142042695","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}