{"title":"LILRB1-directed CAR-T cells for the treatment of hematological malignancies","authors":"Katsiaryna Marhelava, Klaudyna Fidyt, Monika Pepek, Marta Krawczyk, Christopher Forcados, Agata Malinowska, Bianka Swiderska, Narcis Fernandez-Fuentes, Natalia Czerwik, Iwona Baranowska, Agnieszka Krzywdzinska, Lukasz Sedek, Lukasz Slota, Bartosz Perkowski, Alicia Villatoro, Thibault Leray, Ewa Lech-Maranda, Pablo Menendez, Else Marit Inderberg, Sébastien Wälchli, Magdalena Winiarska, Malgorzata Firczuk","doi":"10.1038/s41375-025-02580-z","DOIUrl":"https://doi.org/10.1038/s41375-025-02580-z","url":null,"abstract":"<p>CD19 CAR-T cells have established a new standard for relapsed/refractory B-cell malignancies. However, the treatment fails in 50% of patients, often due to CD19 antigen loss. Alternative immunotherapies targeting other antigens are being tested but show limited efficacy, especially in cases of lineage switching or loss of B-cell phenotype, highlighting the need for novel targets. Herein, we identified leukocyte-immunoglobulin-like-receptor-B1 (LILRB1, CD85j) as a novel target for CAR-T cells through cell surface proteomics on patient-derived samples of high-risk B-cell acute lymphoblastic leukemia (B-ALL). LILRB1, an immune inhibitory receptor, is normally expressed only on monocytes and B-cells. We observed stable LILRB1 expression in B-ALL and B-cell non-Hodgkin lymphoma (B-NHL), even after CD20/CD19-based immunotherapies. LILRB1 CAR-T cells showed antigen-specific antitumor activity in vitro against B-ALL/B-NHL cells, including those resistant to CD19 CAR-T-cells, and in vivo in B-ALL xenografts. Additionally, we identified LILRB1 in monocytic acute myeloid leukemia (AML) and demonstrated LILRB1 CAR-T cell cytotoxicity against AML cell lines in vitro and in vivo. These findings establish LILRB1 as a novel target for cancer immunotherapy and show evidence for the preclinical efficacy of LILRB1 CAR-T cells against haematological malignancies, including cases resistant to previous lines of immunotherapy, thus holding promise for further clinical development.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"23 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143782414","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}
LeukemiaPub Date : 2025-04-04DOI: 10.1038/s41375-025-02590-x
Ivo Veletic, David M. Harris, Uri Rozovski, Maria Teresa S. Bertilaccio, George A. Calin, Koichi Takahashi, Ping Li, Zhiming Liu, Taghi Manshouri, Rares-Constantin Drula, Ken Furudate, Muharrem Muftuoglu, Anwar Hossain, William G. Wierda, Michael J. Keating, Zeev Estrov
{"title":"CLL cell-derived exosomes alter the immune and hematopoietic systems","authors":"Ivo Veletic, David M. Harris, Uri Rozovski, Maria Teresa S. Bertilaccio, George A. Calin, Koichi Takahashi, Ping Li, Zhiming Liu, Taghi Manshouri, Rares-Constantin Drula, Ken Furudate, Muharrem Muftuoglu, Anwar Hossain, William G. Wierda, Michael J. Keating, Zeev Estrov","doi":"10.1038/s41375-025-02590-x","DOIUrl":"https://doi.org/10.1038/s41375-025-02590-x","url":null,"abstract":"<p>The origins of immunosuppression, neutropenia, and anemia in patients with chronic lymphocytic leukemia (CLL) are not fully understood. Because in patients with CLL, circulating exosomes, which participate in cell-to-cell interactions, are CLL cell-derived, we examined whether those exosomes contribute to abnormal features of this disease. Our data revealed that CLL cell-derived exosomes engulfed by healthy donors’ monocytes, fibrocytes, and lymphocytes altered target-cell gene and protein expression and suppressed normal hematopoiesis. CLL cell-derived exosomes increased normal monocytes’ CD14 and CD16 expression such that it mimicked the accessory-cell profile and upregulated T cells’ checkpoint PD-1 and CD160 protein levels, potentially reducing T-cell-mediated anti-CLL activity. In normal B cells, CLL cell-derived exosomes induced apoptosis and CD5 expression, suggesting that CLL cell-derived exosomes eliminate B cells and not all CD19<sup>+</sup>/CD5<sup>+</sup> cells in CLL patients are clonal. RNA sequencing and quantitative real-time PCR revealed that CLL cell-derived exosomes harbored RNAs of pro-apoptotic genes and genes that increase metabolism, induce proliferation, and induce constitutive PI3K-mTOR pathway activation. CLL cell-derived exosomes inhibited hematopoietic progenitor proliferation, hindering the supportive effect of monocyte-derived fibrocytes. Together, our findings suggest that CLL cell-derived exosomes disrupt the immune and hematopoietic systems and contribute to disease progression in patients with CLL.</p><figure></figure>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"37 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143775626","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}
LeukemiaPub Date : 2025-04-02DOI: 10.1038/s41375-025-02564-z
Kelly S. Chien, Julie S. Braish, Ziyi Li, Sanam Loghavi, Alex Bataller, Guillermo Montalban-Bravo, Koji Sasaki, Rashmi Kanagal-Shamanna, Koichi Takahashi, Courtney D. DiNardo, Mahesh Swaminathan, Hagop M. Kantarjian, Guillermo Garcia-Manero
{"title":"Clinicopathologic characteristics and outcomes of patients with clonal hematopoiesis who progress to myeloid neoplasms","authors":"Kelly S. Chien, Julie S. Braish, Ziyi Li, Sanam Loghavi, Alex Bataller, Guillermo Montalban-Bravo, Koji Sasaki, Rashmi Kanagal-Shamanna, Koichi Takahashi, Courtney D. DiNardo, Mahesh Swaminathan, Hagop M. Kantarjian, Guillermo Garcia-Manero","doi":"10.1038/s41375-025-02564-z","DOIUrl":"https://doi.org/10.1038/s41375-025-02564-z","url":null,"abstract":"<p>Clonal hematopoiesis (CH) is a non-malignant clonal expansion of a hematopoietic stem cell population due to the acquisition of somatic mutation(s) that confer advantages in self-renewal and proliferation. These mutations have been detected in healthy individuals and rise in frequency with normal aging [1]. The increase in prevalence of CH with age may reflect the cumulative effect of exposures to environmental stressors, such as radiation, tobacco, and mutagenic drugs, that provide selective pressure for particular hematopoietic stem cells and consequent clonal expansion [2]. Although its presence does not directly lead to oncologic disease, CH has been associated with an increased risk of hematologic malignancies and myeloid neoplasms (MNs), chronic inflammation, and cardiovascular complications [3].</p><p>The Clonal Hematopoiesis Risk Score (CHRS) is a personalized prediction tool incorporating age, peripheral blood laboratory values, specific mutations, and variant allele frequency (VAF) to assess the risk of progression to MNs in healthy adults with CH [4]. The impact of medical histories, especially prior cancer diagnosis and exposure to antineoplastic therapy, is not included. Additionally, although it is well established that CH increases risk of MN transformation, the dynamics of disease evolution in patients with CH who progress to MNs remain unknown. Thus, we aimed to evaluate the clinicopathologic characteristics and survival outcomes of patients with MN with known antecedent CH, with a particular focus on patients with prior non-myeloid malignancies.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"34 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143758605","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}
LeukemiaPub Date : 2025-04-02DOI: 10.1038/s41375-025-02584-9
Maša Zrimšek, Kristina Draganić, Anna Malzer, Verena Doblmayr, Katarina Mišura, Rafael de Freitas E Silva, Jamie D. Matthews, Fabio Iannelli, Sabrina Wohlhaupter, Carlos Uziel Pérez Malla, Heinz Fischer, Helga Schachner, Ana-Iris Schiefer, Raheleh Sheibani-Tezerji, Roberto Chiarle, Suzanne Dawn Turner, Wilfried Ellmeier, Christian Seiser, Gerda Egger
{"title":"HDAC1 acts as a tumor suppressor in ALK-positive anaplastic large cell lymphoma: implications for HDAC inhibitor therapy","authors":"Maša Zrimšek, Kristina Draganić, Anna Malzer, Verena Doblmayr, Katarina Mišura, Rafael de Freitas E Silva, Jamie D. Matthews, Fabio Iannelli, Sabrina Wohlhaupter, Carlos Uziel Pérez Malla, Heinz Fischer, Helga Schachner, Ana-Iris Schiefer, Raheleh Sheibani-Tezerji, Roberto Chiarle, Suzanne Dawn Turner, Wilfried Ellmeier, Christian Seiser, Gerda Egger","doi":"10.1038/s41375-025-02584-9","DOIUrl":"https://doi.org/10.1038/s41375-025-02584-9","url":null,"abstract":"<p>Histone deacetylases (HDACs) are frequently deregulated in cancer, and several HDAC inhibitors (HDACi) have gained approval for treating peripheral T cell lymphomas. Here, we investigated the effects of pharmacological or genetic HDAC inhibition on NPM::ALK positive anaplastic large cell lymphoma (ALCL) development to assess the potential use of HDACi for the treatment of this disease. Short-term systemic pharmacological inhibition of HDACs using the HDACi Entinostat in a premalignant ALCL mouse model postponed or even abolished lymphoma development, despite high expression of the NPM::ALK fusion oncogene. To further disentangle the effects of systemic HDAC inhibition from thymocyte intrinsic effects, conditional genetic deletions of HDAC1 and HDAC2 enzymes were employed. In sharp contrast, T cell-specific deletion of <i>Hdac1</i> or <i>Hdac2</i> in the ALCL mouse model significantly accelerated NPM::ALK-driven lymphomagenesis, with <i>Hdac1</i> loss having a more pronounced effect. Integration of gene expression and chromatin accessibility data revealed that <i>Hdac1</i> deletion selectively perturbed cell type-specific transcriptional programs, crucial for T cell differentiation and signaling. Moreover, multiple oncogenic signaling pathways, including PDGFRB signaling, were highly upregulated. Our findings underscore the tumor-suppressive function of HDAC1 and HDAC2 in T cells during ALCL development. Nevertheless, systemic pharmacological inhibition of HDACs could still potentially improve current therapeutic outcomes.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"5 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143766566","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}
LeukemiaPub Date : 2025-04-02DOI: 10.1038/s41375-025-02589-4
Ran Li, Xiaolu Wu, Kai Xue, Shishuang Wu, Ge Jiang, Mengke He, Yi Xia, Hailing Liu, Miao Zhong, Jianyong Li, Lei Fan, Junmin Li
{"title":"CircTADA2A stabilizes p53 via interacting with TRIM28 and suppresses the maintenance of FLT3-ITD acute myeloid leukemia","authors":"Ran Li, Xiaolu Wu, Kai Xue, Shishuang Wu, Ge Jiang, Mengke He, Yi Xia, Hailing Liu, Miao Zhong, Jianyong Li, Lei Fan, Junmin Li","doi":"10.1038/s41375-025-02589-4","DOIUrl":"https://doi.org/10.1038/s41375-025-02589-4","url":null,"abstract":"<p>Internal tandem duplication mutations in the FMS-like tyrosine kinase 3 (FLT3-ITDs) occur in 25%–30% of acute myeloid leukemia (AML) cases and are associated with adverse prognosis. RNA-based therapeutics exhibit significant potential for treating diseases, prompting us to develop a novel circular RNA (circRNA)-based therapeutic strategy for FLT3-ITD AML. Here, we find circTADA2A is downregulated in FLT3-ITD AML patients. We further demonstrate that the downregulation of circTADA2A is critical for the proliferation of human FLT3-ITD AML cells, the sustenance of AML, and the self-renewal of leukemia stem/initiating cells (LSCs/LICs). Mechanistically, circTADA2A inhibits the TRIM28/MDM2 complexes formation by competitively binding to TRIM28, resulting in decreased levels of p53 ubiquitination and activating the p53 pathway. Importantly, in vitro transcription of circTADA2A and in vivo delivery via lipid nanoparticles (LNPs) significantly enhance the elimination of FLT3-ITD leukemia cells in combination with quizartinib treatment. In conclusion, our work uncovers the crucial functions of circTADA2A in the maintenance of FLT3-ITD AML and highlights a translationally important circTADA2A-based therapeutic approach for FLT3-ITD AML treatment.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"25 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143758143","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}
LeukemiaPub Date : 2025-04-02DOI: 10.1038/s41375-025-02566-x
Chantal Reinhardt, Adrian F. Ochsenbein
{"title":"Immune checkpoints regulate acute myeloid leukemia stem cells","authors":"Chantal Reinhardt, Adrian F. Ochsenbein","doi":"10.1038/s41375-025-02566-x","DOIUrl":"https://doi.org/10.1038/s41375-025-02566-x","url":null,"abstract":"<p>Acute myeloid leukemia stem cells (LSCs) express major histocompatibility complex (MHC) class I and II and many different immune checkpoint ligands and receptors, in which respect they resemble professional antigen-presenting cells. In addition, LSCs reside in the bone marrow (BM), a primary and secondary lymphoid organ, surrounded by immune cells. The function of these immune checkpoints (ICs) in the regulation of an anti-tumor immune response is well studied and IC inhibitors (ICIs) became a standard of care in many solid tumors. However, ICIs have very limited efficacy in AML. Nevertheless, the expression especially of immune activating ligands and receptors on LSCs is somewhat unexpected, since these cells have to evade protective immunity. Many ICs have been shown to mediate direct signaling in AML blasts and LSCs and thereby regulate self-renewal, differentiation and expansion of leukemic cells. Thus, the expression of ICs on the cell surface or their soluble forms often correlate with worse survival. In this review we summarize recent data on selected ICs of the immunoglobulin superfamily (IgSF) and the tumor necrosis factor receptor superfamily (TNFRSF) that have a documented role in the regulation of LSCs, independent of their immune regulatory role, and might become novel therapeutic targets.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"55 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143758142","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}
LeukemiaPub Date : 2025-04-01DOI: 10.1038/s41375-025-02582-x
Gloria Iacoboni, Kai Rejeski, Víctor Navarro, Tom van Meerten, Alex Rampotas, Ana África Martín-López, Mariana Bastos, Ana Benzaquén, Juan Luis Reguera-Ortega, Cecilia Carpio, Claire Roddie, Lucia López-Corral, Javier Delgado-Serrano, Maria Landwehr, Sophia Stock, Pablo Silva de Tena, Pau Abrisqueta, Janneke de Boer, Alejandro Martin Garcia-Sancho, Rafael Hernani, Mi Kwon, Marion Subklewe, Maeve O’Reilly, Pere Barba
{"title":"Site-specific analysis of extranodal involvement in large B-cell lymphoma reveals distinct efficacy with chimeric antigen receptor T-cell therapy","authors":"Gloria Iacoboni, Kai Rejeski, Víctor Navarro, Tom van Meerten, Alex Rampotas, Ana África Martín-López, Mariana Bastos, Ana Benzaquén, Juan Luis Reguera-Ortega, Cecilia Carpio, Claire Roddie, Lucia López-Corral, Javier Delgado-Serrano, Maria Landwehr, Sophia Stock, Pablo Silva de Tena, Pau Abrisqueta, Janneke de Boer, Alejandro Martin Garcia-Sancho, Rafael Hernani, Mi Kwon, Marion Subklewe, Maeve O’Reilly, Pere Barba","doi":"10.1038/s41375-025-02582-x","DOIUrl":"https://doi.org/10.1038/s41375-025-02582-x","url":null,"abstract":"<p>Over 60% of relapsed/refractory large B-cell lymphoma (R/R LBCL) patients treated with chimeric antigen receptor (CAR) T-cells experience progressive disease. The impact of site-specific extranodal involvement on CAR-T outcomes has not been fully elucidated. This multicenter study included 516 R/R LBCL patients infused with CD19-targeted CAR T-cells; 177 (34%) had only-nodal (N), 66 (13%) only-extranodal (E) and 273 (53%) nodal and extranodal (NE) disease at time of CAR T-cells. The NE cohort included more patients with a poor performance status and high tumor burden. In the multivariable analysis, the NE group had a shorter progression-free survival (PFS) (HR 1.27 [95%CI 0.98–1.64], <i>p</i> = 0.07) and overall survival (HR 1.41 [95%CI 1.05–1.88], <i>p</i> = 0.02) compared to N. Conversely, we did not identify efficacy differences between N and E patients. A higher number of extranodal sites and specific organ involvement (liver, adrenal glands, pancreas), were associated with shorter PFS. Finally, extranodal involvement increased at time of relapse, displaying heterogeneous individual site clearance rates. In conclusion, patients with concomitant nodal and extranodal involvement at time of CAR-T had worse outcomes, but this cohort harbored high-risk baseline characteristics. An increasing number of extranodal sites and certain disease locations were associated with lower CAR-T efficacy.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"96 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143744873","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}
LeukemiaPub Date : 2025-03-31DOI: 10.1038/s41375-025-02581-y
Anne-Marie L. Becking, Johannes P. M. van de Mortel, Oliver Tomkins, Thijs W. H. Flinsenberg, Nicole Japzon, Marie José Kersten, Jahanzaib Khwaja, Saskia Kuipers, Henriette Levenga, Sean McKeague, Stephen Opat, Ross T. Salvaris, Sherif Seif, Sheeba K. Thomas, Alexander F. J. E. Vrancken, Shirley D’Sa, Monique C. Minnema, Josephine M. I. Vos
{"title":"Zanubrutinib in Bing Neel syndrome: efficacy and tolerability","authors":"Anne-Marie L. Becking, Johannes P. M. van de Mortel, Oliver Tomkins, Thijs W. H. Flinsenberg, Nicole Japzon, Marie José Kersten, Jahanzaib Khwaja, Saskia Kuipers, Henriette Levenga, Sean McKeague, Stephen Opat, Ross T. Salvaris, Sherif Seif, Sheeba K. Thomas, Alexander F. J. E. Vrancken, Shirley D’Sa, Monique C. Minnema, Josephine M. I. Vos","doi":"10.1038/s41375-025-02581-y","DOIUrl":"https://doi.org/10.1038/s41375-025-02581-y","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"34 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143736596","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}
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