LeukemiaPub Date : 2024-12-23DOI: 10.1038/s41375-024-02496-0
Shivani Handa, Christoph Schaniel, Joseph Tripodi, Daiva Ahire, Md. Babu Mia, Sophie Klingborg, Douglas Tremblay, Bridget K. Marcellino, Ronald Hoffman, Vesna Najfeld
{"title":"HMGA2 overexpression with specific chromosomal abnormalities predominate in CALR and ASXL1 mutated myelofibrosis","authors":"Shivani Handa, Christoph Schaniel, Joseph Tripodi, Daiva Ahire, Md. Babu Mia, Sophie Klingborg, Douglas Tremblay, Bridget K. Marcellino, Ronald Hoffman, Vesna Najfeld","doi":"10.1038/s41375-024-02496-0","DOIUrl":"10.1038/s41375-024-02496-0","url":null,"abstract":"Although multiple genetic events are thought to play a role in promoting progression of the myeloproliferative neoplasms (MPN), the individual events that are associated with the development of more aggressive disease phenotypes remain poorly defined. Here, we report that novel genomic deletions at chromosome 12q14.3, as detected by a high-resolution array comparative genomic hybridization plus single nucleotide polymorphisms platform, occur in 11% of MPN patients with myelofibrosis (MF) and MPN-accelerated/blast phase (AP/BP) but was not detected in patients with polycythemia vera or essential thrombocythemia. These 12q14.3 deletions resulted in the loss of most of the non-coding region of exon 5 and MIRLET7 binding sites in the 3’UTR of the high mobility group AT hook 2 (HMGA2), which negatively regulate HMGA2 expression. These acquired 12q14.3 deletions were predominately detected in MF patients with CALR and ASXL1 co-mutations and led to a greater degree of HMGA2 transcript overexpression, independent of the presence of an ASXL1 mutation. Patients with 12q structural abnormalities involving HMGA2 exhibited a more aggressive clinical course, with a higher frequency of MPN-AP/BP evolution. These findings indicate that HMGA2 overexpression associated with genomic deletion of its 3’UTR region is a newly recognized genetic event that contributes to MPN progression.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 3","pages":"663-674"},"PeriodicalIF":12.8,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02496-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142873946","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}
LeukemiaPub Date : 2024-12-20DOI: 10.1038/s41375-024-02503-4
Qian Cui, Wen Tan, Bao Song, Rou-Jun Peng, Ling Wang, Rajkumar Dorajoo, Kok Pin Ng, Guo-Wang Lin, Wing-Yan Au, Raymond H. S. Liang, Chiea Chuen Khor, Qing-Ling Zhang, Jia Nee FOO, Sheng-Ping Li, Fu-Ren Zhang, Xue-Jun Zhang, Xue-Qing Yu, Qing Lan, Stephen Chanock, Wei-Hua Jia, Soon Thye Lim, Wen-Yu Li, Nathaniel Rothman, Jin-Xin Bei, Jie Liu, Dongxin Lin, Jian-Jun Liu
{"title":"Genetic susceptibility of diffuse large B-cell lymphoma: a meta genome-wide association study in Asian population","authors":"Qian Cui, Wen Tan, Bao Song, Rou-Jun Peng, Ling Wang, Rajkumar Dorajoo, Kok Pin Ng, Guo-Wang Lin, Wing-Yan Au, Raymond H. S. Liang, Chiea Chuen Khor, Qing-Ling Zhang, Jia Nee FOO, Sheng-Ping Li, Fu-Ren Zhang, Xue-Jun Zhang, Xue-Qing Yu, Qing Lan, Stephen Chanock, Wei-Hua Jia, Soon Thye Lim, Wen-Yu Li, Nathaniel Rothman, Jin-Xin Bei, Jie Liu, Dongxin Lin, Jian-Jun Liu","doi":"10.1038/s41375-024-02503-4","DOIUrl":"10.1038/s41375-024-02503-4","url":null,"abstract":"Diffuse large B-cell lymphoma (DLBCL) is an aggressive malignancy and the most common form of non-Hodgkin lymphoma (NHL) that occurs worldwide. To discover risk factors and pathogenesis of DLBCL, we performed the largest GWAS of DLBCL to date in samples of East Asian ancestry, consisting of 2,888 patients with DLBCL and 12,458 controls. The meta-analysis identified three novel loci, rs2233434 on 6p21.1 (OR = 1.26, P = 1.17 × 10−8), rs11066015 on 12q24.12 (OR = 1.24, P = 6.57 × 10−9) and rs6032662 on 20q13.12 (OR = 1.24, P = 5.22 × 10−12). Fine mapping analysis revealed that the extensive association within the MHC region was driven by two novel HLA alleles, HLA-A*02 and HLA-DQB1*03. Functional annotation, eQTL and colocalization analyses of the susceptibility loci implicated NFKBIE/TCTE1, ALDH2/BRAP and CD40 as candidate disease genes. The pleiotropic effect analysis of the DLBCL loci revealed shared genetic susceptibility between DLBCL and several autoimmune diseases. Our study also suggested genetic heterogeneity between Asian and European populations by identifying ancestry-specific genetic associations. Overall, this study has implicated novel disease genes and molecular mechanism for DLBCL.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 3","pages":"694-702"},"PeriodicalIF":12.8,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02503-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142858429","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}
LeukemiaPub Date : 2024-12-19DOI: 10.1038/s41375-024-02502-5
Aurélie Caye-Eude, Grazia Fazio, Agata Pastorczak, Judith M. Boer, Doris Steinemann, Debdutta Ganguli, Edwin Sonneveld, Sabrina Haslinger, Lucía D’Andrea, Jutta Bradtke, Bruno A. Lopes, Marketa Zaliova, Gabriele Escherich, Margit König, Klaus Fortschegger, Andrea Inthal, Irina Stasevich, Mariana Emerenciano, Jan Trka, Luis Castillo, Mayur Parihar, Anthony V. Moorman, Anke K. Bergmann, Monique L. den Boer, Wojciech Młynarski, Giovanni Cazzaniga, Hélène Cavé, Karin Nebral, Dagmar Schinnerl, Sabine Strehl
{"title":"PAX5::AUTS2 childhood B-ALL: a relapse-prone genetic subtype with frequent central nervous system involvement and a poor outcome","authors":"Aurélie Caye-Eude, Grazia Fazio, Agata Pastorczak, Judith M. Boer, Doris Steinemann, Debdutta Ganguli, Edwin Sonneveld, Sabrina Haslinger, Lucía D’Andrea, Jutta Bradtke, Bruno A. Lopes, Marketa Zaliova, Gabriele Escherich, Margit König, Klaus Fortschegger, Andrea Inthal, Irina Stasevich, Mariana Emerenciano, Jan Trka, Luis Castillo, Mayur Parihar, Anthony V. Moorman, Anke K. Bergmann, Monique L. den Boer, Wojciech Młynarski, Giovanni Cazzaniga, Hélène Cavé, Karin Nebral, Dagmar Schinnerl, Sabine Strehl","doi":"10.1038/s41375-024-02502-5","DOIUrl":"10.1038/s41375-024-02502-5","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 2","pages":"482-486"},"PeriodicalIF":12.8,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02502-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142848835","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"ADAR1 is required for acute myeloid leukemia cell survival by modulating post-transcriptional Wnt signaling through impairing miRNA biogenesis","authors":"Zhongrui Shi, Jiaxing Li, Jiayu Ding, Yiwen Zhang, Wenjian Min, Yasheng Zhu, Yi Hou, Kai Yuan, Chengliang Sun, Xuejiao Wang, Hao Shen, Liping Wang, Shun-Qing Liang, Wenbin Kuang, Xiao Wang, Peng Yang","doi":"10.1038/s41375-024-02500-7","DOIUrl":"10.1038/s41375-024-02500-7","url":null,"abstract":"Recent extensive studies on the genomic and molecular profiles of acute myeloid leukemia (AML) have expanded the treatment options, including, a range of compounds represented by fms-like tyrosine kinase 3 and isocitrate dehydrogenase 1/2 inhibitors. However, despite this progress, further treatments for AML are still required. Adenosine deaminase acting on RNA 1 (ADAR1) has been shown to play an important oncogenic role in many cancers, but its involvement in AML progression remains underexplored. In this study, we demonstrated that ADAR1 was overexpressed in AML and served as a crucial oncogenic target. Loss of ADAR1 inhibited the Wnt signaling pathway, blocked AML cell proliferation, and induced apoptosis. Importantly, we demonstrate that ADAR1, as an RNA-binding protein, interacts with pri-miR-766 independently of its editing function, regulating the maturation of miR-766-3p and enhancing the expression of WNT5B. Genetic inhibition or use of the ADAR1 inhibitor ZYS-1 significantly suppressed AML cell growth both in vitro and in vivo. Overall, these results elucidated the tumorigenic mechanism of ADAR1 and validated it as a potential drug target in AML.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 3","pages":"599-613"},"PeriodicalIF":12.8,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02500-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142848836","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}
LeukemiaPub Date : 2024-12-17DOI: 10.1038/s41375-024-02476-4
Brunangelo Falini, Daniele Sorcini, Vincenzo Maria Perriello, Paolo Sportoletti
{"title":"Functions of the native NPM1 protein and its leukemic mutant","authors":"Brunangelo Falini, Daniele Sorcini, Vincenzo Maria Perriello, Paolo Sportoletti","doi":"10.1038/s41375-024-02476-4","DOIUrl":"10.1038/s41375-024-02476-4","url":null,"abstract":"The nucleophosmin (NPM1) gene encodes for the most abundant nucleolar protein. Thanks to its property to act as histone chaperone and to shuttle between the nucleus and cytoplasm, the NPM1 protein is involved in multiple cellular function that are here extensively reviewed and include the formation of the nucleolus through liquid-liquid phase separation, regulation of ribosome biogenesis and transport, control of DNA repair and centrosome duplication as well as response to nucleolar stress. NPM1 is mutated in about 30–35% of adult acute myeloid leukemia (AML). Due to its unique biological and clinical features, NPM1-mutated AML is regarded as a distinct leukemia entity in the WHO 5th edition and ICC classifications of myeloid malignancies. The NPM1 mutant undergoes changes at the C-terminus of the protein that leads to its delocalization in the cytoplasm of the leukemic cells. Here, we focus also on its biological functions discussing the murine models of NPM1 mutations and the various mechanisms that occur at cytoplasmic and nuclear levels to promote and maintain NPM1-mutated AML","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 2","pages":"276-290"},"PeriodicalIF":12.8,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02476-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142832005","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}
LeukemiaPub Date : 2024-12-17DOI: 10.1038/s41375-024-02499-x
Jana Nabki, Bashar Al Deeban, Abel Mehari Sium, Chiara Cosentino, Mohammad Almasri, Bassel Awikeh, Nawar Maher, Matteo Bellia, Riccardo Dondolin, Samir Mouhssine, Donatella Talotta, Eleonora Secomandi, Sreekar Kogila, Joseph Ghanej, Francesca Maiellaro, Luca Cividini, Silvia Rasi, Annalisa Chiarenza, Jacopo Olivieri, Massimo Gentile, Francesco Zaja, Maria Ilaria Del Principe, Luca Laurenti, Riccardo Bomben, Filippo Vit, Tamara Bittolo, Antonella Zucchetto, Valter Gattei, Gianluca Gaidano, Riccardo Moia
{"title":"Immunoglobulin light chain mutational status refines IGHV prognostic value in identifying chronic lymphocytic leukemia patients with early treatment requirement","authors":"Jana Nabki, Bashar Al Deeban, Abel Mehari Sium, Chiara Cosentino, Mohammad Almasri, Bassel Awikeh, Nawar Maher, Matteo Bellia, Riccardo Dondolin, Samir Mouhssine, Donatella Talotta, Eleonora Secomandi, Sreekar Kogila, Joseph Ghanej, Francesca Maiellaro, Luca Cividini, Silvia Rasi, Annalisa Chiarenza, Jacopo Olivieri, Massimo Gentile, Francesco Zaja, Maria Ilaria Del Principe, Luca Laurenti, Riccardo Bomben, Filippo Vit, Tamara Bittolo, Antonella Zucchetto, Valter Gattei, Gianluca Gaidano, Riccardo Moia","doi":"10.1038/s41375-024-02499-x","DOIUrl":"10.1038/s41375-024-02499-x","url":null,"abstract":"The mutational status of immunoglobulin (IG) light chain genes in chronic lymphocytic leukemia (CLL) and its clinical impact have not been extensively studied. To assess their prognostic significance, the IG light chain gene repertoire in CLL patients has been evaluated using a training-validation approach. In the training cohort (N = 573 CLL), 92.5% showed productive IG light chain genes rearrangements, with IGKV4-1 (20.5%) and IGLV3-21 (19.0%) being the most common. A 99.0% somatic hypermutation cut-off was identified as the best predictor for time to first treatment (TTFT) in 414 Binet A CLL patients of the training cohort. Patients with unmutated (UM) light chain genes displayed a 10-year treatment free probability of 32.4% versus 73.2% for those with mutated (M) genes (p < 0.0001). Importantly, UM light chain genes maintained an independent association with a shorter TTFT when adjusted for the IPS-E prognostic model variables, that also includes IGHV mutational status. The validation cohort of 343 Rai 0 patients confirmed these findings, with UM light chain genes predicting a 7-year treatment free probability of 42.0% versus 73.7% for M genes (p < 0.0001). These results indicate that the mutational status of the light chain genes is an independent predictor of shorter TTFT in early-stage CLL patients.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 3","pages":"643-649"},"PeriodicalIF":12.8,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02499-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142832004","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}
LeukemiaPub Date : 2024-12-17DOI: 10.1038/s41375-024-02490-6
Nicole Seifert, Sarah Reinke, Johanna Grund, Berit Müller-Meinhard, Julia Richter, Thorsten Heilmann, Hans Schlößer, Michaela Kotrova, Monika Brüggemann, Peter Borchmann, Paul J. Bröckelmann, Michael Altenbuchinger, Wolfram Klapper
{"title":"T-cell diversity and exclusion of blood-derived T-cells in the tumor microenvironment of classical Hodgkin Lymphoma","authors":"Nicole Seifert, Sarah Reinke, Johanna Grund, Berit Müller-Meinhard, Julia Richter, Thorsten Heilmann, Hans Schlößer, Michaela Kotrova, Monika Brüggemann, Peter Borchmann, Paul J. Bröckelmann, Michael Altenbuchinger, Wolfram Klapper","doi":"10.1038/s41375-024-02490-6","DOIUrl":"10.1038/s41375-024-02490-6","url":null,"abstract":"The Tumor Microenvironment (TME) in classical Hodgkin Lymphoma (HL) contains abundant immune cells and only few neoplastic Hodgkin and Reed-Sternberg cells (HRSC). We analyzed the T-cell receptor (TCR) repertoire to detect T-cell expansion in the TME and blood. In contrast to solid cancer tissue, T-cells in the TME of HL are highly polyclonal at first diagnosis and show only minor clonal expansion during anti-PD1 immune checkpoint blockade (ICB). At relapse and during ICB, pre-amplified T-cell populations increase in the TME of solid cancers but to a much lesser extent in HL. In contrast, T-cell populations in the peripheral blood of HL patients display higher clonality than healthy controls reaching clonality levels comparable to solid cancer. However, pre-amplified blood T-cells in HL patients show only minor additional clonal expansion during ICB. Moreover, blood-derived T-cells do not repopulate the TME of HL to the same extent as observed in solid cancers. Thus, the T-cell repertoire in the TME of HL appears unique by a relatively low clonal T-cell content and the exclusion of clonally expanded T-cells from the peripheral blood. Exclusion of clonally expanded tumor-specific T-cells from the TME may present a novel mechanism of immune evasion in HL.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 3","pages":"684-693"},"PeriodicalIF":12.8,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02490-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142832007","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}
LeukemiaPub Date : 2024-12-16DOI: 10.1038/s41375-024-02493-3
Tommaso Balestra, Lisa M Niswander, Asen Bagashev, Joseph P Loftus, Savannah L Ross, Robert K Chen, Samantha M McClellan, Jacob J Junco, Diego A Bárcenas López, Karen R. Rabin, Terry J Fry, Sarah K Tasian
{"title":"Co-targeting of the thymic stromal lymphopoietin receptor to decrease immunotherapeutic resistance in CRLF2-rearranged Ph-like and Down syndrome acute lymphoblastic leukemia","authors":"Tommaso Balestra, Lisa M Niswander, Asen Bagashev, Joseph P Loftus, Savannah L Ross, Robert K Chen, Samantha M McClellan, Jacob J Junco, Diego A Bárcenas López, Karen R. Rabin, Terry J Fry, Sarah K Tasian","doi":"10.1038/s41375-024-02493-3","DOIUrl":"10.1038/s41375-024-02493-3","url":null,"abstract":"CRLF2 rearrangements occur in >50% of Ph-like and Down syndrome (DS)-associated B-acute lymphoblastic leukemia (ALL) and induce constitutive kinase signaling targetable by the JAK1/2 inhibitor ruxolitinib under current clinical investigation. While chimeric antigen receptor T cell (CART) immunotherapies have achieved remarkable remission rates in children with relapsed/refractory B-ALL, ~50% of CD19CART-treated patients relapse again, many with CD19 antigen loss. We previously reported preclinical activity of thymic stromal lymphopoietin receptor-targeted cellular immunotherapy (TSLPRCART) against CRLF2-overexpressing ALL as an alternative approach. In this study, we posited that combinatorial TSLPRCART and ruxolitinib would have superior activity and first validated potent TSLPRCART-induced inhibition of leukemia proliferation in vitro in CRLF2-rearranged ALL cell lines and in vivo in Ph-like and DS-ALL patient-derived xenograft (PDX) models. However, simultaneous TSLPRCART/ruxolitinib or CD19CART/ruxolitinib treatment during initial CART expansion diminished T cell proliferation, blunted cytokine production, and/or facilitated leukemia relapse, which was abrogated by time-sequenced/delayed ruxolitinib co-exposure. Importantly, ruxolitinib co-administration prevented fatal TSLPRCART cytokine-associated toxicity in ALL PDX mice. Upon ruxolitinib withdrawal, TSLPRCART functionality recovered in vivo with clearance of subsequent ALL rechallenge. These translational studies demonstrate an effective two-pronged therapeutic strategy that mitigates acute CART-induced hyperinflammation and provides potential anti-leukemia ‘maintenance’ relapse prevention for CRLF2-rearranged Ph-like and DS-ALL.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 3","pages":"555-567"},"PeriodicalIF":12.8,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02493-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142825133","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}
LeukemiaPub Date : 2024-12-16DOI: 10.1038/s41375-024-02489-z
Kenzie Lee, Taxiarchis Kourelis, Marcella Tschautscher, Rahma Warsame, Francis Buadi, Morie Gertz, Eli Muchtar, David Dingli, Suzanne Hayman, Ronald Go, Lisa Hwa, Amie Fonder, Wilson Gonsalves, Miriam Hobbs, Robert Kyle, Prashant Kapoor, Nelson Leung, Moritz Binder, Joselle Cook, Yi Lin, Michelle Rogers, S. Vincent Rajkumar, Shaji Kumar, Angela Dispenzieri
{"title":"Capillary leak phenotype as a major cause of death in patients with POEMS syndrome","authors":"Kenzie Lee, Taxiarchis Kourelis, Marcella Tschautscher, Rahma Warsame, Francis Buadi, Morie Gertz, Eli Muchtar, David Dingli, Suzanne Hayman, Ronald Go, Lisa Hwa, Amie Fonder, Wilson Gonsalves, Miriam Hobbs, Robert Kyle, Prashant Kapoor, Nelson Leung, Moritz Binder, Joselle Cook, Yi Lin, Michelle Rogers, S. Vincent Rajkumar, Shaji Kumar, Angela Dispenzieri","doi":"10.1038/s41375-024-02489-z","DOIUrl":"10.1038/s41375-024-02489-z","url":null,"abstract":"Cause of death (COD) in POEMS (polyneuropathy, organomegaly, endocrinopathies, monoclonal protein and skin changes) syndrome is not well described. We investigated COD in patients with POEMS syndrome treated at Mayo Clinic between 2000 and 2022. Of the 89 deaths, 49 patients had known COD and were the subject of this study. Seventeen patients died of unrelated causes, while 32 patients (65%) died from causes related to POEMS syndrome including secondary malignancies like myelodysplastic syndrome and acute leukemia (n = 5) and complications from active therapy (n = 5). Notably, 19 patients died with a stereotypic syndrome we termed capillary leak phenotype (CLP), which was characterized by refractory ascites, effusions and/or anasarca that ultimately resulted in hypotension, renal failure and cardiopulmonary arrest. Alternate causes for these symptoms, such as cardiac and hepatic etiologies, were excluded. CLP as a COD was an earlier event with a median time from diagnosis to death of 2.5 years compared to 12.0 years for all other deceased patients (p = <0.0001). By definition, treatment of terminal CLP was unsuccessful with median survival of only 4 months after CLP onset. The driver of CLP is unknown, but recognition as an entity should allow for systematic study.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 3","pages":"703-709"},"PeriodicalIF":12.8,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02489-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142825130","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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