Leukemia最新文献

{"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⁺ 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}

{"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,&nbsp;Hagop Kantarjian,&nbsp;Jeffrey E. Rubnitz,&nbsp;Todd M. Cooper,&nbsp;C. Michel Zwaan,&nbsp;Jessica A. Pollard,&nbsp;Courtney D. DiNardo,&nbsp;Tapan M. Kadia,&nbsp;Erin Guest,&nbsp;Nicholas J. Short,&nbsp;David McCall,&nbsp;Naval Daver,&nbsp;Cesar Nunez,&nbsp;Fadi G. Haddad,&nbsp;Miriam Garcia,&nbsp;Kapil N. Bhalla,&nbsp;Abhishek Maiti,&nbsp;Samanta Catueno,&nbsp;Warren Fiskus,&nbsp;Bing Z. Carter,&nbsp;Amber Gibson,&nbsp;Michael Roth,&nbsp;Sajad Khazal,&nbsp;Priti Tewari,&nbsp;Hussein A. Abbas,&nbsp;Wallace Bourgeois,&nbsp;Michael Andreeff,&nbsp;Neerav N. Shukla,&nbsp;Danh D. Truong,&nbsp;Jeremy Connors,&nbsp;Joseph A. Ludwig,&nbsp;Janine Stutterheim,&nbsp;Elisabeth Salzer,&nbsp;Kristian L. Juul-Dam,&nbsp;Koji Sasaki,&nbsp;Kris M. Mahadeo,&nbsp;Sarah K. Tasian,&nbsp;Gautam Borthakur,&nbsp;Samantha Dickson,&nbsp;Nitin Jain,&nbsp;Elias Jabbour,&nbsp;Soheil Meshinchi,&nbsp;Guillermo Garcia-Manero,&nbsp;Farhad Ravandi,&nbsp;Eytan M. Stein,&nbsp;E. Anders Kolb,&nbsp;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}

{"title":"STING is crucial for the survival of RUNX1::RUNX1T1 leukemia cells","authors":"Yue Sun,&nbsp;Yushuang Wu,&nbsp;Guozheng Pang,&nbsp;Jingru Huang,&nbsp;Mengyao Sheng,&nbsp;Jiaying Xie,&nbsp;Pingyue Chen,&nbsp;Yin Wang,&nbsp;Dongrui Yin,&nbsp;Guangjie Zhao,&nbsp;Stefan K. Bohlander,&nbsp;Jian Huang,&nbsp;Guo-Liang Xu,&nbsp;Hai Gao,&nbsp;Dan Zhou,&nbsp;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}

{"title":"Chromosome 9p trisomy increases stem cells clonogenic potential and fosters T-cell exhaustion in JAK2-mutant myeloproliferative neoplasms","authors":"Chiara Carretta,&nbsp;Sandra Parenti,&nbsp;Matteo Bertesi,&nbsp;Sebastiano Rontauroli,&nbsp;Filippo Badii,&nbsp;Lara Tavernari,&nbsp;Elena Genovese,&nbsp;Marica Malerba,&nbsp;Elisa Papa,&nbsp;Samantha Sperduti,&nbsp;Elena Enzo,&nbsp;Margherita Mirabile,&nbsp;Francesca Pedrazzi,&nbsp;Anita Neroni,&nbsp;Camilla Tombari,&nbsp;Barbara Mora,&nbsp;Margherita Maffioli,&nbsp;Marco Mondini,&nbsp;Marco Brociner,&nbsp;Monica Maccaferri,&nbsp;Elena Tenedini,&nbsp;Silvia Martinelli,&nbsp;Niccolò Bartalucci,&nbsp;Elisa Bianchi,&nbsp;Livio Casarini,&nbsp;Leonardo Potenza,&nbsp;Mario Luppi,&nbsp;Enrico Tagliafico,&nbsp;Paola Guglielmelli,&nbsp;Manuela Simoni,&nbsp;Francesco Passamonti,&nbsp;Ruggiero Norfo,&nbsp;Alessandro Maria Vannucchi,&nbsp;Rossella Manfredini,&nbsp;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}

{"title":"Downregulation of UBA1 expression in myelodysplastic neoplasm","authors":"Yue Wei,&nbsp;Hong Zheng,&nbsp;Ziyi Li,&nbsp;Pamela Pennington Lockyer,&nbsp;Faezeh Darbaniyan,&nbsp;Rashmi Kanagal-Shamanna,&nbsp;Hui Yang,&nbsp;Danielle Hammond,&nbsp;Guillermo Garcia-Manero","doi":"10.1038/s41375-024-02364-x","DOIUrl":"10.1038/s41375-024-02364-x","url":null,"abstract":"","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/s41375-024-02364-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142042694","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":"Evolution of T-cell fitness through AML progression: enhanced bispecific T-cell engager-mediated function of bone marrow T cells at remission compared to initial diagnosis and relapse","authors":"Maryam Kazerani,&nbsp;Anetta Marcinek,&nbsp;Nora Philipp,&nbsp;Bettina Brauchle,&nbsp;Jonathan Jonas Taylor,&nbsp;Helena Domínguez Moreno,&nbsp;Andrea Terrasi,&nbsp;Benjamin Tast,&nbsp;Lisa Rohrbacher,&nbsp;Yingshuai Wang,&nbsp;Maximilian Warm,&nbsp;Alica-Joana Emhardt,&nbsp;Giulia Magno,&nbsp;Karsten Spiekermann,&nbsp;Tobias Herold,&nbsp;Tobias Straub,&nbsp;Sebastian Theurich,&nbsp;Gunnar Schotta,&nbsp;Roman Kischel,&nbsp;Veit L. Bücklein,&nbsp;Marion Subklewe","doi":"10.1038/s41375-024-02387-4","DOIUrl":"10.1038/s41375-024-02387-4","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02387-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142021855","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":"Optimal prognostic threshold for measurable residual disease positivity by multiparameter flow cytometry in acute myeloid leukemia (AML)","authors":"Eduardo Rodríguez-Arbolí,&nbsp;Megan Othus,&nbsp;Sylvie D. Freeman,&nbsp;Francesco Buccisano,&nbsp;Lok Lam Ngai,&nbsp;Ian Thomas,&nbsp;Raffaele Palmieri,&nbsp;Jacqueline Cloos,&nbsp;Sean Johnson,&nbsp;Elisa Meddi,&nbsp;Nigel H. Russell,&nbsp;Adriano Venditti,&nbsp;Patrycja Gradowska,&nbsp;Gert J. Ossenkoppele,&nbsp;Bob Löwenberg,&nbsp;Roland B. Walter","doi":"10.1038/s41375-024-02378-5","DOIUrl":"10.1038/s41375-024-02378-5","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142013838","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}

{"title":"Identification of leukemia stem cell subsets with distinct transcriptional, epigenetic and functional properties","authors":"Héléna Boutzen,&nbsp;Alex Murison,&nbsp;Alexa Oriecuia,&nbsp;Suraj Bansal,&nbsp;Christopher Arlidge,&nbsp;Jean C. Y. Wang,&nbsp;Mathieu Lupien,&nbsp;Kerstin B. Kaufmann,&nbsp;John E. Dick","doi":"10.1038/s41375-024-02358-9","DOIUrl":"10.1038/s41375-024-02358-9","url":null,"abstract":"The leukemia stem cell (LSC) compartment is a complex reservoir fueling disease progression in acute myeloid leukemia (AML). The existence of heterogeneity within this compartment is well documented but prior studies have focused on genetic heterogeneity without being able to address functional heterogeneity. Understanding this heterogeneity is critical for the informed design of therapies targeting LSC, but has been hampered by LSC scarcity and the lack of reliable cell surface markers for viable LSC isolation. To overcome these challenges, we turned to the patient-derived OCI-AML22 cell model. This model includes functionally, transcriptionally and epigenetically characterized LSC broadly representative of LSC found in primary AML samples. Focusing on the pool of LSC, we used an integrated approach combining xenograft assays with single-cell analysis to identify two LSC subtypes with distinct transcriptional, epigenetic and functional properties. These LSC subtypes differed in depth of quiescence, differentiation potential, repopulation capacity, sensitivity to chemotherapy and could be isolated based on CD112 expression. A majority of AML patient samples had transcriptional signatures reflective of either LSC subtype, and some even showed coexistence within an individual sample. This work provides a framework for investigating the LSC compartment and designing combinatorial therapeutic strategies in AML.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02358-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142013836","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":"Efficacy and safety of bosutinib in previously treated patients with chronic myeloid leukemia: final results from the BYOND trial","authors":"Carlo Gambacorti-Passerini,&nbsp;Tim H. Brümmendorf,&nbsp;Elisabetta Abruzzese,&nbsp;Kevin R. Kelly,&nbsp;Vivian G. Oehler,&nbsp;Valentín García-Gutiérrez,&nbsp;Henrik Hjorth-Hansen,&nbsp;Thomas Ernst,&nbsp;Eric Leip,&nbsp;Simon Purcell,&nbsp;Gerald Luscan,&nbsp;Andrea Viqueira,&nbsp;Francis J. Giles,&nbsp;Andreas Hochhaus","doi":"10.1038/s41375-024-02372-x","DOIUrl":"10.1038/s41375-024-02372-x","url":null,"abstract":"This final analysis from the phase 4 BYOND trial reports outcomes with bosutinib in patients with previously treated chronic myeloid leukemia (CML); 163 patients with CML resistant/intolerant to previous tyrosine kinase inhibitors received bosutinib (starting dose: 500 mg QD). At study completion (median follow-up, 47.8 months), 48.1% (n = 75/156) of patients with Philadelphia chromosome–positive chronic phase CML were still receiving treatment. Among evaluable patients, 71.8% (95% CI, 63.9–78.9) and 59.7% (95% CI, 51.4–67.7) attained or maintained major molecular response (MMR) and molecular response (MR)4, respectively, at any time on treatment. The majority of patients achieved a deeper molecular response relative to baseline while on bosutinib. Kaplan-Meier probabilities (95% CI) of maintaining MMR and MR4 at 36 months were 87.2% (78.0–92.7) and 80.7% (69.4–88.1), respectively. At 48 months, the Kaplan-Meier overall survival rate was 88.3% (95% CI, 81.8–92.6); there were 17 deaths, including 2 that were considered CML related. Long-term adverse events (AEs) were consistent with the known safety profile of bosutinib, and no new safety issues were identified. The management of AEs through dose reduction maintained efficacy while improving tolerability. These results support the use of bosutinib in patients with previously treated CML. ClinicalTrials.gov, NCT02228382","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02372-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142007633","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":"Prevalence of metabolic comorbidities and viral co-infections in monoclonal gammopathy: a retrospective analysis","authors":"Tinatin Muradashvili,&nbsp;Mansen Yu,&nbsp;Sabrina L. Browning,&nbsp;Noffar Bar,&nbsp;Elan Gorshein,&nbsp;Terri L. Parker,&nbsp;Natalia Neparidze","doi":"10.1038/s41375-024-02380-x","DOIUrl":"10.1038/s41375-024-02380-x","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142007639","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}