Leukemia最新文献

{"title":"Gemtuzumab ozogamicin in first-line treatment of CBF-AML: insights from a retrospective multi-center analysis","authors":"Julian Ronnacker, Philippe J. Muller, Jan-Henrik Mikesch, Sven Zukunft, Barbora Weinbergerová, Jiří Šrámek, Jan Valka, Jan Novak, Pavel Zak, Tomas Szotkowski, Zdenek Koristek, Carolin Krekeler, Julia M. Unglaub, Tim Sauer, Leo Ruhnke, Sabrina Kraus, Judith Schaffrath, Lutz P. Müller, Sabrina Kaes, Dirk Niemann, Lars Fransecky, Patrick P. Hess, Martina Crysandt, Edgar Jost, Joana Millo, Johannes Gaertner, Roland Repp, Madlen Jentzsch, Lea Hoppe, Stefan Klein, Franziska Modemann, Nina Michalowski, Klaudia Fischbach, Wolfgang Blau, Marion Ruhs, Markus Ritter, Julian Lohmeyer, Björn Steffen, Sarah Hauser, Martin Kaufmann, Stefan W. Krause, Ricarda Knabe, Karsten Spiekermann, Hubert Serve, Uwe Platzbecker, Claudia D. Baldus, Carsten Müller-Tidow, Georg Lenz, Hans Christian Reinhardt, Jirí Mayer, Martin Bornhäuser, Christoph Röllig, Christoph Schliemann, Maher Hanoun","doi":"10.1038/s41375-025-02700-9","DOIUrl":"10.1038/s41375-025-02700-9","url":null,"abstract":"The addition of gemtuzumab ozogamicin (GO) to intensive chemotherapy (IC) has become a mainstay in treating patients with core binding factor acute myeloid leukemia (CBF-AML). However, evidence for the efficacy of GO in this particular subgroup is primarily based on meta-analytic data from different trials conducted more than a decade ago. In this registry-based study, we evaluated the impact of adding GO to IC in 265 CBF-AML patients from the SAL, AMLCG, and CELL cooperative study groups. Patients receiving GO had a 2-year overall survival of 90% compared with 80% in those without GO (hazard ratio [HR] 0.45, 95% confidence interval [CI] 0.21–0.95, P = 0.036) and a 2-year event-free survival of 51% versus 36% (HR 0.69, 95% CI 0.48–0.99, P = 0.046). While complete remission rates in GO vs. non-GO patients were comparable (89% vs. 90%, P = 0.81), more GO patients achieved measurable residual disease-negative remission (77% vs. 49%, P < 0.001), resulting in numerically reduced cumulative incidence of relapse (HR 0.67, 95% CI 0.43–1.02, P = 0.06). Despite delayed platelet recovery, high-grade toxicities were not increased in GO-treated patients. These findings support the integration of GO into treatment protocols for IC-eligible patients with CBF-AML.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 9","pages":"2174-2180"},"PeriodicalIF":13.4,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02700-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144677461","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":"Erythroid-predominant myelodysplastic neoplasms exhibit a distinct genomic landscape with poor outcomes after venetoclax-based therapy","authors":"Alexandre Bazinet, Sanam Loghavi, Yue Wei, Alex Bataller, Koji Sasaki, Naszrin Arani, Faezeh Darbaniyan, Kelly Chien, Danielle Hammond, Ian Bouligny, Rashmi Kanagal-Shamanna, Natthakan Thongon, Guilin Tang, Samuel Urrutia, Tapan Kadia, Courtney DiNardo, Naval Daver, Nicholas Short, Ghayas Issa, Naveen Pemmaraju, Elias Jabbour, Sa A. Wang, Wei Wang, Gautam Borthakur, Carlos Bueso-Ramos, Farhad Ravandi, L. Jeffrey Medeiros, Hagop Kantarjian, Guillermo Garcia-Manero, Guillermo Montalban-Bravo","doi":"10.1038/s41375-025-02711-6","DOIUrl":"10.1038/s41375-025-02711-6","url":null,"abstract":"Erythroid differentiation confers BCL-XL dependence and venetoclax resistance in acute myeloid leukemia (AML). However, whether myelodysplastic neoplasms (MDS) with erythroid predominance (EP), defined by ≥50% erythroid bone marrow elements, have distinct biology and drug sensitivities remains unknown. To study this, we evaluated an MDS patient cohort (n = 371) and showed that EP MDS (n = 67, 18%) are characterized by higher TP53 (multihit TP53: 36% vs 17%, p = 0.004), BCOR and WT1 and lower ASXL1 and SRSF2 mutation frequencies compared to non-EP (NEP) MDS (n = 304, 82%). TP53-mutant variant allele frequencies and allelic states correlated with erythroid population expansions. EP MDS was characterized by 3 genetic subgroups with distinct survival (TP53 mutant: 11.4 months; splicing mutant: not reached; not otherwise specifiable (NOS): 19.5 months, p < 0.001). EP MDS had a higher incidence of leukemic transformation (32% vs 12%, p = 0.040) and worse survival (8.3 months vs not reached, p = 0.041) after HMA-venetoclax therapy among 112 HMA-venetoclax-treated MDS patients. Expansion of erythroid populations during venetoclax failure was observed in 11 (33%) patients. EP MDS had higher BCL-XL expression levels at the RNA and protein levels compared to NEP MDS. These data support the dynamic assessment of erythroid predominance in MDS and warrant evaluation of BCL-XL inhibitors in these patients.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 9","pages":"2256-2265"},"PeriodicalIF":13.4,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144677635","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":"5-Azacytidine and decitabine induce C > G transversions in both murine and human cells","authors":"Ryan Bertoli, Dengchao Cao, Olivia Tuckey, Susannah Gammell, Anthony Wokasch, Yang Jo Chung, Jason M. Foulks, Peter D. Aplan","doi":"10.1038/s41375-025-02670-y","DOIUrl":"10.1038/s41375-025-02670-y","url":null,"abstract":"5-Azacytidine (5AZA) is a DNA methyltransferase inhibitor (DNMTi) used clinically to treat myelodysplastic neoplasm (MDS), and is used off-label for a number of malignancies including acute myeloid leukemia. This cytidine analog depletes intracellular DNMT1, and it has been hypothesized that DNMT1 depletion leads to hypomethylation and de-repression of methylated tumor suppressor genes. We used a pre-clinical model of MDS to investigate the efficacy of 5-azacytidine. Unexpectedly, we found an increased frequency of acute lymphoid leukemia (ALL) in 5AZA treated mice. Whole exome sequencing (WES) revealed a large number of C > G transversions in 5AZA treated mice, including genes known to be important for ALL such as Chd4, Ikzf1, and Trp53. Single base substitution (SBS) profiling revealed increased C > G mutations in the ALL cells, with a mutation signature similar to the previously described SBS39 signature. An in vitro GEMINI (Genotoxic Mutational Signature Identified After Clonal Expansion In vitro) assay recapitulated the finding of increased C > G mutations in both murine and human cell lines. Furthermore, similar GEMINI assays revealed induction of C > G mutations in cells treated with decitabine. Taken together, these findings demonstrate that azanucleosides induce C > G mutations both in vitro and in vivo, and are linked to leukemic transformation in murine cells.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 9","pages":"2112-2124"},"PeriodicalIF":13.4,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02670-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144652154","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":"Hypomethylating agents induce epigenetic and transcriptional heterogeneity with implications for acute myeloid leukemia cell self-renewal","authors":"Danielle R. Bond, Sean M. Burnard, Kumar Uddipto, Kooper V. Hunt, Brooke M. Harvey, Luiza Steffens Reinhardt, Charley Lawlor-O’Neill, Ellise A. Roper, Sam Humphries, Heather C. Murray, Abdul Mannan, Matthew D. Dun, Charles E. de Bock, Nikola A. Bowden, Anoop K. Enjeti, Nicole M. Verrills, Carlos Riveros, Kim-Anh Lê Cao, Heather J. Lee","doi":"10.1038/s41375-025-02693-5","DOIUrl":"10.1038/s41375-025-02693-5","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 9","pages":"2275-2280"},"PeriodicalIF":13.4,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02693-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144652197","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 clonal hematopoiesis on and off lenalidomide maintenance for multiple myeloma","authors":"Jennifer H. Cooperrider, Diren Arda Karaoglu, Tadeusz Kubicki, Can Rui Jiang, Ella Postich, Kathryn Shimamoto, Olivia Arnold, Jommel Macaraeg, Aubrianna Ramsland, Anna Pula, Ashwin Kishtagari, Yash Pershad, Taralynn M. Mack, Angela Jones, Alexander G. Bick, Michael Savona, Michael W. Drazer, Dominik Dytfeld, Andrzej Jakubowiak, Benjamin A. Derman, Caner Saygin","doi":"10.1038/s41375-025-02707-2","DOIUrl":"10.1038/s41375-025-02707-2","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 9","pages":"2285-2288"},"PeriodicalIF":13.4,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02707-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144640347","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":"Genetic lesions in nodular lymphocyte-predominant Hodgkin lymphoma and T cell/histiocyte-rich large B-cell lymphoma identified by whole genome sequencing","authors":"Tobias Rausch, Hendrik Schäfer, Julia Bein, Felix Mölder, Lilian Kara Beeck, Bernd Kölsch, Sabrina Borchert, Vladimir Benes, Teresa Halbsguth, Uta Brunnberg, Thomas Oellerich, Thomas Tousseyn, Maurilio Ponzoni, Johannes Köster, Martin-Leo Hansmann, Ralf Küppers, Sylvia Hartmann","doi":"10.1038/s41375-025-02679-3","DOIUrl":"10.1038/s41375-025-02679-3","url":null,"abstract":"Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare malignant lymphoma characterised by a few large tumour cells expressing B-cell antigens in an inflammatory background. T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is now considered to be closely related to NLPHL. Little is known about the mutational spectrum of the lymphoma cells in primary NLPHL and THRLBCL due to the rarity of the diseases and the technical challenges of analysing these tumours. Therefore, the aim of the present study was to elucidate mechanisms contributing to the pathogenesis of NLPHL and THRLBCL by whole genome sequencing of laser microdissected tumour cells from seven cases. We observed a heterogeneity of transforming events, with cases showing abundant somatic mutations, others with a predominance of structural variations, and cases with few aberrations. The genes that were most frequently affected by aberrations encode factors influencing JAK-STAT, NF-κB, and/or WNT signaling, and apoptosis regulators. However, the mutated genes, such as SOCS3, JUNB, IRF1 and ITPKB, were not the typical targets known from classical Hodgkin lymphoma (cHL). Two cases showed recurrent rearrangements of BCL6 and CD74. In conclusion, our data enrich our understanding of NLPHL and THRLBCL and highlight common and distinct features with respect to cHL.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 9","pages":"2215-2225"},"PeriodicalIF":13.4,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02679-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144640350","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":"Targeting of IRAK4 and GSPT1 enhances therapeutic efficacy in AML via c-Myc destabilization","authors":"Eric J. Vick, Aishlin Hassan, Kwangmin Choi, Joshua Bennett, Tomoya Muto, Courtnee A. Clough, Ashley E. Culver-Cochran, Kathleen Hueneman, Lyndsey C. Bolanos, Mark Wunderlich, Xiaohu Zhang, Crystal McKnight, Michele Ceribelli, David Holland, Carleen Klumpp-Thomas, Kenneth D. Greis, Craig J. Thomas, Daniel T. Starczynowski","doi":"10.1038/s41375-025-02695-3","DOIUrl":"10.1038/s41375-025-02695-3","url":null,"abstract":"IRAK4 is a therapeutic target in myeloid malignancies, but current IRAK4 inhibitors show only modest clinical efficacy in acute myeloid leukemia, highlighting the need for combination strategies. To identify drugs with synergistic potential alongside IRAK4 inhibitors, we conducted a high-throughput screen of 2803 investigational and approved drugs in isogenic IRAK4-deficient and wild-type human AML cells. The top hit from this screen was the Cereblon E3 ligase modulator (CELMoD) CC-885. Validation in vitro and in vivo confirmed that CC-885 and related CELMoDs synergize with IRAK4 inhibitors to suppress leukemic cells. Among CC-885 substrates, GSPT1 loss showed the most pronounced effects in IRAK4-inhibited leukemic cells. Transcriptional and proteomic analyses revealed that CC-885 treatment led to c-Myc suppression in IRAK4-deficient leukemic cells. GSPT1 loss reduces translation efficiency, particularly for proteins with short half-lives, such as c-Myc. Accelerated c-Myc protein loss was confirmed following GSPT1 degradation in leukemic cells, with decreased protein stability observed following inhibition of IRAK4. These effects were validated in AML patient cells, supporting the potential of IRAK4 inhibitors to modulate c-Myc activity and enhance combinatorial therapies. This study demonstrates that IRAK4 is a therapeutic target in AML, and that combination therapies, such as with certain GSPT1-targeting CELMoDs, will be necessary to achieve maximal clinical responses.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 9","pages":"2163-2173"},"PeriodicalIF":13.4,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02695-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144640351","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":"Patterns of relapse in patients with multiple myeloma receiving chimeric antigen receptor T cell therapy: a multi-center analysis","authors":"Kritika Yadav, Meera Mohan, Charlotte Wagner, Rajshekhar Chakraborty, Douglas Sborov, Amandeep Godara, Brian McClune, Carolina Schinke, Binod Dhakal, Anita D’Souza, Aniko Szabo, Ghulam Rehman Mohyuddin","doi":"10.1038/s41375-025-02702-7","DOIUrl":"10.1038/s41375-025-02702-7","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 9","pages":"2289-2291"},"PeriodicalIF":13.4,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144640346","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":"Molecular profiling is critical to guide MEK inhibitor use in Erdheim-Chester disease","authors":"Gaurav Goyal, Aldo A. Acosta-Medina, Ronald S. Go, Jithma P. Abeykoon, on behalf of the Mayo Clinic - University of Alabama at Birmingham Histiocytosis Working Group","doi":"10.1038/s41375-025-02704-5","DOIUrl":"10.1038/s41375-025-02704-5","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 9","pages":"2306-2307"},"PeriodicalIF":13.4,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144629673","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":"DNA demethylation-mediated downregulation of MNX1 in acute myeloid leukemia","authors":"Simge Kelekçi, Katherine Kelly, Ashish Goyal, Nick Wehrwein, Anna Riedel, Dieter Weichenhan, Michael Scherer, Birgitta E. Michels, Cindy Körner, Irene Orzella, Mariam Hakobyan, Marion Bähr, Elena Everatt, James Dunford, Daniel B. Lipka, Pavlo Lutsik, Udo Oppermann, Christoph Plass","doi":"10.1038/s41375-025-02680-w","DOIUrl":"10.1038/s41375-025-02680-w","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 9","pages":"2270-2274"},"PeriodicalIF":13.4,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02680-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144622353","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}