Leukemia最新文献

{"title":"QRISK3 score is predictive of thrombotic risk in patients with myeloproliferative neoplasms","authors":"Andrea Duminuco, Raj Vaghela, Sukhraj Virdee, Claire Woodley, Susan Asirvatham, Natalia Curto-Garcia, Priya Sriskandarajah, Jennifer O’Sullivan, Hugues de Lavallade, Deepti Radia, Shahram Kordasti, Giuseppe A. Palumbo, Claire Harrison, Patrick Harrington","doi":"10.1038/s41375-025-02681-9","DOIUrl":"10.1038/s41375-025-02681-9","url":null,"abstract":"Thromboembolic events (TE) represent the commonest cause of morbidity and mortality in polycythemia vera (PV) and essential thrombocythaemia (ET). The QRISK3 model is a tool for predicting TE in the general population, with 7.5% recognised as a threshold to identify high-risk patients. We analyzed data of 937 patients (490 ET and 447 PV) with a median follow-up of 85 and 95 months, reporting an occurrence of 52 and 73 TE, respectively. Median QRISK3 scores at diagnosis were higher in conventional high-risk patients in both cohorts (ET; 4.2 in high-risk vs. 2.4 in low-risk, PV; 8.8 vs. 2.8, p < 0.001). During follow-up, a QRISK3 score greater than 7.5%, demonstrated potential to further stratify individuals at high risk of TE, outperforming standard risk assessments in both low and high-risk patients. Using cytoreductive treatment instead of active surveillance in patients with QRISK3 ≥ 7.5% conferred a reduced risk of thrombosis in both cohorts. Of this group, 79.7% with ET and 86.9% with PV, on cytoreductive therapy, remained thrombosis free, compared with 64.1% and 57.1% of those not receiving cytoreductive therapy (p = 0.018/0.034). QRISK3 identifies patients in whom cytoreductive therapies may be indicated, and provides a tool that allows patients to assess, monitor and reduce their cardiovascular risk.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 10","pages":"2384-2390"},"PeriodicalIF":13.4,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02681-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144693974","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":"Endogenous T cell responses to fusion-derived neoantigens in pediatric acute leukemias","authors":"Ricky Tirtakusuma, Mohamed A. Ghonim, Stefan Schattgen, Bradley Muller, Lee Ann Van de Velde, Tanya M. Khan, Jeremy Chase Crawford, Jing Ma, Sherif Abdelhamed, Kasi Vegesana, Walid Awad, E. Kaitlynn Allen, Ilaria Iacobucci, Charles G. Mullighan, Jeffery M. Klco, Paul G. Thomas","doi":"10.1038/s41375-025-02710-7","DOIUrl":"10.1038/s41375-025-02710-7","url":null,"abstract":"Pediatric patients with fusion-driven leukemias frequently have a poor prognosis and need more effective therapies. Adoptive T-cell therapies, using expanded autologous T cells, have shown promise as an immunotherapeutic for patients with tumors characterized by high mutational burdens. However, this approach has not been shown to be effective in pediatric leukemias. In this study, we analyzed samples from pediatric patients with fusion-driven acute lymphoblastic, acute myeloid, and mixed phenotypic leukemias, including those with KMT2A-rearrangements. T cells were attained from bone marrow samples, expanded, and their reactivity against autologous leukemic blasts was tested. Strikingly, we observed leukemia-reactive T cells in nearly all patients (33 of 34) at diagnosis or relapse. Furthermore, some patients contained clones reactive to fusion neoantigens and other tumor-associated antigens, and candidate samples were further enriched by selecting for PD1hi and CD39+ T-cell populations. These clones were only present at the initial diagnostic timepoint and could not be detected at later times after treatment, even with deep sequence profiling. Altogether, our data suggest that adoptive T cell therapy, using expanded leukemia-reactive T cells identified at diagnosis, has potential as a novel therapeutic for these patients.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 10","pages":"2419-2431"},"PeriodicalIF":13.4,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02710-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144693975","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":"Deubiquitinase USP6 stabilizes oncogenic RUNX1 fusion proteins to promote the leukemic potential and malignant progression","authors":"Xingya Zhang, Minjun Li, Yingqian Chen, Jiayi Liu, Jianhua Zhang, Chen Shao, Boyu Deng, Jianing Zhang, Tianrui Wang, Ji Cao, Xiaojun Xu, Qiaojun He, Bo Yang, Xuejing Shao, Meidan Ying","doi":"10.1038/s41375-025-02698-0","DOIUrl":"10.1038/s41375-025-02698-0","url":null,"abstract":"RUNX1-rearranged leukemia is one of the most common subtypes of leukemia associated with genetic abnormalities. Although the majority of patients respond to chemotherapy, relapse and long-term adverse effects remain significant challenges. RUNX1 fusions, resulting from chromosomal rearrangements, are pivotal oncogenic drivers, with over 70 distinct variants identified. Therefore, elucidating their regulatory mechanisms may help to develop novel therapeutic strategies. Herein, we identify a universal deubiquitinase, USP6, that stabilizes RUNX1 fusion proteins with different partners. Importantly, USP6 is specifically upregulated in RUNX1-rearranged leukemia and strongly correlates with poor patient outcomes. Mechanistically, USP6 stabilizes RUNX1 fusions to facilitate the formation of phase separation, leading to robust transcriptional activation of the fusions. Depletion of USP6 dramatically inhibits proliferation and induces differentiation of RUNX1-rearranged leukemic cells. The marketed drug auranofin is identified as a potential USP6 inhibitor, which induces degradation of different RUNX1 fusions, further triggering myeloid differentiation and arresting xenograft tumor growth. Notably, auranofin exhibits selective therapeutic efficacy in patient-derived leukemia blasts from RUNX1-rearranged cases. Together, we not only uncover a new biological function of USP6 in regulating the transcriptional activity of RUNX1 fusions but also validate USP6 as a promising drug target and auranofin as a candidate therapy for RUNX1-rearranged leukemia.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 10","pages":"2355-2363"},"PeriodicalIF":13.4,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144694027","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":"Superoxide-mediated phosphorylation and stabilization of Mcl-1 by AKT underlie venetoclax resistance in hematologic malignancies","authors":"Stephen J. F. Chong, Jolin X. H. Lai, Kartini Iskandar, Benedict J. Leong, Chuqi Wang, Yuhan Wang, Romain Guièze, Deepika Raman, Rachel H. F. Lim, Catherine J. Wu, Wee Joo Chng, Alice M. S. Cheung, Charles Chuah, Matthew S. Davids, Shazib Pervaiz","doi":"10.1038/s41375-025-02694-4","DOIUrl":"10.1038/s41375-025-02694-4","url":null,"abstract":"Resistance to the Bcl-2-specific inhibitor, Venetoclax (VEN), poses a therapeutic challenge in the management of chronic lymphocytic leukemia and acute myeloid leukemia. Although VEN resistance has been linked to Mcl-1 upregulation, thereby switching survival dependence from Bcl-2 to Mcl-1, the mechanism underlying increased Mcl-1 expression remains elusive. Given that changes in cellular redox state affect cancer cell fate, we investigated the crosstalk between intracellular redox milieu and Mcl-1 upregulation in VEN-resistant cells. Results show that increased Mcl-1 protein levels in VEN-resistant hematologic malignant cells are associated with elevated intracellular superoxide (O2.−) levels. Validating that, augmenting intracellular O2.− in VEN-sensitive cells increases Mcl-1 phosphorylation at threonine-163 (T163pMcl-1) and protein stability via reduced Mcl-1 ubiquitination and degradation. Furthermore, redox-activated AKT/PKB is implicated in O2.−-induced T163pMcl-1, as reducing intracellular O2.− or inhibiting AKT significantly decreases T163pMcl-1 and Mcl-1 accumulation, which amplifies mitochondrial apoptotic priming and restores VEN sensitivity. Importantly, combination therapy with AKT inhibitor, capivasertib, and VEN reduced VEN-resistant cells systemically and prolonged survival in a murine model. Collectively, a novel redox-dependent mechanism of Mcl-1 stability is demonstrated for the acquisition of VEN resistance, which has therapeutic implications for employing redox modulating strategies and AKT inhibitors against VEN-resistant hematologic malignancies.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 10","pages":"2477-2491"},"PeriodicalIF":13.4,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02694-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144693976","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":"Current risk stratification and staging of multiple myeloma and related clonal plasma cell disorders","authors":"Saurabh Zanwar, S. Vincent Rajkumar","doi":"10.1038/s41375-025-02654-y","DOIUrl":"https://doi.org/10.1038/s41375-025-02654-y","url":null,"abstract":"<p>Clonal plasma cell disorders encompass a spectrum of conditions such as multiple myeloma (MM), monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), Waldenström macroglobulinemia (WM), and immunoglobulin light chain (AL) amyloidosis. In MGUS, SMM, and MM, progression risk varies widely and is influenced by a complex interplay of tumor burden, cytogenetic abnormalities, bone marrow microenvironment, and host factors. Waldenström macroglobulinemia, while usually indolent, presents its own distinct spectrum of molecular abnormalities and disparate clinical outcomes. In AL amyloidosis, clinical trajectories are heavily dictated by the nature and extent of organ involvement. In this review, we provide a comprehensive overview of current risk stratification schema used across the spectrum of clonal plasma cell disorders, highlight the strengths and limitations of major risk stratification frameworks, and provide our recommendations for clinical practice.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"25 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144684664","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":"Correction: A novel approach for highly sensitive and rapid identification of HMGA2 submicroscopic deletions in myeloproliferative neoplasms","authors":"Niccolò Bartalucci,&nbsp;Danilo Tarantino,&nbsp;Alessio Enderti,&nbsp;Daniele Colazzo,&nbsp;Paola Guglielmelli,&nbsp;Alessandro M. Vannucchi","doi":"10.1038/s41375-025-02716-1","DOIUrl":"10.1038/s41375-025-02716-1","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 9","pages":"2308-2308"},"PeriodicalIF":13.4,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12380592/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144698954","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":"Heat stress targets and degrades BCR::ABL1 oncoproteins to overcome drug-resistance in Philadelphia chromosome-positive acute lymphoblastic leukemia","authors":"Chang Yang,&nbsp;Yuan-Yuan Kang,&nbsp;Chen-Ying Zhu,&nbsp;Yafang Ma,&nbsp;Pei-Han Yu,&nbsp;Tao Yang,&nbsp;Yong-Qin Liu,&nbsp;Ze-Yan Zhang,&nbsp;Noriyuki Suzuki,&nbsp;Yasumitsu Ogra,&nbsp;Mikael Björklund,&nbsp;Hua Naranmandura","doi":"10.1038/s41375-025-02709-0","DOIUrl":"10.1038/s41375-025-02709-0","url":null,"abstract":"BCR::ABL1 oncofusion protein drives Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ ALL), making it a critical therapeutic target. Tyrosine kinase inhibitors (TKIs) targeting BCR::ABL1 have revolutionized the treatment of Ph+ ALL patients. However, mutations in the kinase domain of BCR::ABL1 commonly impair the sensitivity to TKIs, resulting in drug resistance and poor prognosis in Ph+ ALL. Here we report that heat stress selectively destabilizes BCR::ABL1 and its common drug-resistant mutants without affecting the native BCR and ABL proteins through inducing liquid-to-solid phase transition. Mechanistic studies revealed that heat stress facilitated recruitment of BCR::ABL1 signaling components (e.g., SHIP2, Sts1, PI3K-p85α and Shc) in a kinase activity dependent manner and stimulated BCR::ABL1 oligomerization through its coiled-coil domain, resulting in formation of a large, thermally unstable signaling complex. This process triggers non-canonical K27-linked ubiquitination mediated by c-Cbl E3 ubiquitin ligase, ultimately leading to BCR::ABL1 degradation via the ubiquitin-proteasome pathway. Functionally, heat stress effectively suppressed proliferation of BCR::ABL1-driven leukemia cells, including drug resistant mutants in vitro and decreased tumor burden in vivo. Our findings established that thermal-based therapy as a novel strategy to selectively target and degrade both unmutated and drug-resistant BCR::ABL1 oncoproteins, offering a promising adjuvant approach to overcome TKI resistance in Ph+ ALL.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 9","pages":"2140-2151"},"PeriodicalIF":13.4,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02709-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144677458","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":"Gemtuzumab ozogamicin in first-line treatment of CBF-AML: insights from a retrospective multi-center analysis","authors":"Julian Ronnacker,&nbsp;Philippe J. Muller,&nbsp;Jan-Henrik Mikesch,&nbsp;Sven Zukunft,&nbsp;Barbora Weinbergerová,&nbsp;Jiří Šrámek,&nbsp;Jan Valka,&nbsp;Jan Novak,&nbsp;Pavel Zak,&nbsp;Tomas Szotkowski,&nbsp;Zdenek Koristek,&nbsp;Carolin Krekeler,&nbsp;Julia M. Unglaub,&nbsp;Tim Sauer,&nbsp;Leo Ruhnke,&nbsp;Sabrina Kraus,&nbsp;Judith Schaffrath,&nbsp;Lutz P. Müller,&nbsp;Sabrina Kaes,&nbsp;Dirk Niemann,&nbsp;Lars Fransecky,&nbsp;Patrick P. Hess,&nbsp;Martina Crysandt,&nbsp;Edgar Jost,&nbsp;Joana Millo,&nbsp;Johannes Gaertner,&nbsp;Roland Repp,&nbsp;Madlen Jentzsch,&nbsp;Lea Hoppe,&nbsp;Stefan Klein,&nbsp;Franziska Modemann,&nbsp;Nina Michalowski,&nbsp;Klaudia Fischbach,&nbsp;Wolfgang Blau,&nbsp;Marion Ruhs,&nbsp;Markus Ritter,&nbsp;Julian Lohmeyer,&nbsp;Björn Steffen,&nbsp;Sarah Hauser,&nbsp;Martin Kaufmann,&nbsp;Stefan W. Krause,&nbsp;Ricarda Knabe,&nbsp;Karsten Spiekermann,&nbsp;Hubert Serve,&nbsp;Uwe Platzbecker,&nbsp;Claudia D. Baldus,&nbsp;Carsten Müller-Tidow,&nbsp;Georg Lenz,&nbsp;Hans Christian Reinhardt,&nbsp;Jirí Mayer,&nbsp;Martin Bornhäuser,&nbsp;Christoph Röllig,&nbsp;Christoph Schliemann,&nbsp;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 &lt; 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,&nbsp;Sanam Loghavi,&nbsp;Yue Wei,&nbsp;Alex Bataller,&nbsp;Koji Sasaki,&nbsp;Naszrin Arani,&nbsp;Faezeh Darbaniyan,&nbsp;Kelly Chien,&nbsp;Danielle Hammond,&nbsp;Ian Bouligny,&nbsp;Rashmi Kanagal-Shamanna,&nbsp;Natthakan Thongon,&nbsp;Guilin Tang,&nbsp;Samuel Urrutia,&nbsp;Tapan Kadia,&nbsp;Courtney DiNardo,&nbsp;Naval Daver,&nbsp;Nicholas Short,&nbsp;Ghayas Issa,&nbsp;Naveen Pemmaraju,&nbsp;Elias Jabbour,&nbsp;Sa A. Wang,&nbsp;Wei Wang,&nbsp;Gautam Borthakur,&nbsp;Carlos Bueso-Ramos,&nbsp;Farhad Ravandi,&nbsp;L. Jeffrey Medeiros,&nbsp;Hagop Kantarjian,&nbsp;Guillermo Garcia-Manero,&nbsp;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 &lt; 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,&nbsp;Dengchao Cao,&nbsp;Olivia Tuckey,&nbsp;Susannah Gammell,&nbsp;Anthony Wokasch,&nbsp;Yang Jo Chung,&nbsp;Jason M. Foulks,&nbsp;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 &gt; 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 &gt; 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 &gt; G mutations in both murine and human cell lines. Furthermore, similar GEMINI assays revealed induction of C &gt; G mutations in cells treated with decitabine. Taken together, these findings demonstrate that azanucleosides induce C &gt; 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}