Leukemia最新文献_第2页

IF 11.4 1区医学

Leukemia Pub Date : 2025-04-22 DOI: 10.1038/s41375-025-02621-7

Natalya Plakhova, Vasilios Panagopoulos, Melissa D. Cantley, Laura J. Trainor, Duncan R. Hewett, Kimberley C. Clark, Jo Gardiner, Angelina Yong, Cindy Lee, Noemi Horvath, Peter I. Croucher, Dimitrios Cakouros, Sheila A. Stewart, Stan Gronthos, Andrew C. W. Zannettino, Krzysztof M. Mrozik, Kate Vandyke

{"title":"Age-related mesenchymal stromal cell senescence is associated with progression from MGUS to multiple myeloma","authors":"Natalya Plakhova, Vasilios Panagopoulos, Melissa D. Cantley, Laura J. Trainor, Duncan R. Hewett, Kimberley C. Clark, Jo Gardiner, Angelina Yong, Cindy Lee, Noemi Horvath, Peter I. Croucher, Dimitrios Cakouros, Sheila A. Stewart, Stan Gronthos, Andrew C. W. Zannettino, Krzysztof M. Mrozik, Kate Vandyke","doi":"10.1038/s41375-025-02621-7","DOIUrl":"https://doi.org/10.1038/s41375-025-02621-7","url":null,"abstract":"The risk of progression of monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM) increases with advancing age, suggesting that progression may be influenced by age-related changes within the bone marrow (BM) microenvironment. We hypothesise that senescent mesenchymal stromal cells (MSCs), which accumulate in the BM with age, may contribute to MGUS progression to MM. Here, we show that, like BM MSCs from aged non-cancer controls, BM MSCs from both MM and MGUS patients exhibit a senescent phenotype characterised by enlarged, flattened morphology, increased β-galactosidase activity and CDKN2A expression, and decreased proliferation rate compared with BM MSCs from healthy young individuals. While coculture with BM MSCs suppresses the proliferative capacity of MM cell lines in vitro, induction of senescence via irradiation or replicative exhaustion in healthy MSCs relieves this suppression, compared with non-senescent MSCs. This may, in part, be attributable to upregulated expression of the BMP antagonist Gremlin1 in senescent MSCs, which facillitates MM cell proliferation. Notably, the risk of progression to MM was significantly elevated in MGUS patients with increased MSC senescence. Collectively, our data provide evidence that age-related accumulation of senescent MSCs may be a driver of MGUS to MM progression.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"41 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862953","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}

引用次数: 0

Loss of NOL10 leads to impaired disease progression of NUP98::DDX10 leukemia 缺失 NOL10 会导致 NUP98::DDX10 白血病的疾病进展受阻

IF 11.4 1区医学

Leukemia Pub Date : 2025-04-22 DOI: 10.1038/s41375-025-02607-5

Yutaka Shima, Kazutsune Yamagata, Yoko Kuroki, Kazuki Sasaki, Yukiko Aikawa, Issay Kitabayashi

引用次数: 0

Impact of myelodysplasia-related gene mutations and residual mutations at remission in venetoclax/azacitidine for AML venetoclax/ az胞苷治疗急性髓性白血病缓解时骨髓增生异常相关基因突变和残留突变的影响

IF 11.4 1区医学

Leukemia Pub Date : 2025-04-21 DOI: 10.1038/s41375-025-02625-3

Yoshikazu Ikoma, Nobuhiko Nakamura, Yuto Kaneda, Hiroyuki Takamori, Tomokazu Seki, Nobuhiro Hiramoto, Junichi Kitagawa, Junya Kanda, Kei Fujita, Tetsuji Morishita, Yotaro Ochi, Shigeru Chiba, Nana Sasaki, Michiko Ichii, Kazunori Imada, Mizuki Watanabe, Masakatsu Hishizawa, Yasuko Miyahara, Yoshitomo Maesako, Yasuhiro Tanaka, Satoko Oka, Masaaki Tsuji, Satoshi Yoshihara, Kinuko Mitani, Yasunori Ueda, Toshiyuki Kitano, Mitsumasa Watanabe, Nobuo Sezaki, Tadakazu Kondo, Senji Kasahara, Akifumi Takaori-Kondo, Nobuhiro Kanemura, Seishi Ogawa, Yasuhito Nannya

{"title":"Impact of myelodysplasia-related gene mutations and residual mutations at remission in venetoclax/azacitidine for AML","authors":"Yoshikazu Ikoma, Nobuhiko Nakamura, Yuto Kaneda, Hiroyuki Takamori, Tomokazu Seki, Nobuhiro Hiramoto, Junichi Kitagawa, Junya Kanda, Kei Fujita, Tetsuji Morishita, Yotaro Ochi, Shigeru Chiba, Nana Sasaki, Michiko Ichii, Kazunori Imada, Mizuki Watanabe, Masakatsu Hishizawa, Yasuko Miyahara, Yoshitomo Maesako, Yasuhiro Tanaka, Satoko Oka, Masaaki Tsuji, Satoshi Yoshihara, Kinuko Mitani, Yasunori Ueda, Toshiyuki Kitano, Mitsumasa Watanabe, Nobuo Sezaki, Tadakazu Kondo, Senji Kasahara, Akifumi Takaori-Kondo, Nobuhiro Kanemura, Seishi Ogawa, Yasuhito Nannya","doi":"10.1038/s41375-025-02625-3","DOIUrl":"https://doi.org/10.1038/s41375-025-02625-3","url":null,"abstract":"Venetoclax plus azacitidine (VEN + AZA) is widely used in acute myeloid leukemia (AML). This study explored the role of static and dynamic profiles of mutational clonal burden to predict outcomes by analyzing marrow samples from 228 VEN + AZA treated AML cases at “Pre-treatment” (n = 228), “Best-response” (n = 105), and “Relapse” (n = 27) phases using targeted-capture sequencing. In a multivariate model, older age, prior AZA, TP53 mutation with variant allele frequency ≥0.10, and RAS-pathway mutations predicted shorter overall survival (OS), while BCORL1 mutation predicted longer OS. Notably, myelodysplasia-related gene mutations, which constitute adverse factors in ELN 2022, predicted favorable survival. Achieving composite complete remission (CRc) significantly predicted longer OS (P < 0.001) but showed residual mutations in 76.2% of the cases. Among CRc cases, relapse-free survival was stratified by molecular clearance of mutations other than DNMT3A, ASXL1, and TET2 (P = 0.04). In addition, 37% of relapsed cases showed a change of major clones, with 40% having potential targets of molecular-targeting treatment. This study revealed the novel prognostic role of myelodysplasia-related gene mutations and established the importance of molecular response assessment in CRc phase.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"58 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143857362","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}

引用次数: 0

Myelodysplastic syndrome/myeloproliferative neoplasm overlap syndromes: a practical guide to diagnosis and management 骨髓增生异常综合征/骨髓增生性肿瘤重叠综合征：诊断和管理的实用指南

IF 11.4 1区医学

Leukemia Pub Date : 2025-04-19 DOI: 10.1038/s41375-025-02620-8

Douglas Tremblay, Robert P. Hasserjian, Raajit K. Rampal

引用次数: 0

GVHD prophylaxis in matched related stem cell transplantation: Why post-transplant cyclophosphamide can be recommended a study by the EBMT transplant complications working party 匹配相关干细胞移植的GVHD预防：为什么移植后环磷酰胺可以推荐EBMT移植并发症工作组的一项研究

IF 11.4 1区医学

Leukemia Pub Date : 2025-04-17 DOI: 10.1038/s41375-025-02619-1

Olaf Penack, Mouad Abouqateb, Christophe Peczynski, William Boreland, Malek Benakli, Nicolaus Kröger, Igor Wolfgang Blau, Didier Blaise, Jaime Sanz, Matthias Eder, Hakan Ozdogu, Dominik Schneidawind, Annoek E. C. Broers, Gerald. G. Wulf, Alberto Mussetti, Ivan Moiseev, Charlotte Graham, Hélène Schoemans, Zinaida Peric

{"title":"GVHD prophylaxis in matched related stem cell transplantation: Why post-transplant cyclophosphamide can be recommended a study by the EBMT transplant complications working party","authors":"Olaf Penack, Mouad Abouqateb, Christophe Peczynski, William Boreland, Malek Benakli, Nicolaus Kröger, Igor Wolfgang Blau, Didier Blaise, Jaime Sanz, Matthias Eder, Hakan Ozdogu, Dominik Schneidawind, Annoek E. C. Broers, Gerald. G. Wulf, Alberto Mussetti, Ivan Moiseev, Charlotte Graham, Hélène Schoemans, Zinaida Peric","doi":"10.1038/s41375-025-02619-1","DOIUrl":"https://doi.org/10.1038/s41375-025-02619-1","url":null,"abstract":"Rabbit anti-thymocyte globulin (rATG) reduced chronic GVHD after matched related donor (MRD) allogeneic stem cell transplantation (alloSCT) from 69% to 32% in a randomized trial and is the recommended standard in Europe. Post-transplantation Cyclophosphamide (PTCy) is an emerging alternative but lacks such solid data in MRD alloSCT. We therefore analyzed outcomes of rATG (n = 4140) vs. PTCy (n = 1069) in adult patients with hematologic malignancies undergoing MRD alloSCT between 2017 and 2021 in the EBMT database. The provided hazard ratios (HR) and P-values are adjusted for potential risk factors using multivariate analysis. Results are given at 2 years after alloSCT for all endpoints except for acute GVHD (100 days). The main difference was a lower relapse incidence after PTCy vs. rATG (26.2% vs. 32.8%; HR 0.78 [CI 95%: 0.66–0.92], p = 0.003). Interaction analyses confirmed the consistency of this result across different disease risk index and conditioning intensity subgroups. Other major transplant outcomes showed no significant differences: non-relapse mortality, overall survival, progression-free survival, GVHD-free relapse-free survival, incidence and severity of acute GVHD as well as chronic GVHD. In summary, PTCy results in comparable GVHD and survival outcomes but lower relapse rates compared to rATG. We conclude that PTCy can be recommended in MRD alloSCT.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"266 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143847089","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}

引用次数: 0

T-cell acute lymphoblastic leukaemia: subtype prevalence, clinical outcome, and emerging targeted treatments t细胞急性淋巴细胞白血病：亚型流行，临床结果，和新兴的靶向治疗

IF 11.4 1区医学

Leukemia Pub Date : 2025-04-17 DOI: 10.1038/s41375-025-02599-2

Maxim Buckley, David T. Yeung, Deborah L. White, Laura N. Eadie

{"title":"T-cell acute lymphoblastic leukaemia: subtype prevalence, clinical outcome, and emerging targeted treatments","authors":"Maxim Buckley, David T. Yeung, Deborah L. White, Laura N. Eadie","doi":"10.1038/s41375-025-02599-2","DOIUrl":"https://doi.org/10.1038/s41375-025-02599-2","url":null,"abstract":"T-cell Acute Lymphoblastic Leukaemia (T-ALL) is a high-risk hematological disease constituting ~20% of acute leukemias. To date, the only subtype recognized by the World Health Organization’s International Consensus Classification is early T-cell precursor ALL. To improve clinical outcomes, several studies have investigated and defined T-ALL genomic subtypes within cohorts of varied ages and geographical locations. These studies have also utilized differing analysis methods including whole transcriptome, exome, or genome sequencing as well as immunophenotyping and cytogenetic testing. As a result, there are significant differences in reported subtypes as well as the frequency at which each occurs. The reported clinical outcomes for specific genomic alterations also depend on patient demographics and treatment protocols. This review synthesizes the data from four T-ALL genomic landscape studies establishing consensus and highlighting differences, details clinical outcomes for the most common genomic alterations observed in T-ALL patients, and proposes novel avenues for future investigation and treatment.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"108 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143841342","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}

引用次数: 0

An oncolytic adenovirus targeting SLAMF7 demonstrates anti-myeloma efficacy 一种靶向SLAMF7的溶瘤腺病毒显示出抗骨髓瘤的功效

IF 11.4 1区医学

Leukemia Pub Date : 2025-04-17 DOI: 10.1038/s41375-025-02617-3

Georgia Stewart, Simon Tazzyman, Yidan Sun, Rebecca E. Andrews, Jack Harrison, Darren Lath, Jenny Down, Georgia Robinson, Xue Wang, Munitta Muthana, Andrew. D. Chantry, Michelle A. Lawson

{"title":"An oncolytic adenovirus targeting SLAMF7 demonstrates anti-myeloma efficacy","authors":"Georgia Stewart, Simon Tazzyman, Yidan Sun, Rebecca E. Andrews, Jack Harrison, Darren Lath, Jenny Down, Georgia Robinson, Xue Wang, Munitta Muthana, Andrew. D. Chantry, Michelle A. Lawson","doi":"10.1038/s41375-025-02617-3","DOIUrl":"https://doi.org/10.1038/s41375-025-02617-3","url":null,"abstract":"We investigated a novel SLAMF7-promoter driven oncolytic adenovirus (Ad[CE1A]) as a potential therapeutic for multiple myeloma, an incurable hematological malignancy. Ad[CE1A] infection, replication, and oncolysis were assessed in a panel of myeloma cell lines (n = 8) and ex vivo samples from myeloma patients (n = 17) and healthy donors (HDs) (n = 14). Ad[CE1A] efficiently infected, replicated, and induced oncolysis in myeloma cells, but not in control cell lines or HDs, demonstrating selective cytotoxicity. Mechanistic studies revealed Ad[CE1A]-induced cell death is caspase-independent, with a potential involvement of necroptosis. Ad[CE1A] also altered immunogenic cell death markers (calreticulin, CD47, extracellular ATP), enhanced antigen presentation via increased MHC class I and II receptor expression (HLA-ABC and HLA-DR), and stimulated bystander cytokine killing, indicating potential for direct and immune-mediated anti-myeloma responses. In vivo experiments with 5TGM1 syngeneic and U266 xenograft models showed Ad[CE1A] significantly reduced myeloma tumor burden compared to vehicle control. Combination therapy with anti-myeloma drugs, bortezomib, melphalan, panobinostat and pomalidomide, enhanced Ad[CE1A] efficacy, with melphalan upregulating SLAMF7, resulting in increased viral replication. In summary, these findings support Ad[CE1A] as a promising myeloma therapy.<figure></figure>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"9 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143847094","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}

引用次数: 0

Patient-reported outcomes in Philadelphia chromosome-positive acute lymphoblastic leukemia patients treated with ponatinib or imatinib: results from the PhALLCON trial 患者报告的费城染色体阳性急性淋巴细胞白血病患者接受波纳替尼或伊马替尼治疗的结果：来自PhALLCON试验的结果

IF 11.4 1区医学

Leukemia Pub Date : 2025-04-16 DOI: 10.1038/s41375-025-02608-4

Ajibade Ashaye, Ling Shi, Ibrahim Aldoss, Pau Montesinos, Pankit Vachhani, Vanderson Rocha, Cristina Papayannidis, Jessica T. Leonard, Maria R. Baer, Jose-Maria Ribera, James McCloskey, Jianxiang Wang, Sujun Gao, Deepali Rane, Shien Guo

{"title":"Patient-reported outcomes in Philadelphia chromosome-positive acute lymphoblastic leukemia patients treated with ponatinib or imatinib: results from the PhALLCON trial","authors":"Ajibade Ashaye, Ling Shi, Ibrahim Aldoss, Pau Montesinos, Pankit Vachhani, Vanderson Rocha, Cristina Papayannidis, Jessica T. Leonard, Maria R. Baer, Jose-Maria Ribera, James McCloskey, Jianxiang Wang, Sujun Gao, Deepali Rane, Shien Guo","doi":"10.1038/s41375-025-02608-4","DOIUrl":"https://doi.org/10.1038/s41375-025-02608-4","url":null,"abstract":"In the Phase 3 PhALLCON trial (NCT03589326), ponatinib demonstrated superior efficacy and comparable safety profile versus imatinib in adults with newly diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). Here we report patient-reported outcomes (PRO) from PhALLCON assessed as exploratory endpoints using the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu) and EQ-5D-5L. Primary PRO domains included FACT-G physical well-being, FACT-Leu subscale (FACT-LeuS), Trial Outcome Index (TOI), FACT-Leu total score, FACT-G total score, and EQ-5D visual analogue scale. Differences in least-squares mean score changes from baseline to the end of induction (EOI)/consolidation (EOC) and time to confirmed improvement/deterioration were analyzed. Overall treatment tolerability was assessed using the FACT-GP5. Analyses included 238 patients (ponatinib 159, imatinib 79) with ≥1 PRO assessment. Least-squares mean changes from baseline favored ponatinib, with significant and meaningful differences in FACT-LeuS, TOI, and FACT-Leu total score at EOI and across the primary domains except for FACT-LeuS at EOC. Median time to confirmed improvement was shorter with ponatinib versus imatinib for key measures. Ponatinib-treated patients tended to report being less bothered by treatment side effects as assessed by FACT-GP5. These findings highlight ponatinib’s potentially favorable impact on health-related quality of life, supporting its use as frontline treatment for Ph+ ALL.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"41 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143837020","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}

引用次数: 0

Molecular landscape of distinct follicular lymphoma histologic grades: insights from genomic and transcriptome analyses 不同滤泡淋巴瘤组织学分级的分子图谱：基因组和转录组分析的启示

IF 11.4 1区医学

Leukemia Pub Date : 2025-04-15 DOI: 10.1038/s41375-025-02603-9

Cong Sun, Wei Li, Jingwei Yu, Tingting Zhang, Wenchen Gong, Hengqi Liu, Fenghua Gao, Zheng Song, Lanfang Li, Lihua Qiu, Zhengzi Qian, Shiyong Zhou, Bin Meng, Yanan Gao, Junzhi Li, Xia Liu, Weicheng Ren, Qiang Pan-Hammarström, Xianhuo Wang, Huilai Zhang

{"title":"Molecular landscape of distinct follicular lymphoma histologic grades: insights from genomic and transcriptome analyses","authors":"Cong Sun, Wei Li, Jingwei Yu, Tingting Zhang, Wenchen Gong, Hengqi Liu, Fenghua Gao, Zheng Song, Lanfang Li, Lihua Qiu, Zhengzi Qian, Shiyong Zhou, Bin Meng, Yanan Gao, Junzhi Li, Xia Liu, Weicheng Ren, Qiang Pan-Hammarström, Xianhuo Wang, Huilai Zhang","doi":"10.1038/s41375-025-02603-9","DOIUrl":"https://doi.org/10.1038/s41375-025-02603-9","url":null,"abstract":"The 2022 World Health Organization Classification of Haematolymphoid tumours classifies follicular lymphoma grades 1–2 (FL1-2) and grade 3A (FL3A) as classic follicular lymphoma (cFL) and reclassifies grade 3B (FL3B) as follicular large B-cell lymphoma (FLBL), without addressing cases of patients with concurrent FL and diffuse large B-cell lymphoma (FL/DLBCL). However, genetic information on FL histologic grading remains limited, and the latest classification lacks sufficient evidence to resolve whether these subgroups represent single or multiple distinct biological entities. This study analyzed clinical data from 831 patients, whole-exome sequencing (WES) from 149 patients, and transcriptome sequencing from 63 patients to explore differences among FL1-2, FL3A, FL3B, and FL/DLBCL. Clinical analyses revealed two distinct groups: an indolent group (FL1-2 and FL3A) with favorable prognosis and an aggressive group (FL3B and FL/DLBCL) characterized by poor prognosis. Genomics revealed that FL1-2 and FL3A share a common genetic background, whereas FL3B and FL/DLBCL lack mutations in epigenetic regulators CREBBP and KMT2D but exhibit additional copy number variations (CNVs), such as 1p36.32 losses and 3p21.1 gains, which are linked to poor prognosis. Transcriptomics revealed that with increasing histologic grade, immune-related pathway activity decreases, while the activity of metabolic and cell cycle pathways increases, which may be associated with the upregulation of MYC, IRF4, and BATF expression. Together, these findings define FL3B and FL/DLBCL as biologically and clinically distinct B-cell lymphomas, differing from traditional FL. FL1-2 and FL3A differ in their tumor microenvironments rather than genetic profiles.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"247 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143832128","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}

引用次数: 0

Dual STAT3/STAT5 inhibition as a novel treatment strategy in T-prolymphocytic leukemia 双重抑制STAT3/STAT5作为t -原淋巴细胞白血病的新治疗策略

IF 11.4 1区医学

Leukemia Pub Date : 2025-04-15 DOI: 10.1038/s41375-025-02577-8

Annika Dechow, Sanna Timonen, Aleksandr Ianevski, Qu Jiang, Linus Wahnschaffe, Yayi Peng, Dennis Jungherz, Kerstin Becker, Heidi A. Neubauer, Susann Schönefeldt, Elvin de Araujo, Patrick Gunning, Roman Fleck, Alexandra Schrader, Michael Hallek, Natali Pflug, Richard Moriggl, Tero Aittokallio, Satu Mustjoki, Till Braun, Marco Herling

{"title":"Dual STAT3/STAT5 inhibition as a novel treatment strategy in T-prolymphocytic leukemia","authors":"Annika Dechow, Sanna Timonen, Aleksandr Ianevski, Qu Jiang, Linus Wahnschaffe, Yayi Peng, Dennis Jungherz, Kerstin Becker, Heidi A. Neubauer, Susann Schönefeldt, Elvin de Araujo, Patrick Gunning, Roman Fleck, Alexandra Schrader, Michael Hallek, Natali Pflug, Richard Moriggl, Tero Aittokallio, Satu Mustjoki, Till Braun, Marco Herling","doi":"10.1038/s41375-025-02577-8","DOIUrl":"https://doi.org/10.1038/s41375-025-02577-8","url":null,"abstract":"T-prolymphocytic leukemia (T-PLL) is a rare, aggressive T-cell malignancy with poor outcomes and an urgent need for new therapeutic approaches. Integrating genomic data and new transcriptomic profiling, we identified recurrent JAK/STAT mutations (predominantly in JAK3 and STAT5B) as hallmarks in a cohort of 335 T-PLL cases. In line, transcriptomic and protein analyses revealed constitutive JAK/STAT activation in virtually all samples. Consequently, we explored the anti-leukemic potential of dual STAT3/STAT5 non-PROTAC degraders in T-PLL, with JPX-1244 as our lead substance. JPX-1244 efficiently and selectively induced cell death in primary T-PLL samples, including those resistant to conventional therapies, by blocking STAT3 and STAT5 phosphorylation and by inducing their degradation. The extent of STAT3/STAT5 degradation directly correlated with cytotoxicity. RNA-sequencing confirmed the treatment-related downregulation of STAT5 target genes. While JAK/STAT mutations did not predict responses to pharmacologic STAT3/STAT5 degradation, elevated expression of TOX, PAK6, and SPINT1 were associated with drug sensitivity. In subsequent combination screenings, cladribine, venetoclax, and azacytidine emerged as most effective combination partners of STAT3/STAT5 degraders, even in low-responding T-PLL samples, all synergistically reducing STAT5 phosphorylation. These findings highlight dual STAT3/STAT5 inhibition, particularly in combination with hypomethylating and BCL2-targeting agents, as a promising interventional approach in T-PLL, warranting further investigation.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"15 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143832129","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}

引用次数: 0