Blood Cancer Journal最新文献

{"title":"WNK2 oncogenicity revealed by the discovery and functional characterization of novel gene isoforms in MYD88 mutated Waldenström's Macroglobulinemia.","authors":"Maria Luisa Guerrera,Xia Liu,Nickolas Tsakmaklis,Abigail L Peachey,Amanda Kofides,John Hatcher,Andres Ramirez Gamero,Alberto Guijosa,Guang Yang,Hao Sun,Shirong Liu,Christopher J Patterson,Kirsten Meid,Catherine Flynn,Ruben D Carrasco,Andrew R Branagan,Shayna R Sarosiek,Jorge J Castillo,Kenneth C Anderson,Nikhil Munshi,Steven P Treon,Zachary R Hunter","doi":"10.1038/s41408-026-01554-3","DOIUrl":"https://doi.org/10.1038/s41408-026-01554-3","url":null,"abstract":"WNK2 is a known tumor suppressor in a set of solid tumors, including glioblastoma multiforme and pancreatic ductal adenocarcinoma. WNK2 functions are largely unknown beyond the kinase domain (KD)-dependent inhibition of ERK1/2 signaling. Waldenström's Macroglobulinemia (WM) is an indolent, yet incurable, B cell lymphoma characterized by highly recurrent MYD88 (MYD88MUT) and CXCR4 (CXCR4MUT) mutations that trigger sustained NF-κB and ERK1/2 signaling. Although not expressed in healthy B cells, WNK2 is a top dysregulated gene in MYD88MUT WM. To study WNK2 regulation and signaling, we performed multi-omics analyses, including bulk and PacBio Iso-Seq RNA-Seq and methylome, in 264 untreated WM and functional studies in cell lines and primary WM cells. Aberrant expression of WNK2 emerged as a near universal feature of early-stage WM and a hallmark of plasma cell-like MYD88MUT WM. We identified novel isoforms that carried a shared aberrant splicing event, either contained or lacked the KD and were highly expressed by the tumor cells, unlike the canonical full-length isoforms. Functionally, WNK2/S-NK1, the most expressed of the KD-lacking isoforms in WM, triggered a pro-inflammatory cascade that activated ERK1/2 and NF-κB signaling. We observed a similar, cancer-specific upregulation of WNK2 in a set of solid tumors, including the highly aggressive cholangiocarcinoma. Our findings reveal an undocumented oncogenic function for WNK2 driven by novel, cancer-specific isoforms and provide a framework for its further investigation as a determinant of disease progression in MYD88MUT WM and a novel therapeutic target in hematological and solid tumor oncology.","PeriodicalId":8989,"journal":{"name":"Blood Cancer Journal","volume":"230 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148408039","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":"Adult acute lymphoblastic leukemia: incorporation of recent advances into current treatment strategies.","authors":"Elias Jabbour,Hagop Kantarjian","doi":"10.1038/s41408-026-01566-z","DOIUrl":"https://doi.org/10.1038/s41408-026-01566-z","url":null,"abstract":"Outcomes in B-cell acute lymphoblastic leukemia (ALL) have improved over time due to therapeutic advances, and improved disease monitoring and prognostication. The BCR::ABL1 tyrosine kinase inhibitors (TKIs) were the first targeted therapies to significantly impact the therapeutic trajectory and outcomes of Philadelphia chromosome-positive (Ph-positive) ALL. Similarly, antibodies targeting CD19/20/22 and engineered chimeric antigen receptor (CAR) T-cell immunotherapies have drastically changed the therapeutic landscape and outcomes of B-cell ALL. Incorporation of the bispecific T-cell engager (BiTE) blinatumomab has demonstrated a significant survival advantage in patients with both newly diagnosed Philadelphia chromosome-negative (Ph-negative) and Ph-positive ALL. Inotuzumab ozogamicin, the anti-CD22 antibody drug conjugate (ADC), has also been safely integrated into the frontline treatment backbones in both younger and older patients. CAR T-cell therapy has resulted in durable remissions in relapsed/refractory (R/R) ALL, especially with lower disease burden. CAR T-cell therapy consolidation in the frontline setting is being pursued with the goal of reducing the need for allogeneic stem cell transplantation (alloSCT). Future research is focusing on treatment optimization through replacement of chemotherapy with immunotherapies with the goal of reducing toxicities, minimizing the need for alloSCT, and shortening the intensity and duration of therapy while improving long-term outcomes.","PeriodicalId":8989,"journal":{"name":"Blood Cancer Journal","volume":"214 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2026-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148385693","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":"Genomic loss of MLH1/PMS2 loci defines a mismatch repair deficient subgroup in monomorphic epitheliotropic intestinal T-cell lymphoma.","authors":"Luis Veloza,Anja Fischer,Vimel Rattina,David Vallois,Rita Sarkis,Karine Lefort,Bettina Bisig,Doriane Cavalieri,Olivier Tournilhac,Philippe Gaulard,Reiner Siebert,Laurence de Leval,Edoardo Missiaglia","doi":"10.1038/s41408-026-01562-3","DOIUrl":"https://doi.org/10.1038/s41408-026-01562-3","url":null,"abstract":"Primary intestinal T-cell lymphomas (ITCLs), comprising enteropathy-associated T-cell lymphoma (EATL) and monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), are rare aggressive tumors. The role of DNA mismatch repair (MMR) deficiency (dMMR) and microsatellite instability (MSI) in the development of ITCLs remains largely unexplored. Here, we investigated the incidence, molecular mechanisms and clinical relevance of dMMR/MSI in 86 ITCLs (30 EATLs, 56 MEITLs) using whole-exome sequencing, PCR-based MSI testing, DNA methylation profiling, and immunohistochemistry for MLH1, MSH2, MSH6 and PMS2. MMR deficiency was detected in 3 of 53 MEITLs (6%) but in none of the EATLs. dMMR MEITLs showed the highest tumor mutational burden (8.3-17.1 mutations/Mb), compared to median TMBs of 1.9 in MEITL and 2.4 in EATL. The complete loss of MLH1/PMS2 expression in two MSI-high tumors and isolated PMS2 loss in the third case were all associated with biallelic deletions of the affected loci. Notably, MLH1 deletions significantly co‑occurred with SETD2 deletions (p = 0.001), the latter representing a major driver of MEITL tumorigenesis. dMMR MEITLs lacked distinctive clinicopathologic features. These findings indicate that dMMR/MSI occurs in a subset of MEITLs probably during tumor progression, rather than being an initiating driver event, and provide a biological rationale to explore the efficacy of immune checkpoint inhibitors in some of this unfavorable subtype of ITCL.","PeriodicalId":8989,"journal":{"name":"Blood Cancer Journal","volume":"40 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148379902","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":"Response profile and long-term outcomes in Cyclin D1-overexpressing multiple myeloma: insights from the CASSIOPEIA trial.","authors":"Aurore Perrot,Cyrille Touzeau,Stéphane Minvielle,Cyrille Hulin,Denis Caillot,Salomon Manier,Xavier Leleu,Cécile Sonntag,Karim Belhadj,Bertrand Arnulf,Thomas Chalopin,Jean-Richard Eveillard,Martine Escoffre-Barbe,Lionel Karlin,Laure Vincent,Margaret Macro,Hervé Avet-Loiseau,Soraya Wuilleme,Ariane Boumendil,Jill Corre,Philippe Moreau","doi":"10.1038/s41408-026-01542-7","DOIUrl":"https://doi.org/10.1038/s41408-026-01542-7","url":null,"abstract":"","PeriodicalId":8989,"journal":{"name":"Blood Cancer Journal","volume":"66 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148379901","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":"Expression profile of CASSIOPEIA patients refines prognostic value of MRD negativity in multiple myeloma.","authors":"Florence Magrangeas, Catherine Guérin-Charbonnel, Victor Bessonneau-Gaborit, Marie Denoulet, Nils Giordano, Aurore Perrot, Cyrille Touzeau, Mark van Duin, Magali Devic, Elise Douillard, Eric Letouzé, Pieter Sonneveld, Jill Corre, Stéphane Minvielle, Philippe Moreau","doi":"10.1038/s41408-026-01550-7","DOIUrl":"10.1038/s41408-026-01550-7","url":null,"abstract":"<p><p>Long-term follow-up of the CASSIOPEIA trial (NCT02541383) demonstrated superior progression-free survival (PFS) with daratumumab, both in combination with bortezomib, thalidomide, and dexamethasone during induction and consolidation, and during maintenance therapy, in transplant-eligible patients newly diagnosed with multiple myeloma (MM). However, outcomes among CASSIOPEIA patients remain heterogeneous across treatment groups. Measurable residual disease (MRD) is a strong indicator of the depth and duration of therapeutic response and is independently associated with both PFS and overall survival (OS), but it does not fully capture the biological diversity of MM. We performed a risk prediction analysis based on transcriptomic subgroups in CASSIOPEIA patients. A subset of 628 patients was characterized using RNA sequencing and consensus clustering identified five subtypes of MM grouped into three transcriptomic risk categories, with estimated 72-month PFS rates of 70%, 51%, and 27% for low, intermediate, and high-risk groups, respectively, among patients who received daratumumab in at least one treatment phase. We showed that post-consolidation MRD negativity was higher in low- and high-risk groups compared to intermediate, and that its prognostic impact was distinct and reduced in high-risk patients. These findings indicate that transcriptomic profiling refines the prognostic value of MRD by identifying high-risk patients in whom MRD alone is insufficient to predict clinical outcome. This suggests that MRD negativity may not capture clinically relevant residual disease in this subgroup, potentially reflecting aggressive disease dynamics. Overall, these results support integrating baseline molecular features with MRD assessment and highlight the need for novel therapeutic strategies in high-risk MM.</p>","PeriodicalId":8989,"journal":{"name":"Blood Cancer Journal","volume":" ","pages":""},"PeriodicalIF":13.8,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13597487/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148374371","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":"Long-term clinical outcomes from the smart start trial: rituximab, lenalidomide and ibrutinib in patients with newly diagnosed large B-cell lymphoma.","authors":"Karan L Chohan, Eduardo Edelman Saul, R Eric Davis, Fredrick Hagemeister, Raphael Steiner, Luis Fayad, Sairah Ahmed, Alma Rodriguez, Swaminathan P Iyer, Ranjit Nair, Francisco Vega, Dai Chihara, Paolo Strati, Preetesh Jain, Luis Malpica Castillo, Chijioke Nze, Fateeha Furqan, Ayushi Chauhan, Mark P Hamilton, Jared Henderson, Anath C Lionel, Christopher R Flowers, Sattva Neelapu, Michael R Green, Jason Westin","doi":"10.1038/s41408-026-01524-9","DOIUrl":"10.1038/s41408-026-01524-9","url":null,"abstract":"","PeriodicalId":8989,"journal":{"name":"Blood Cancer Journal","volume":"16 1","pages":""},"PeriodicalIF":13.8,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13328379/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148374395","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":"Zanubrutinib combined with R-CHOP in previously untreated diffuse large B-cell lymphoma with specific gene alteration: a phase II study.","authors":"Qunling Zhang,Shiyu Jiang,Ran Wei,Wenhao Zhang,Longlong Bao,Yizhen Liu,Jia Jin,Fangfang Lv,Chuanxu Liu,Xiaojian Liu,Hui Sun,Jiachen Wang,Rong Tao,Xiaoyan Zhou,Junning Cao","doi":"10.1038/s41408-026-01553-4","DOIUrl":"https://doi.org/10.1038/s41408-026-01553-4","url":null,"abstract":"Diffuse large B-cell lymphoma (DLBCL) remains clinically heterogeneous, and outcomes with R-CHOP are suboptimal in patients carrying high-risk genomic alterations such as MYD88, CD79B, NOTCH1, TP53 mutations or MYC rearrangements. Many of these lesions are associated with aberrant BCR signaling, and prior studies in relapsed disease have suggested a degree of sensitivity to BTK inhibitors. These observations provided the rationale for evaluating zanubrutinib in the frontline setting for genomically defined high-risk disease. We conducted a prospective, single-center phase II study in previously untreated DLBCL patients aged 18-75 years with one or more of the above molecular features. To accommodate molecular testing time, patients received one initial cycle of R-CHOP, followed by five cycles of zanubrutinib plus R-CHOP (ZR-CHOP). Response was assessed using Lugano 2014 criteria. Primary endpoint is 3-year PFS; key secondary endpoints include ORR, OS, EFS, and safety. From February 2022 to April 2024, 59 patients were enrolled; 58 were evaluable for efficacy. Molecular subtyping identified 25 MCD-like, 16 A53-like, 3 N1-like, 10 other subtypes, and 4 MYC-rearranged cases. The ORR was 91.4% (53/58), with a CMR rate of 79.3% (46/58). MCD-like patients showed particularly favorable responses, with 84% achieving CMR. After a median follow-up of 30.1 months, the estimated 3-year PFS and OS were 80.3% (95%CI 70.5-91.5%) and 89.1% (95%CI 81.2-97.8%), respectively. MCD-like subgroup showed a 3-year OS of 100%, whereas N1-like had markedly poorer survival (2-year OS 33.3%). AEs occurred in 56/59 patients, mostly grade 1-2. Grade ≥ 3 events occurred in 57.6%, most commonly myelosuppression. No atrial fibrillation or other cardiac toxicities were observed. ZR-CHOP demonstrates encouraging activity and acceptable safety in molecularly selected high-risk DLBCL, particularly in the MCD-like subgroup. (ClinicalTrials.gov number, NCT05290337).","PeriodicalId":8989,"journal":{"name":"Blood Cancer Journal","volume":"35 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148365144","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":"Effect of anemia developed after ruxolitinib initiation on adverse outcomes in patients with myelofibrosis: a nationwide cohort study.","authors":"Minjeong Jeon,Yubin Lee,Jieun Woo,Ju Hwan Kim,Ju-Young Shin","doi":"10.1038/s41408-026-01557-0","DOIUrl":"https://doi.org/10.1038/s41408-026-01557-0","url":null,"abstract":"","PeriodicalId":8989,"journal":{"name":"Blood Cancer Journal","volume":"8 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148365244","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":"Dynamics of IDH1/2 mutated clones in acute myeloid leukemia challenge their use as universal MRD markers.","authors":"Giovanni Marconi, Lorenza Bandini, Agnese Patuelli, Valentina Robustelli, Claudia Venturi, Giorgia Simonetti, Jacopo Nanni, Gianluca Cristiano, Chiara Sartor, Michela Rondoni, Cristina Papayannidis, Francesco Lanza, Emanuela Ottaviani, Antonio Curti","doi":"10.1038/s41408-026-01538-3","DOIUrl":"10.1038/s41408-026-01538-3","url":null,"abstract":"","PeriodicalId":8989,"journal":{"name":"Blood Cancer Journal","volume":"16 1","pages":""},"PeriodicalIF":13.8,"publicationDate":"2026-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13319202/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148359367","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":"Outcomes of patients with higher-risk myelodysplastic syndromes/neoplasms treated with hypomethylating agents + venetoclax-an analysis from the International Consortium for MDS (icMDS) VALIDATE database.","authors":"Jan Philipp Bewersdorf,Tariq Kewan,Luca Lanino,Wei Wei,Tulika Rudra Gupta,Jessica M Stempel,Najla H Al Ali,Amy E DeZern,Mikkael A Sekeres,Geoffrey L Uy,Samuel Urrutia,Hetty E Carraway,Pinkal Desai,Elizabeth A Griffiths,Eytan M Stein,Andrew M Brunner,Christine McMahon,Rory M Shallis,Joshua F Zeidner,Michael R Savona,Hayley Hawkins,Namrata Sonia Chandhok,Constantine N Logothetis,Aram Bidikian,Ted M Getz,Gail J Roboz,Benjamin Rolles,Eunice S Wang,Amyah C Harris,Maria L Amaya,Somedeb Ball,Justin Grenet,Zhuoer Xie,Yazan F Madanat,Yasmin Abaza,Talha Badar,Jaclynn Campos,Torsten Haferlach,Jaroslaw P Maciejewski,David Sallman,Anoop Enjeti,Kamal Al-Rabi,Khalid Halahleh,Devendra Hiwase,Maria Diez-Campelo,David Valcarcel,Claudia Haferlach,Lisa Pleyer,Ioannis Kotsianidis,Vassiliki Pappa,Valeria Santini,Angela Consagra,Aref Al-Kali,Seishi Ogawa,Yasuhito Nannya,Maximilian Stahl,Matteo Giovanni Della Porta,Rami S Komrokji,Amer M Zeidan","doi":"10.1038/s41408-026-01543-6","DOIUrl":"https://doi.org/10.1038/s41408-026-01543-6","url":null,"abstract":"Monotherapy with hypomethylating agents (HMA) remains the standard of care for patients with higher-risk myelodysplastic neoplasms (HR-MDS). Recently, the randomized phase III VERONA study evaluating azacitidine plus venetoclax (VEN) versus azacitidine plus placebo in newly diagnosed HR-MDS showed no difference in overall survival (OS) between the two arms. However, whether the addition of VEN to HMA improves outcomes among subsets of patients with HR-MDS remains debated. We analyzed 1907 patients with HR-MDS from 31 centers in 9 countries who were treated with HMA monotherapy or HMA/VEN in the frontline setting (HMA monotherapy: n = 1773; HMA/VEN: n = 134). Responses were assessed centrally by two investigators using the IWG 2023 response criteria. Addition of VEN improved composite complete remission (cCR) rates (48.8% vs. 27.7%; p < 0.001) but not CR rates (17.1% vs. 11.7%; p = 0.16). In multivariable logistic regression analysis, cCR remained favorable for HMA/VEN vs. HMA monotherapy (Odds Ratio [OR]: 2.49; 95% CI: 1.56-3.96; p < 0.001). However, we did not observe a statistically significant difference in OS for HMA/VEN vs. HMA monotherapy (Hazard Ratio [HR]: 0.83; 95% CI: 0.64-1.07; p = 0.15). In subgroup analyses, patients with TP53 wild-type disease (HR: 0.47; 95% CI: 0.29-0.74; p = 0.002) had a significant improvement in OS and those with ≥10% bone marrow blasts (HR: 0.73; 95% CI: 0.53-1.01; p = 0.06) had a trend towards OS benefit with HMA/VEN.","PeriodicalId":8989,"journal":{"name":"Blood Cancer Journal","volume":"34 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2026-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148348907","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}