Blood advances最新文献

{"title":"A Simple and Efficient Method for the Robust Expansion of Human ILC2s to Prevent Acute GvHD.","authors":"Danny W Bruce, Sonia J Laurie, Yan Xing, Heather E Stefanski, Keli L Hippen, Alec Wilkinson, Mark G Woodcock, James Coghill, Karen Peterson McKinnon, Bruce R Blazar, Jonathan Serody","doi":"10.1182/bloodadvances.2024013609","DOIUrl":"https://doi.org/10.1182/bloodadvances.2024013609","url":null,"abstract":"<p><p>Reconstitution of stem cells and enhancement of the barrier function of the gastrointestinal (GI) tract is critical to the resolution of intestinal acute graft-versus-host disease (aGvHD). Previously, our group has shown in murine models that type II innate lymphoid cells (ILC2) cells generate proteins in the GI tract that enhanced GI tract barrier function and diminished the expansion and function of pro-inflammatory donor cells when given to allogeneic stem cell transplant recipients. Therefore, the infusion of donor ILC2 cells could treat or prevent GI tract acute GvHD, but for this approach to be clinically applicable, robust expansion of a homogenous population of human ILC2 cells is needed. Here, we describe a method for the rapid expansion of a uniform population of human ILC2 cells which decrease GvHD in (NOD scid gamma mouse) NSG mice. The addition of IL-4 to the culture was critical to prevent the expansion of pro-inflammatory ILC1-like cells. Our approach should allow for the evaluation of human ILC2 cells to treat therapy-resistant GI tract acute GvHD.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144681971","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":"Advances and updates in pediatric anaplastic large cell lymphoma.","authors":"Lianna J Marks, Eric J Lowe, Kala Y Kamdar","doi":"10.1182/bloodadvances.2025015935","DOIUrl":"https://doi.org/10.1182/bloodadvances.2025015935","url":null,"abstract":"<p><p>Anaplastic large cell lymphoma (ALCL) is a rare form of mature T-cell non-Hodgkin lymphoma. In pediatric patients, the majority of cases are Anaplastic Lymphoma Kinase (ALK)-positive. Despite intensive multi-agent chemotherapy regimens, treatment failure rates remain at 25-30%. Recent advancements in targeted therapies, notably ALK inhibitors and the anti-CD30 antibody-drug conjugate brentuximab vedotin, have demonstrated substantial activity in relapsed and refractory settings. Molecular detection of minimal disseminated disease (MDD) and minimal residual disease (MRD) offer improved prognostic stratification. For patients with relapsed or refractory disease, targeted therapies have increased treatment options, but more work needs to be done to define optimal treatment regimens, duration, and need for hematopoietic stem cell transplantation in this group. Immune therapies such as checkpoint inhibitors or Chimeric Antigen Receptor T-cell therapy provide additional therapeutic options. Incorporating targeted therapies and MDD/MRD assessments into clinical trials could significantly improve outcomes for pediatric and adolescent patients with ALCL.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144681972","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":"Can baseline Cytomegalovirus IgG titers predict Cytomegalovirus reactivation after ide-cel therapy?","authors":"Taku Kikuchi, Ukyo Kondo, Shotaro Sugita, Miyu Watanabe, Chiaki Matsumoto, Moe Yogo, Kodai Kunisada, Haruka Sawada, Kota Sato, Tomomi Takei, Mizuki Ogura, Yu Abe, Kenshi Suzuki, Osamu Hosoya, Tadao Ishida, Nobuhiro Tsukada","doi":"10.1182/bloodadvances.2025017174","DOIUrl":"https://doi.org/10.1182/bloodadvances.2025017174","url":null,"abstract":"","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144658484","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":"High-grade B-cell lymphoma, not otherwise specified: an LLMPP study.","authors":"Brett J Collinge, Laura K Hilton, Jasper Chun Hei Wong, Waleed Alduaij, Susana Ben-Neriah, Graham W Slack, Pedro Farinha, Merrill Boyle, Barbara Meissner, James R Cook, German Ott, Andreas Rosenwald, Elías Campo, Catalina Amador, Timothy C Greiner, Philipp W Raess, Joo Y Song, Giorgio Ga Inghirami, Sarah L Ondrejka, Elaine S Jaffe, Dennis D Weisenburger, Wing C Chan, Harald Holte, Klaus Beiske, Kai Fu, Jan Delabie, Stefania Pittaluga, Javeed Iqbal, George Wright, Kerry J Savage, Andrew J Mungall, Louis M Staudt, Christian Steidl, Andrew L Feldman, Ryan D Morin, Lisa M Rimsza, David W Scott","doi":"10.1182/bloodadvances.2025016651","DOIUrl":"10.1182/bloodadvances.2025016651","url":null,"abstract":"<p><p>Molecular characterization of high-grade B-cell lymphoma, not otherwise specified (HGBCL-NOS), is hindered by its rarity, evolving definition, and poor diagnostic reproducibility. To address this challenge, we analyzed 92 HGBCL-NOS tumors collected across Lymphoma/Leukemia Molecular Profiling Project sites. Leveraging comparison cohorts of diffuse large B-cell lymphoma (DLBCL-NOS) and Burkitt lymphoma (BL), and molecular frameworks described in these entities, our analysis revealed a heterogenous molecular landscape, reminiscent of DLBCL-NOS but with an enrichment of BL features. By cell-of-origin, 59% were germinal center B-cell-like (GCB), and 25% were activated B-cell-like (ABC). LymphGen, a genetic classifier for DLBCL-NOS, assigned a genetic subtype to 34% of HGBCL-NOS. Although classification rate was lower than in DLBCL-NOS (66%), assigned subtypes spanned the spectrum of LymphGen classes, including 31% of ABCs classified as MCD. Features differentiating HGBCL-NOS from DLBCL-NOS included MYC-rearrangement (47% vs. 6%), dark zone signature (DZsig) expression (45% vs. 7%), and more frequent mutation of ID3, MYC, CCND3, and TP53 - all common to BL. A genetic classifier that differentiates DLBCL-NOS from BL classified 53% of DZsig+ tumors as BL-like, with those classified as DLBCL-like frequently BCL2-rearranged. Among DZsig- GCB tumors, 95% were DLBCL-like. Centralized pathology review reclassified almost half of tumors as DLBCL-NOS but did not identify a more homogenous HGBCL-NOS population, with no difference in features between confirmed and reclassified tumors. In conclusion, molecular testing enables a subset of HGBCL-NOS to be assigned to established categories. Based on rarity and diagnostic challenges, broader inclusion of HGBCL-NOS should be considered in biomarker-driven DLBCL trials.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144658486","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":"Interferon gamma rebalances immunopathological signatures in Chronic Granulomatous Disease through metabolic rewiring.","authors":"Mariolina Bruno, Charlotte Kröger, Anaísa V Ferreira, Bowen Zhang, Rutger J Röring, Ruiqi Liu, Caspar I van der Made, Norman van Rhijn, Lazslo Groh, Viola Klück, Nico A F Janssen, Wenchao Li, Diletta Rosati, Ahmed Alaswad, Helin Tercan, Jorge Saiz, Carolina Gonzalez-Riano, Martina van Uelft, Orsi Gaal, Sophie Müller, Humberto J Ferreira, Stefanie Warnat-Herresthal, Matthias Becker, Lisa Holsten, Michael Kraut, Jonas Schulte-Schrepping, Lorenzo Bonaguro, Kristian Händler, Cristina Cunha, Manfred Schmolz, Joachim L Schultze, Leo Joosten, Coral Barbas, Mihai G Netea, Yang Li, Anna C Aschenbrenner, Agostinho Carvalho, Frank L van de Veerdonk","doi":"10.1182/bloodadvances.2025016213","DOIUrl":"https://doi.org/10.1182/bloodadvances.2025016213","url":null,"abstract":"<p><p>Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by recurrent life-threatening infections and hyperinflammatory complications. It is caused by mutations in the NADPH oxidase complex and the consequent loss of reactive oxygen species (ROS) production. Recombinant human interferon gamma (rIFN-γ) prophylaxis reduces the risk of severe infections, but the mechanisms behind its efficacy in CGD are still an open question, as it does not restore NADPH oxidase-dependent ROS production. Here, we show that innate immune cells of CGD patients are transcriptionally and functionally reprogrammed to a hyperactive inflammatory status, displaying an impaired in vitro induction of trained immunity. CGD monocytes have reduced intracellular amino acids concentrations and profound functional metabolic defects, both at the level of glycolysis and mitochondrial respiration. Ex vivo and in vivo treatment with IFN-γ restored these metabolic defects and reduced excessive IL-1β and IL-6 production in response to fungal stimuli in CGD monocytes. These data suggest that prophylactic rIFN-γ modulates the metabolic status of innate immune cells in CGD. These data shed light on the effects of NADPH-oxidase-derived ROS deficiency to the metabolic programs of immune cells and pose the basis for targeting this immunometabolic axis, potentially beyond CGD, with IFN-γ immunotherapy.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144658489","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":"Dual targeting of G9a and DNMTs induces anti-tumour effects in multiple myeloma.","authors":"Patrick William Nylund, Berta Garrido-Zabala, Stefania Iliana Tziola, Tabassom Mohajershojai, Hanna Berglund, Catharina Muylaert, Lien Ann Van Hemelrijck, Alba Atienza Párraga, Louella Vasquez, Jim Jacob, Eric Bergquist, José-Ignacio Martín-Subero, Fredrik Öberg, Torbjörn Karlsson, Marika Nestor, Elke De Bruyne, Antonia Kalushkova, Helena Jernberg-Wiklund","doi":"10.1182/bloodadvances.2023010571","DOIUrl":"https://doi.org/10.1182/bloodadvances.2023010571","url":null,"abstract":"<p><p>Multiple myeloma (MM) is a haematological disease of the plasma cell that remains clinically challenging despite the development of novel therapies. Epigenetic alterations have been demonstrated to contribute to MM pathogenesis, yet comprehensive studies into the links between different epigenetic regulatory systems in myeloma progression and drug resistance though clinically relevant, are largely lacking. G9a and the DNMTs are epigenetic modifiers that exhibit increased activity in MM, correlating with poor prognosis. To investigate the partnership between G9a and DNMTs, we used a combinatorial treatment approach involving small molecule inhibitors. In-depth molecular analysis of the H3K9me2 distribution, the DNA methylome and the transcriptome of MM revealed a silencing mechanism involving G9a and DNMTs, that represses key tumour suppressor genes. Moreover, dual inhibition of G9a and DNMTs reduced cell viability in primary MM cells and induced apoptosis in MM cell lines. This was accompanied by increased expression of apoptosis-related genes and decreased protein levels of the MM-associated oncoproteins IRF4, XBP1, and MYC. To assess the translational relevance of our in vitro findings, we evaluated the combination therapy in an in vivo preclinical xenograft MM model. Specifically, we demonstrate that the G9a inhibitor A366 synergize with the DNMTs inhibitor Decitabine to promote a robust tumour regression in vivo. Together, these data provide new insights into the cooperative role of G9a and the DNMTs in regulating gene silencing in MM and support dual epigenetic inhibition as a promising therapeutic strategy.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144658485","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":"Ibrutinib plus rituximab versus ibrutinib monotherapy in patients with Waldenström macroglobulinemia: A pooled analysis.","authors":"Alberto Guijosa, Andres Ramirez-Gamero, Shayna Sarosiek, Andrew R Branagan, Gottfried von Keudell, Steven P Treon, Jorge J Castillo","doi":"10.1182/bloodadvances.2025016536","DOIUrl":"https://doi.org/10.1182/bloodadvances.2025016536","url":null,"abstract":"<p><p>Ibrutinib monotherapy (I) and ibrutinib plus rituximab (I+R) are highly efficacious in treating Waldenström Macroglobulinemia (WM). However, the benefit of adding rituximab remains unclear, and a prospective trial to compare these two regimens has not been undertaken. Therefore, we performed a pooled analysis of prospective studies to compare their effectiveness. Patient-level demographic, response, and survival data were pooled from three prospective studies (NCT01614821, NCT02604511, NCT02165397). We included patients treated with I+R or I, excluding those without MYD88 mutations. Among 174 patients (58 I+R, 116 I), very good partial response (VGPR) rates were comparable across treatment groups (38% I+R vs. 28% I, p=0.21). The 48-month progression-free survival (PFS) rate was 74% with I+R versus 61% with I (p=0.22), and the 48-month overall survival (OS) rate was 94% versus 89% (p=0.45). In patients with CXCR4 mutations, I+R trended toward higher VGPR (27% vs. 11%; p=0.10) and had a superior 48-month PFS rate (72% vs. 43%; p=0.03). CXCR4 mutations were associated with inferior VGPR (42% vs. 17%; p=0.001) and 48-month PFS in the I arm (43% vs. 72%; p=0.002). In the I+R arm, CXCR4 mutations were associated with numerically inferior VGPR (47% vs. 27%; p=0.12), but the 48-month PFS rate was not impacted (74% vs. 72%; p=0.96). I+R significantly improved PFS over I in patients with CXCR4-mutated WM, along with a non-significant increase in VGPR in this subgroup. These results support routine CXCR4 testing in patients with WM and clinical trials of rituximab with covalent or non-covalent BTK inhibitors.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144658487","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":"In vivo CRISPR screening reveals cooperation of KMT2D and TP53 deficiencies in B-cell lymphomagenesis.","authors":"Kentaro Yamaguchi, Junji Koya, Kota Mizuno, Yosuke Mizukami, Kota Yoshifuji, Yuki Saito, Mariko Tabata, Sumito Shingaki, Mitsuhiro Yuasa, Yuta Ito, Kazutaka Nakashima, Kostiantyn Dreval, Ryan D Morin, Kenichi Chiba, Ai Okada, Yuichi Shiraishi, Koichi Murakami, Yasunori Kogure, Koichi Ohshima, Keisuke Kataoka","doi":"10.1182/bloodadvances.2024015519","DOIUrl":"https://doi.org/10.1182/bloodadvances.2024015519","url":null,"abstract":"<p><p>Although recent genetic studies have identified numerous genetic alterations in diffuse large B-cell lymphoma (DLBCL), their biological relevance remains elusive. Here we performed in vivo CRISPR loss-of-function screening targeting 86 genes recurrently altered in DLBCL to examine oncogenicity of sgRNA-targeted genes, association between genotype and lineage, occurrence of second-hit alterations, and cooperability among sgRNA-targeted genes and second-hit alterations. Transplantation of the CRISPR library-transduced hematopoietic stem/progenitor cells induces various hematologic malignancies, including B-lymphomas in mice. Enrichment analysis of sgRNA-targeted genes demonstrates significant overrepresentation of Kmt2d, Pax5, and Trp53 in B-lymphomas. Whole-exome sequencing identifies recurrent second-hit driver alterations, showing significant enrichment of Trp53 alterations in sgKmt2d-targeted B-lymphomas. Importantly, KMT2D and TP53 mutations are found to be the most prevalent co-occurring combination in human DLBCL, which is more prominent in relapsed/refractory DLBCL. Moreover, this combination confers significantly worse prognosis independent of clinical factors. Transcriptomic sequencing identifies overexpression of Yap1, the Hippo pathway component, in double sgKmt2d-targeted/Trp53-altered B-lymphomas. Furthermore, chromatin accessibility analysis demonstrates enrichment of TEAD1 binding motifs in regions that gained accessibility and increased expression of their nearest genes in these B-lymphomas. Most importantly, genetic and pharmacological inhibition of YAP1 suppresses in vitro cell proliferation and in vivo tumor growth of a human KMT2D/TP53-altered DLBCL cell line and prolongs survival of mice transplanted with double sgKmt2d-targeted/Trp53-altered B-lymphoma cells. Our findings demonstrate the utility of in vivo CRISPR screening to integrate human cancer genomics with mouse modeling, and highlight the functional interplay between KMT2D and TP53 aberrations, providing insights into therapeutic strategies in DLBCL.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144658488","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":"Long term follow-up of patients with AL amyloidosis treated on a phase 1 trial of CAEL-101.","authors":"Michael Sang Hughes, Samuel S Pan, Rajshekhar Chakraborty, Jayant Raikhelkar, Mathew S Maurer, Markus Y Mapara, Andrew Eisenberger, Suzanne Lentzsch, Divaya Bhutani","doi":"10.1182/bloodadvances.2025016731","DOIUrl":"https://doi.org/10.1182/bloodadvances.2025016731","url":null,"abstract":"","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144658490","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":"The Efficacy of Teclistamab in Multiple Myeloma Patients with Secondary Plasma Cell Leukemia.","authors":"Asis Shrestha, Sharmilan Thanendrarajan, Aishee Bag, Binod Dhakal, Maurizio Zangari, Samer Al Hadidi, Frits van Rhee, Anita D'Souza, Nishi Shah, Mansi R Shah, Meera Mohan, Carolina Schinke","doi":"10.1182/bloodadvances.2025016695","DOIUrl":"https://doi.org/10.1182/bloodadvances.2025016695","url":null,"abstract":"","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144658494","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}