Blood最新文献

{"title":"Sequential epigenetic therapy in AML.","authors":"Yuanting Wang, Christopher R Vakoc","doi":"10.1182/blood.2024026916","DOIUrl":"https://doi.org/10.1182/blood.2024026916","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"145 7","pages":"660-661"},"PeriodicalIF":21.0,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143405485","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":"Mosunetuzumab next up to bat … is it a home run?","authors":"Reem Karmali, Jane N Winter","doi":"10.1182/blood.2024027223","DOIUrl":"https://doi.org/10.1182/blood.2024027223","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"145 7","pages":"655-657"},"PeriodicalIF":21.0,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143405573","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":"Unraveling MCL biology to understand resistance and identify vulnerabilities.","authors":"Clémentine Sarkozy, Benoit Tessoulin, David Chiron","doi":"10.1182/blood.2023022351","DOIUrl":"10.1182/blood.2023022351","url":null,"abstract":"<p><strong>Abstract: </strong>Mantle cell lymphoma (MCL) is a rare (5%-7%), aggressive B-cell non-Hodgkin lymphoma with well-defined hallmarks (eg, cyclin D1, SOX11), and its expansion is highly dependent on the tumor microenvironment (TME). Parallel drastic progress in the understanding of lymphomagenesis and improved treatments led to a paradigm shift in this B-cell malignancy with now prolonged disease-free survival after intensive chemotherapy and anti-CD20-based maintenance. However, this toxic strategy is not applicable in frail or older patients, and a small but significant part of the cases present a refractory disease representing unmet medical needs. Importantly, the field has recently seen the rapid emergence of targeted and immune-based strategies with effective combinations relying on biological rationales to overcome malignant plasticity and intratumor heterogeneity. In this review, we expose how unraveling the biology of MCL allows to better understand the therapeutic resistances and to identify neo-vulnerabilities in tumors, which are essential to offer efficient novel strategies for high-risk patients. We first highlight the tumor intrinsic resistance mechanisms and associated Achilles heels within various pathways, such as NF-κB, mitochondrial apoptosis, DNA repair, and epigenetic regulators. We then place the tumor in its complex ecosystem to decipher the dialog with the multiple TME components and show how the resulting protumoral signals could be disrupted with innovative therapeutic strategies. Finally, we discuss how these progresses could be integrated into a personalized approach in MCL.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"696-707"},"PeriodicalIF":21.0,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140326377","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":"Treatment of relapsed/refractory MCL.","authors":"Elisabeth Silkenstedt, Martin Dreyling","doi":"10.1182/blood.2023022353","DOIUrl":"10.1182/blood.2023022353","url":null,"abstract":"<p><strong>Abstract: </strong>Mantle cell lymphoma (MCL) is a rare subtype of B-cell non-Hodgkin lymphoma that is clinically characterized by its heterogeneous behavior, with courses ranging from indolent to highly aggressive cases with limited prognosis. Targeted treatment alternatives in first-line and relapse settings are more and more shaping the therapeutic landscape of MCL. The development and implementation of new targeted and immunotherapeutic approaches have already improved outcomes for patients with MCL with refractory or relapsed disease. However, long-term prognosis is still limited, and patients with relapsed/refractory (R/R) disease, especially those failing Bruton tyrosine kinase (BTK) inhibitor treatment, usually have a dismal outcome. This review summarizes the current and emerging treatment options for R/R MCL, focusing on the implementation of combined targeted treatment strategies such as BTK inhibitors and BCL2 inhibitors, as well as immune-therapeutic approaches including chimeric antigen receptor T cells and bispecific antibodies.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"673-682"},"PeriodicalIF":21.0,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141765368","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":"Heme promotes venetoclax resistance in multiple myeloma through MEK-ERK signaling and purine biosynthesis.","authors":"Remya Nair, An H Vu, Abigail K Freer, Karanpreet S Bhatia, Dongxue Wang, Milan R Savani, Shannon M Matulis, Sagar Lonial, David L Jaye, Lawrence H Boise, Seung-Yong Seo, Timothy W Corson, Ajay K Nooka, Shruti Bhatt, Samuel K McBrayer, Vikas A Gupta, Xin Hu, Benjamin G Barwick, Amit R Reddi, Mala Shanmugam","doi":"10.1182/blood.2024025690","DOIUrl":"10.1182/blood.2024025690","url":null,"abstract":"<p><strong>Abstract: </strong>We previously demonstrated that reduced intrinsic electron transport chain (ETC) activity predicts and promotes sensitivity to the B-cell lymphoma 2 (BCL-2) antagonist, venetoclax (Ven), in multiple myeloma (MM). Heme, an iron-containing prosthetic group and metabolite, is fundamental to maintaining ETC activity. Interrogation of the cyclin D1 group 2 subgroup of MM from the Relating Clinical Outcomes in MM to Personal Assessment of Genetic Profile (CoMMpass) trial (NCT01454297), which can be used as a proxy for Ven-sensitive MM (VS MM), shows reduced expression of the conserved heme biosynthesis pathway gene signature. Consistent with this, we identified that VS MM exhibits reduced heme biosynthesis and curiously elevated hemin (oxidized heme) uptake. Supplementation with hemin or protoporphyrin IX (heme lacking iron) promotes Ven resistance, whereas targeting ferrochetalase, the penultimate enzyme involved in heme biosynthesis, increases Ven sensitivity in cell lines and primary MM cells. Mechanistically, heme-mediated activation of prosurvival rapidly accelerated fibrosarcoma-rat sarcoma virus-mitogen-activated protein kinase (MEK) signaling and metabolic rewiring, increasing de novo purine synthesis, were found to contribute to heme-induced Ven resistance. Cotargeting BCL-2 and myeloid cell leukemia-1 suppresses heme-induced Ven resistance. Interrogation of the Multiple Myeloma Research Foundation CoMMpass study of patients shows increased purine and pyrimidine biosynthesis to corelate with poor progression-free survival and overall survival. Elevated heme and purine biosynthesis gene signatures were also observed in matched relapse refractory MM, underscoring the relevance of heme metabolism in therapy-refractory MM. Overall, our findings reveal, for the first time, a role for extrinsic heme, a physiologically relevant metabolite, in modulating proximity to the apoptotic threshold with translational implications for BCL-2 antagonism in MM therapy.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"732-747"},"PeriodicalIF":21.0,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142852711","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":"Acute resistance to BET inhibitors remodels compensatory transcriptional programs via p300 coactivation.","authors":"Viral Shah, George Giotopoulos, Hikari Osaki, Markus Meyerhöfer, Eshwar Meduri, Aaron Gallego-Crespo, Malte A Behrendt, Maria Saura-Pañella, Aarti Tarkar, Benedict Schubert, Haiyang Yun, Sarah J Horton, Shuchi Agrawal-Singh, Patricia S Haehnel, Faisal Basheer, Dave Lugo, Ioanna Eleftheriadou, Olena Barbash, Arindam Dhar, Michael W M Kühn, Borhane Guezguez, Matthias Theobald, Thomas Kindler, Paolo Gallipoli, Paul Yeh, Mark A Dawson, Rab K Prinjha, Brian J P Huntly, Daniel Sasca","doi":"10.1182/blood.2022019306","DOIUrl":"10.1182/blood.2022019306","url":null,"abstract":"<p><strong>Abstract: </strong>Initial clinical trials with drugs targeting epigenetic modulators, such as bromodomain and extraterminal protein (BET) inhibitors, demonstrate modest results in acute myeloid leukemia (AML). A major reason for this involves an increased transcriptional plasticity within AML, which allows the cells to escape therapeutic pressure. In this study, we investigated the immediate epigenetic and transcriptional responses after BET inhibition and demonstrated that BET inhibitor-mediated release of bromodomain-containing protein 4 from chromatin is accompanied by acute compensatory feedback that attenuates downregulation or even increases the expression of specific transcriptional modules. This adaptation is marked at key AML maintenance genes and is mediated by p300, suggesting a rational therapeutic opportunity to improve outcomes by combining BET and p300 inhibition. p300 activity is required during all steps of resistance adaptation; however, the specific transcriptional programs that p300 regulates to induce resistance to BET inhibition differ, in part, between AML subtypes. As a consequence, in some AMLs, the requirement for p300 is highest during the earlier stages of resistance to BET inhibition, when p300 regulates transitional transcriptional patterns that allow leukemia-homeostatic adjustments. In other AMLs, p300 shapes a linear resistance to BET inhibition and remains critical throughout all stages of the evolution of resistance. Altogether, our study elucidates the mechanisms that underlie an \"acute\" state of resistance to BET inhibition, achieved through p300 activity, and how these mechanisms remodel to mediate \"chronic\" resistance. Importantly, our data also suggest that sequential treatment with BET and p300 inhibition may prevent resistance development, thereby improving outcomes.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"748-764"},"PeriodicalIF":21.0,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142799432","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":"Novel CAR T cells to combat antigen escape in AML.","authors":"Nadia El Khawanky","doi":"10.1182/blood.2024027364","DOIUrl":"https://doi.org/10.1182/blood.2024027364","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"145 7","pages":"657-658"},"PeriodicalIF":21.0,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143405536","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":"Heme fuels venetoclax resistance in multiple myeloma.","authors":"Mariateresa Fulciniti","doi":"10.1182/blood.2024027671","DOIUrl":"https://doi.org/10.1182/blood.2024027671","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"145 7","pages":"658-660"},"PeriodicalIF":21.0,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143405566","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":"Frontline management of mantle cell lymphoma.","authors":"Christine E Ryan, Philippe Armand, Ann S LaCasce","doi":"10.1182/blood.2023022352","DOIUrl":"10.1182/blood.2023022352","url":null,"abstract":"<p><strong>Abstract: </strong>Despite many recent therapeutic advances, mantle cell lymphoma (MCL) remains a largely incurable disease. Treatments for patients with relapsed/refractory (R/R) disease are limited in number and in response durability. Therefore, improving the efficacy of frontline (1L) treatment, and specifically maximizing the duration of first remission, remains of critical importance to obtain favorable long-term outcomes. As 1L treatments become more effective, improving tolerability is also becoming an increasingly realistic goal. Targeted agents, which are now mainstays of treatment in R/R MCL, are establishing new, paradigm-changing roles in frontline treatment. Here, we review data supporting current standard-of-care approaches and explore 6 main areas of possible focus for advancement of 1L management: optimizing the chemoimmunotherapy (CIT) backbone, adding targeted agents to CIT, redefining the role of autologous stem cell transplantation, improving maintenance therapy, using targeted agent combinations with omission of CIT, and using measurable residual disease-guided therapy. We highlight several ongoing phase 3 trials that may soon impact frontline MCL management, and outline some areas of necessary investigation as the field continues to strive toward a cure for this disease.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"663-672"},"PeriodicalIF":21.0,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140159878","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":"Ferroptosis regulates hemolysis in stored murine and human red blood cells.","authors":"Angelo D'Alessandro, Gregory R Keele, Ariel Hay, Travis Nemkov, Eric J Earley, Daniel Stephenson, Matthew Vincent, Xutao Deng, Mars Stone, Monika Dzieciatkowska, Kirk C Hansen, Steven Kleinman, Steven L Spitalnik, Nareg Roubinian, Philip J Norris, Michael P Busch, Grier P Page, Brent R Stockwell, Gary A Churchill, James C Zimring","doi":"10.1182/blood.2024026109","DOIUrl":"10.1182/blood.2024026109","url":null,"abstract":"<p><strong>Abstract: </strong>Red blood cell (RBC) metabolism regulates hemolysis during aging in vivo and in the blood bank. However, the genetic underpinnings of RBC metabolic heterogeneity and extravascular hemolysis at population scale are incompletely understood. On the basis of the breeding of 8 founder strains with extreme genetic diversity, the Jackson Laboratory diversity outbred population can capture the impact of genetic heterogeneity in like manner to population-based studies. RBCs from 350 outbred mice, either fresh or stored for 7 days, were tested for posttransfusion recovery, as well as metabolomics and lipidomics analyses. Metabolite and lipid quantitative trait loci (QTL) mapped >400 gene-metabolite associations, which we collated into an online interactive portal. Relevant to RBC storage, we identified a QTL hotspot on chromosome 1, mapping on the region coding for the ferrireductase 6-transmembrane epithelial antigen of the prostate 3 (Steap3), a transcriptional target to p53. Steap3 regulated posttransfusion recovery, contributing to a ferroptosis-like process of lipid peroxidation, as validated via genetic manipulation in mice. Translational validation of murine findings in humans, STEAP3 polymorphisms were associated with RBC iron content, lipid peroxidation, and in vitro hemolysis in 13 091 blood donors from the Recipient Epidemiology and Donor Evaluation Study. QTL analyses in humans identified a network of gene products (fatty acid desaturases 1 and 2, epoxide hydrolase 2, lysophosphatidylcholine acetyl-transferase 3, solute carrier family 22 member 16, glucose 6-phosphate dehydrogenase, very long chain fatty acid elongase, and phospholipase A2 group VI) associated with altered levels of oxylipins. These polymorphisms were prevalent in donors of African descent and were linked to allele frequency of hemolysis-linked polymorphisms for Steap3 or p53. These genetic variants were also associated with lower hemoglobin increments in thousands of single-unit transfusion recipients from the vein-to-vein database.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"765-783"},"PeriodicalIF":21.0,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142614268","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}