Blood最新文献

{"title":"Failure of metabolic checkpoint control during late-stage granulopoiesis drives neutropenia in reticular dysgenesis.","authors":"Wenqing Wang, Martin Arreola, Thomas Mathews, Andrew DeVilbiss, Zhiyu Zhao, Misty Martin-Sandoval, Abdulvasey Mohammed, Giorgia Benegiamo, Avni Awani, Ludger Goeminne, Daniel Dever, Yusuke Nakauchi, Matthew H Porteus, Mara Pavel-Dinu, Waleed Al-Herz, Johan Auwerx, Sean J Morrison, Katja G Weinacht","doi":"10.1182/blood.2024024123","DOIUrl":"10.1182/blood.2024024123","url":null,"abstract":"<p><strong>Abstract: </strong>Cellular metabolism is highly dynamic during hematopoiesis, yet the regulatory networks that maintain metabolic homeostasis during differentiation are incompletely understood. Herein, we have studied the grave immunodeficiency syndrome reticular dysgenesis caused by loss of mitochondrial adenylate kinase 2 (AK2) function. By coupling single-cell transcriptomics in samples from patients with reticular dysgenesis with a CRISPR model of this disorder in primary human hematopoietic stem cells, we found that the consequences of AK2 deficiency for the hematopoietic system are contingent on the effective engagement of metabolic checkpoints. In hematopoietic stem and progenitor cells, including early granulocyte precursors, AK2 deficiency reduced mechanistic target of rapamycin (mTOR) signaling and anabolic pathway activation. This conserved nutrient homeostasis and maintained cell survival and proliferation. In contrast, during late-stage granulopoiesis, metabolic checkpoints were ineffective, leading to a paradoxical upregulation of mTOR activity and energy-consuming anabolic pathways such as ribonucleoprotein synthesis in AK2-deficient cells. This caused nucleotide imbalance, including highly elevated adenosine monophosphate and inosine monophosphate levels, the depletion of essential substrates such as NAD+ and aspartate, and ultimately resulted in proliferation arrest and demise of the granulocyte lineage. Our findings suggest that even severe metabolic defects can be tolerated with the help of metabolic checkpoints but that the failure of such checkpoints in differentiated cells results in a catastrophic loss of homeostasis.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"2718-2734"},"PeriodicalIF":21.0,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142387919","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":"Venetoclax dose escalation rapidly activates a BAFF/BCL-2 survival axis in chronic lymphocytic leukemia.","authors":"Meng-Xiao Luo, Tania Tan, Marie Trussart, Annika Poch, Thi Minh Hanh Nguyen, Terence P Speed, Damien G Hicks, Esther Bandala-Sanchez, Hongke Peng, Stéphane Chappaz, Charlotte Slade, Daniel T Utzschneider, Rachel M Koldej, David Ritchie, Andreas Strasser, Rachel Thijssen, Matthew E Ritchie, Constantine S Tam, Geoffrey J Lindeman, David C S Huang, Thomas E Lew, Mary Ann Anderson, Andrew W Roberts, Charis E Teh, Daniel H D Gray","doi":"10.1182/blood.2024024341","DOIUrl":"10.1182/blood.2024024341","url":null,"abstract":"<p><strong>Abstract: </strong>Venetoclax, a first-in-class BH3 mimetic drug that targets B-cell lymphoma-2 (BCL-2), has improved the outcomes of patients with chronic lymphocytic leukemia (CLL). Early measurements of the depth of the venetoclax treatment response, assessed by minimal residual disease, are strong predictors of long-term clinical outcomes. However, there are limited data on the early changes induced by venetoclax treatment that might inform strategies to improve responses. To address this gap, we conducted longitudinal mass cytometric profiling of blood cells from patients with CLL during the first 5 weeks of venetoclax monotherapy. At baseline, we resolved CLL heterogeneity at the single-cell level to define multiple subpopulations in all patients based on proliferative, metabolic, and cell survival proteins. Venetoclax induced a significant reduction in all CLL subpopulations and caused rapid upregulation of the prosurvival BCL-2, BCL-extra large, and mantle cell lymphoma-1 proteins in surviving cells, which had reduced sensitivity to the drug. In mouse models, the venetoclax-induced elevation of survival proteins in B cells and CLL-like cells that persisted was recapitulated, and genetic models demonstrated that extensive apoptosis and access to the B-cell cytokine, B-cell activating factor (BAFF), were essential. Accordingly, in patients with CLL who were treated with venetoclax or the anti-CD20 antibody obinutuzumab there was marked elevation in BAFF and an increase in prosurvival proteins in leukemic cells that persisted. Overall, these data highlight the rapid adaptation of CLL cells to targeted therapies through homeostatic factors and support cotargeting of cytokine signals to achieve deeper and more durable long-term responses.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"2748-2761"},"PeriodicalIF":21.0,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543583","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":"Stage-specific tuning of granulopoiesis by AK2.","authors":"Julia Skokowa,Maksim Klimiankou","doi":"10.1182/blood.2024026717","DOIUrl":"https://doi.org/10.1182/blood.2024026717","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"122 1","pages":"2686-2688"},"PeriodicalIF":20.3,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142887480","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":"An ALPINE guide to covalent BTKis in CLL.","authors":"Stephen P Mulligan","doi":"10.1182/blood.2024026812","DOIUrl":"https://doi.org/10.1182/blood.2024026812","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"144 26","pages":"2685-2686"},"PeriodicalIF":21.0,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892062","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":"Masthead Subscription","authors":"","doi":"10.1016/s0006-4971(24)11183-4","DOIUrl":"https://doi.org/10.1016/s0006-4971(24)11183-4","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"35 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142939856","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":"Non-V600E BRAF mutations and treatment for Hairy Cell Leukemia.","authors":"Evgeny Arons, Chin-Hsien Tai, Joshi Suraj, Yuelin Liu, Chi-Ping Day, Mark Raffeld, Liqiang Xi, Mory Gould, Isaac David Shpilman, Christopher C Oakes, Seema Ali Bhat, Michael Rhodes Grever, Daniel Jones, Kerry A Rogers, Hao-Wei Wang, Constance M Yuan, S Cenk Sahinalp, Robert J Kreitman","doi":"10.1182/blood.2024026894","DOIUrl":"https://doi.org/10.1182/blood.2024026894","url":null,"abstract":"<p><p>We found 18 patients with immunophenotype consistent with classic hairy cell leukemia (HCL) and BRAF mutations other than just V600E. Twelve had 1 non-V600E BRAF mutation and 6 had V600E with 1 (n=5) or 2 (n=1) non-V600E BRAF co-mutations.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142885130","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":"Menin inhibitors in the treatment of acute myeloid leukemia.","authors":"Gerwin A Huls, Carolien M Woolthuis, Jan Jacob Schuringa","doi":"10.1182/blood.2024026232","DOIUrl":"https://doi.org/10.1182/blood.2024026232","url":null,"abstract":"<p><p>Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by the (oligo)clonal expansion of myeloid progenitor cells. Despite advances in treatment, AML remains challenging to cure, particularly in patients with specific genetic abnormalities. Menin inhibitors have emerged as a promising therapeutic approach, targeting key genetic drivers of AML such as KMT2A rearrangements and NPM1 mutations. Here, we review the clinical value of menin inhibitors, highlighting their mechanism of action, efficacy, safety, and potential to transform AML treatment.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142885126","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":"How I Treat AML relapse after allogeneic HCT.","authors":"Mahasweta Gooptu, H Moses Murdock, Robert J Soiffer","doi":"10.1182/blood.2024025705","DOIUrl":"https://doi.org/10.1182/blood.2024025705","url":null,"abstract":"<p><p>Allogeneic hematopoietic stem-cell transplantation (HCT) is one of the principal curative approaches in the treatment of acute myeloid leukemia (AML); however, relapse post-transplantation remains a catastrophic event with poor prognosis. The incidence of relapse has remained unchanged over the last three decades despite an evolving understanding of the immunobiology of the graft-versus leukemia effect and the immune escape mechanisms that lead to post-HCT relapse. The approach to post-transplant relapse is highly individualized and is dictated both by disease biology and genomics as well as the patient's clinical status at the time of relapse and the interval between relapse and transplantation. With the help of three illustrative cases, we discuss our approach to early, late, and incipient relapse. Current therapeutic strategies incorporate immunosuppression taper when feasible, a variety of targeted and non-targeted chemotherapeutic agents and consolidative cellular therapies including donor lymphocyte infusions or a second allogeneic transplant. We then summarize evolving frontiers in the treatment and prognostication of relapse including the critical role of measurable residual disease. Finally, we emphasize enrollment on clinical trials and thoughtful discussions regarding goals of care and supporting frail patients as universal principles that should be incorporated in approaches to treatment of AML relapse post-transplantation.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142885123","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":"How to make transplanted stem cells feel at home.","authors":"Rafal Machowicz","doi":"10.1182/blood.2024026611","DOIUrl":"https://doi.org/10.1182/blood.2024026611","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"144 25","pages":"2564-2566"},"PeriodicalIF":21.0,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142852716","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":"CAR T-cells in autoimmunity: game changer or stepping stone?","authors":"Dimitrios Mougiakakos, Everett Meyer, Georg Schett","doi":"10.1182/blood.2024025413","DOIUrl":"https://doi.org/10.1182/blood.2024025413","url":null,"abstract":"<p><p>The advent of chimeric antigen receptor (CAR) T-cells has revolutionized the treatment landscape for hematologic malignancies, and emerging evidence suggests their potential in autoimmune diseases (AIDs). This article examines the early successes and future implications of B-cell-targeting CAR T-cell therapy in AIDs. Initial applications, particularly in refractory systemic lupus erythematosus (SLE), have demonstrated significant and durable clinical remissions, with accompanying evaluation of the immune system suggesting a so-called \"reset\" of innate inflammation and adaptive autoimmunity. This has generated widespread interest in expanding this therapeutic approach. CAR T-cells offer unique advantages over other treatment modalities, including very deep B-cell depletion and unique therapeutic activity within inflamed tissues and associated lymph structures. However, the field must address key concerns, including long-term toxicity, particularly the risk of secondary malignancies, and future accessibility given the higher prevalence of AIDs compared to malignancies. Technological advances in cell therapy, such as next-generation CAR T-cells, allogeneic off-the-shelf products and alternative cell types such as regulatory CAR T-cells, are being explored in AIDs to improve efficacy and safety. In addition, bispecific antibodies are emerging as potential alternatives or complements to CAR T-cells, potentially offering comparable efficacy without the need for complex logistics, lymphodepletion and the risk of insertional mutagenesis. As the field evolves, cellular therapists will play a critical role in the multidisciplinary teams managing these complex cases. The transformative potential of CAR T-cells in AIDs is undeniable, but careful consideration of safety, efficacy, and implementation is essential as this novel therapeutic approach moves forward.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142863345","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}