Seminars in hematology最新文献

{"title":"Special issue on chronic lymphocytic leukemia: Prognostication and therapeutic options introductory editorial","authors":"Barbara Eichhorst , Elisa ten Hacken","doi":"10.1053/j.seminhematol.2024.03.002","DOIUrl":"10.1053/j.seminhematol.2024.03.002","url":null,"abstract":"","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":"61 2","pages":"Pages 69-72"},"PeriodicalIF":3.6,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0037196324000556/pdfft?md5=8df5c206157416b9e199e1a6d6a9ad49&pid=1-s2.0-S0037196324000556-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140400955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transforming CLL management with immunotherapy: Investigating the potential of CAR T-cells and bispecific antibodies","authors":"Azra Borogovac,&nbsp;Tanya Siddiqi","doi":"10.1053/j.seminhematol.2024.01.001","DOIUrl":"10.1053/j.seminhematol.2024.01.001","url":null,"abstract":"<div><p><span><span>Immunotherapies<span><span>, such as chimeric antigen receptor (CAR) T-cell therapy and bispecific antibodies or T-cell engagers, have revolutionized the </span>treatment landscape for various B-cell </span></span>malignancies<span><span>, including B-acute lymphoblastic leukemia and many non-Hodgkin lymphomas. Despite their significant impact on these malignancies, their application in chronic lymphocytic leukemia (CLL) management is still largely under investigation. Although the initial success of CD19-directed CAR T-cell therapy was observed in 3 multiply relapsed CLL patients, with 2 of them surviving over 10 years without relapse, recent CAR T-cell therapy trials in CLL have shown reduced response rates compared to their efficacy in other B-cell malignancies. One of the challenges with using immunotherapy in CLL is the compromised T-cell fitness from persistent CLL-related antigenic stimulation, and an </span>immunosuppressive<span> tumor microenvironment<span> (TME). These challenges underscore a critical gap in therapeutic options for CLL patients intolerant or resistant to current therapies, emphasizing the imperative role of effective immunotherapy. Encouragingly, innovative strategies are emerging to overcome these challenges. These include integrating synergistic agents like ibrutinib to enhance CAR T-cell function and persistence and engineering newer CAR T-cell constructs targeting diverse antigens or employing dual-targeting approaches. Bispecific antibodies are an exciting \"off-the-shelf\" prospect for these patients, with their investigation in CLL currently entering the realm of </span></span></span></span>clinical trials. Additionally, the development of allogeneic CAR T-cells and natural killer (NK) cells from healthy donors presents a promising solution to address the diminished T-cell fitness observed in CLL patients. This comprehensive review delves into the latest insights regarding the role of immunotherapy in CLL, the complex landscape of resistance mechanisms, and a spectrum of innovative approaches to surmount therapeutic challenges.</p></div>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":"61 2","pages":"Pages 119-130"},"PeriodicalIF":3.6,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139376452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The molecular map of CLL and Richter's syndrome","authors":"Amit Sud ,&nbsp;Erin M. Parry ,&nbsp;Catherine J. Wu","doi":"10.1053/j.seminhematol.2024.01.009","DOIUrl":"10.1053/j.seminhematol.2024.01.009","url":null,"abstract":"<div><p>Clonal expansion of B-cells, from the early stages of monoclonal B-cell lymphocytosis through to chronic lymphocytic leukemia (CLL), and then in some cases to Richter's syndrome (RS) provides a comprehensive model of cancer evolution, notable for the marked morphological transformation and distinct clinical phenotypes. High-throughput sequencing of large cohorts of patients and single-cell studies have generated a molecular map of CLL and more recently, of RS, yielding fundamental insights into these diseases and of clonal evolution. A selection of CLL driver genes have been functionally interrogated to yield novel insights into the biology of CLL. Such findings have the potential to impact patient care through risk stratification, treatment selection and drug discovery. However, this molecular map remains incomplete, with extant questions concerning the origin of the B-cell clone, the role of the TME, inter- and intra-compartmental heterogeneity and of therapeutic resistance mechanisms. Through the application of multi-modal single-cell technologies across tissues, disease states and clinical contexts, these questions can now be addressed with the answers holding great promise of generating translatable knowledge to improve patient care.</p></div>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":"61 2","pages":"Pages 73-82"},"PeriodicalIF":3.6,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S003719632400009X/pdfft?md5=e6b68a13a1d84b6cd8bb87a533d2c797&pid=1-s2.0-S003719632400009X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139584477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clonal hematopoiesis in children with predisposing conditions","authors":"Enrico Attardi ,&nbsp;Seth J. Corey ,&nbsp;Marcin W. Wlodarski","doi":"10.1053/j.seminhematol.2024.01.005","DOIUrl":"10.1053/j.seminhematol.2024.01.005","url":null,"abstract":"<div><p>Clonal hematopoiesis in children and young adults differs from that occuring in the older adult population. A variety of stressors drive this phenomenon, sometimes independent of age-related processes. For the purposes of this review, we adopt the term clonal hematopoiesis in predisposed individuals (CHIPI) to differentiate it from classical, age-related clonal hematopoiesis of indeterminate potential (CHIP). Stress-induced CHIPI selection can be extrinsic, such as following immunologic, infectious, pharmacologic, or genotoxic exposures, or intrinsic, involving germline predisposition from inherited bone marrow failure syndromes. In these conditions, clonal advantage relates to adaptations allowing improved cell fitness despite intrinsic defects affecting proliferation and differentiation. In certain contexts, CHIPI can improve competitive fitness by compensating for germline defects; however, the downstream effects of clonal expansion are often unpredictable - they may either counteract the underlying pathology or worsen disease outcomes. A more complete understanding of how CHIPI arises in young people can lead to the definition of preleukemic states and strategies to assess risk, surveillance, and prevention to leukemic transformation. Our review summarizes current research on stress-induced clonal dynamics in individuals with germline predisposition syndromes.</p></div>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":"61 1","pages":"Pages 35-42"},"PeriodicalIF":3.6,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0037196324000064/pdfft?md5=4ec64461a4831e4dcae2bf65e1bfb1a1&pid=1-s2.0-S0037196324000064-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139470232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immune-driven clonal cell selection at the intersection among cancer, infections, autoimmunity and senescence","authors":"Simona Pagliuca ,&nbsp;Francesca Ferraro","doi":"10.1053/j.seminhematol.2024.01.002","DOIUrl":"10.1053/j.seminhematol.2024.01.002","url":null,"abstract":"<div><p>Immune surveillance mechanisms play a crucial role in maintaining lifelong immune homeostasis in response to pathologic stimuli and aberrant cell states. However, their persistence, especially in the context of chronic antigenic exposure, can create a fertile ground for immune evasion. These escaping cell phenotypes, harboring a variety of genomic and transcriptomic aberrances, chiefly in human leukocyte antigen (HLA) and antigen presentation machinery genes, may survive and proliferate, featuring a scenario of clonal cell expansion with immune failure characteristics. While well characterized in solid and, to some extent, hematological malignancies, little is known about their occurrence and significance in other disease contexts.</p><p>Historical literature highlights the role for escaping HLA-mediated recognition as a strategy adopted by virus to evade from the immune system, hinting at the potential for immune aberrant cell expansion in the context of chronic infections. Additionally, unmasked in idiopathic aplastic anemia as a mechanism able to rescue failing hematopoiesis, HLA clonal escape may operate in autoimmune disorders, particularly in tissues targeted by aberrant immune responses. Furthermore, senescent cell status emerging as immunogenic phenotypes stimulating T cell responses, may act as a bottleneck for the selection of such immune escaping clones, blurring the boundaries between neoplastic transformation, aging and inflammation. Here we provide a fresh overview and perspective on this immune-driven clonal cell expansion, linking pathophysiological features of neoplastic, autoimmune, infectious and senescence processes exposed to immune surveillance.</p></div>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":"61 1","pages":"Pages 22-34"},"PeriodicalIF":3.6,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0037196324000015/pdfft?md5=735f93d1eb51fc06c833a2ce8eddfcac&pid=1-s2.0-S0037196324000015-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139500726","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A tower of babel of acronyms? The shadowlands of MGUS/MBL/CHIP/TCUS","authors":"Carlos Bravo-Perez ,&nbsp;Carmelo Gurnari","doi":"10.1053/j.seminhematol.2024.01.004","DOIUrl":"10.1053/j.seminhematol.2024.01.004","url":null,"abstract":"<div><p>With the advent of outperforming and massive laboratory tools, such as multiparameter flow cytometry and next-generation sequencing, hematopoietic cell clones with putative abnormalities for a variety of blood malignancies have been appreciated in otherwise healthy individuals. These conditions do not fulfill the criteria of their presumed cancer counterparts, and thus have been recognized as their precursor states. This is the case of monoclonal gammopathy of unknown significance (MGUS), the first blood premalignancy state described, preceding multiple myeloma (MM) or Waldenström macroglobulinemia (WM). However, in the last 2 decades, an increasing list of clonopathies has been recognized, including monoclonal B cell lymphocytosis (MBL), which antecedes chronic lymphocytic leukemia (CLL), clonal hematopoiesis of indeterminate potential (CHIP) for myeloid neoplasms (MN), and T-cell clones of uncertain significance (TCUS) for T-cell large chronic lymphocytic leukemia (LGLL). While for some of these entities diagnostic boundaries are precisely set, for others these are yet to be fully defined. Moreover, despite mostly considered of “uncertain significance,” they have not only appeared to predispose to malignancy, but also to be capable of provoking set of immunological and cardiovascular complications that may require specialized management. The clinical implications of the aberrant clones, together with the extensive knowledge generated on the pathogenetic events driving their evolution, raises the question whether earlier interventions may alter the natural history of the disease. Herein, we review this Tower of Babel of acronyms pinpointing diagnostic definitions, differential diagnosis, and the role of genomic profiling of these precursor states, as well as potential interventional strategies.</p></div>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":"61 1","pages":"Pages 43-50"},"PeriodicalIF":3.6,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139509535","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TET2 mutation as prototypic clonal hematopoiesis lesion","authors":"Luca Guarnera ,&nbsp;Babal K. Jha","doi":"10.1053/j.seminhematol.2024.01.013","DOIUrl":"10.1053/j.seminhematol.2024.01.013","url":null,"abstract":"<div><p>Loss of function <em>TET2</em> mutation (<em>TET2^MT</em>) is one of the most frequently observed lesions in clonal hematopoiesis (CH). TET2 a member TET-dioxygenase family of enzymes that along with TET1 and TET3, progressively oxidize 5-methyl cytosine (mC) resulting in regulated demethylation of promoter, enhancer and silencer elements of the genome. This process is critical for efficient transcription that determine cell lineage fate, proliferation and survival and the maintenance of the genomic fidelity with aging of the organism. Partial or complete loss-of-function <em>TET2</em> mutations create regional and contextual DNA hypermethylation leading to gene silencing or activation that result in skewed myeloid differentiation and clonal expansion. In addition to myeloid skewing, loss of <em>TET2</em> creates differentiation block and provides proliferative advantage to hematopoietic stem and progenitor cells (HSPCs). <em>TET2^MT</em> is a prototypical lesion in CH, since the mutant clones dominate during stress hematopoiesis and often associates with evolution of myeloid malignancies. <em>TET2^MT</em> clones has unique privilege to create and persist in pro-inflammatory milieu. Despite extensive knowledge regarding biochemical mechanisms underlying distorted myeloid differentiation, and enhanced self-replication of <em>TET2^MT</em> HSPC, the mechanistic link of various pathogenesis associated with <em>TET2</em> loss in CHIP is less understood. Here we review the recent development in <em>TET2</em> biology and its probable mechanistic link in CH with aging and inflammation. We also explored the therapeutic strategies of targeting <em>TET2^MT</em> associated CHIP and the utility of targeting <em>TET2</em> in normal hematopoiesis and somatic cell reprograming. We explore the biochemical mechanisms and candidate therapies that emerged in last decade of research.</p></div>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":"61 1","pages":"Pages 51-60"},"PeriodicalIF":3.6,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139666291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"outside front cover, PMS 8883 metallic AND 4/C","authors":"","doi":"10.1053/S0037-1963(24)00040-4","DOIUrl":"https://doi.org/10.1053/S0037-1963(24)00040-4","url":null,"abstract":"","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":"61 1","pages":"Page CO1"},"PeriodicalIF":3.6,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140296055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clonal hematopoiesis in the setting of hematopoietic cell transplantation","authors":"Christopher J. Gibson ,&nbsp;R. Coleman Lindsley ,&nbsp;Lukasz P. Gondek","doi":"10.1053/j.seminhematol.2024.01.011","DOIUrl":"10.1053/j.seminhematol.2024.01.011","url":null,"abstract":"<div><p>Clonal hematopoiesis (CH) in autologous transplant recipients and allogeneic transplant donors has genetic features and clinical associations that are distinct from each other and from non-cancer populations. CH in the setting of autologous transplant is enriched for mutations in DNA damage response pathway genes and is associated with adverse outcomes, including an increased risk of therapy-related myeloid neoplasm and inferior overall survival. Studies of CH in allogeneic transplant donors have yielded conflicting results but have generally shown evidence of potentiated alloimmunity in recipients, with some studies showing an association with favorable recipient outcomes.</p></div>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":"61 1","pages":"Pages 9-15"},"PeriodicalIF":3.6,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139666719","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The crossroads of cancer therapies and clonal hematopoiesis","authors":"Abhay Singh ,&nbsp;Suresh Balasubramanian","doi":"10.1053/j.seminhematol.2024.01.006","DOIUrl":"10.1053/j.seminhematol.2024.01.006","url":null,"abstract":"<div><p>The intricate interplay between Clonal Hematopoiesis (CH) and the repercussions of cancer therapies has garnered significant research focus in recent years. Previously perceived as an age-related phenomenon, CH is now closely linked to inflammation (“Inflammaging”) and cancer, impacting leukemogenesis, cancer progression, and treatment responses. This review explores the complex interplay between CH and diverse cancer therapies, including chemotherapy, targeted treatments, radiation, stem cell transplants, CAR-T cell therapy, and immunotherapy, like immune checkpoint inhibitors. Notably, knowledge about post-chemotherapy CH mutation/acquisition has evolved from a <em>de novo</em> incident to more of a clonal selection process. Chemotherapy and radiation exposure, whether therapeutic or environmental, increases CH risk, particularly in genes like <em>TP53</em> and <em>PPM1D</em>. Environmental toxins, especially in high-risk environments like post-disaster sites or space exploration, are associated with CH. CH affects clinical outcomes in stem cell transplant scenarios, including engraftment, survival, and t-MN development. The presence of CH also alters CAR-T cell therapy responses and impacts the efficacy and toxicity of immunotherapies. Furthermore, specific mutations like <em>DNMT3A</em> and <em>TET2</em> thrive under inflammatory stress, influencing therapy outcomes and justifying the ongoing tailored interventions in clinical trials. This review underscores the critical need to integrate CH analysis into personalized medicine, enhancing risk assessments and refining treatment strategies. As we progress, multidisciplinary collaboration and comprehensive studies are imperative. Understanding CH's impact, especially concerning genotoxic stressors, will inform screening, surveillance, and early detection strategies, decreasing the risk of therapy-related myeloid neoplasms and revolutionizing cancer treatment paradigms.</p></div>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":"61 1","pages":"Pages 16-21"},"PeriodicalIF":3.6,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0037196324000076/pdfft?md5=9ebeaac0cb20f6a2472ddf443fbcff2c&pid=1-s2.0-S0037196324000076-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139500978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}