{"title":"TET2 mutation as prototypic clonal hematopoiesis lesion","authors":"Luca Guarnera , 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<sup>MT</sup></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<sup>MT</sup></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<sup>MT</sup></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<sup>MT</sup></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<sup>MT</sup></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}
Christopher J. Gibson , R. Coleman Lindsley , Lukasz P. Gondek
{"title":"Clonal hematopoiesis in the setting of hematopoietic cell transplantation","authors":"Christopher J. Gibson , R. Coleman Lindsley , 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 , 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}
{"title":"Germline predisposition for clonal hematopoiesis","authors":"Yasuo Kubota , Aaron D. Viny","doi":"10.1053/j.seminhematol.2024.01.007","DOIUrl":"10.1053/j.seminhematol.2024.01.007","url":null,"abstract":"<div><p><span><span>Clonal hematopoiesis (CH) is an entity hallmarked by skewed hematopoiesis with persistent overrepresentation of cells from a common stem/progenitor lineage harboring single-nucleotide variants and/or insertions/deletions. CH is a common and age-related phenomenon that is associated with an increased risk of </span>hematological malignancies, cardiovascular disease, and all-cause mortality. While CH is a term of the hematological aspect, there exists a complex interaction with other organ systems, especially the cardiovascular system. The strongest factor in the development of CH is aging, however, other multiple factors also affect the development of CH including lifestyle-related factors and co-morbid diseases. In recent years, germline </span>genetic factors have been linked to CH risk. In this review, we synthesize what is currently known about how genetic variation affects the risk of CH, how this genetic architecture intersects with myeloid neoplasms, and future prospects for CH.</p></div>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":"61 1","pages":"Pages 61-67"},"PeriodicalIF":3.6,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139475175","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}
Ashwin Kishtagari , Robert W. Corty , Valeria Visconte
{"title":"Clonal hematopoiesis and autoimmunity","authors":"Ashwin Kishtagari , Robert W. Corty , Valeria Visconte","doi":"10.1053/j.seminhematol.2024.01.012","DOIUrl":"10.1053/j.seminhematol.2024.01.012","url":null,"abstract":"<div><p>Clonal hematopoiesis (CH) has been associated with aging, occurring in about 10% of individuals aged >70 years, and immune dysfunction. Aged hematopoietic stem and progenitor cells exhibit pathological changes in immune function and activation of inflammatory pathways. CH clones commonly harbor a loss of function mutation in <em>DNMT3A</em> or <em>TET2</em>, which causes increased expression of inflammatory signaling genes, a proposed mechanism connected to CH and the development of age-related diseases. Additionally, inflammation may stress the hematopoietic compartment, driving the expansion of mutant clones. While the epidemiologic overlap between CH, hematologic malignancies, and atherosclerotic cardiovascular diseases has been reported, the mechanisms linking these concepts are largely unknown and merit much further investigation. Here, we review studies highlighting the interplay between CH, inflamm-aging, the immune system, and the prevalence of CH in autoimmune diseases.</p></div>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":"61 1","pages":"Pages 3-8"},"PeriodicalIF":3.6,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139666261","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","authors":"Jaroslaw P. Maciejewski (Editor)","doi":"10.1053/j.seminhematol.2024.01.014","DOIUrl":"10.1053/j.seminhematol.2024.01.014","url":null,"abstract":"","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":"61 1","pages":"Pages 1-2"},"PeriodicalIF":3.6,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0037196324000143/pdfft?md5=424848dc0e4a0c07344787f75a54edb6&pid=1-s2.0-S0037196324000143-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139666468","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":"Epidemiology and etiology of diffuse large B-cell lymphoma","authors":"Sophia S. Wang","doi":"10.1053/j.seminhematol.2023.11.004","DOIUrl":"10.1053/j.seminhematol.2023.11.004","url":null,"abstract":"<div><div>As the most common non-Hodgkin lymphoma subtype, diffuse large B-cell lymphoma (DLBCL) incidence patterns generally parallel that for NHL overall. Globally, DLBCL accounts for a third of all NHLs, ranging between 20% and 50% by country. Based on United States (U.S.) cancer registry data, age-standardized incidence rate for DLBCL was 7.2 per 100,000. DLBCL incidence rises with age and is generally higher in males than females; in the U.S., incidence is highest among non-Hispanic whites (9.2/100,000). Like NHL incidence, DLBCL incidence rose in the first half of the 20th century but has largely plateaued. However, there is some evidence that incidence rates are rising in areas of historically low rates, such as Asia; there are also estimates for rising DLBCL incidence in the near future due to the changing demographics in developed countries whose aging population is growing. Established risk factors for DLBCL include those that result in severe immune deficiency such as HIV/AIDS, inherited immunodeficiency syndromes, and organ transplant recipients. Factors that lead to chronic immune dysregulations are also established risk factors, and include a number of autoimmune conditions (eg, Sjögren syndrome, systemic lupus erythematosus, rheumatoid arthritis), viral infections (eg, HIV, KSHV/HHV8, HCV, EBV), and obesity. Family history of NHL/DLBCL, personal history of cancer, and multiple genetic susceptibility loci are also well-established risk factors for DLBCL. There is strong evidence for multiple environmental exposures in DLBCL etiology, including exposure to trichloroethylene, benzene, and pesticides and herbicides, with recent associations noted with glyphosate. There is also strong evidence for associations with other viruses, such as HBV. Recent estimates suggest that obesity accounts for nearly a quarter of DLBCLs that develop, but despite recent gains in the understanding of DLBCL etiology, the majority of disease remain unexplained. An understanding of the host and environmental contributions to disease etiology, and concerted efforts to expand our understanding to multiple race/ethnic groups, will be essential for constructing clinically relevant risk prediction models and develop effective strategies for disease prevention.</div></div>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":"60 5","pages":"Pages 255-266"},"PeriodicalIF":5.0,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138537283","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}
Hannah Kinoshita , Catherine M. Bollard , Keri Toner
{"title":"CD19 CAR-T cell therapy for relapsed or refractory diffuse large B cell lymphoma: Why does it fail?","authors":"Hannah Kinoshita , Catherine M. Bollard , Keri Toner","doi":"10.1053/j.seminhematol.2023.11.007","DOIUrl":"10.1053/j.seminhematol.2023.11.007","url":null,"abstract":"<div><div><span>Chimeric antigen receptor T (CAR-T) cell therapy is an effective treatment for relapsed or refractory </span>diffuse large B cell lymphoma<span> (DLBCL) with 3 CD19 targeting products now FDA-approved for this indication. However, up to 60% of patients ultimately progress or relapse following CAR-T cell therapy. Mechanisms of resistance to CAR-T cell therapy in patients with DLBCL are likely multifactorial and have yet to be fully elucidated. Determining patient, tumor and therapy-related factors that may predict an individual's response to CAR-T cell therapy requires ongoing analysis of data from clinical trials and real-world experience in this population. In this review we will discuss the factors identified to-date that may contribute to failure of CAR-T cell therapy in achieving durable remissions in patients with DLBCL.</span></div></div>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":"60 5","pages":"Pages 329-337"},"PeriodicalIF":5.0,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138548154","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":"Biological heterogeneity in diffuse large B-cell lymphoma","authors":"Laura K. Hilton , David W. Scott , Ryan D. Morin","doi":"10.1053/j.seminhematol.2023.11.006","DOIUrl":"10.1053/j.seminhematol.2023.11.006","url":null,"abstract":"<div><div>Diffuse large B-cell lymphoma (DLBCL) is heterogeneous both in clinical outcomes and the underlying disease biology. Over the last 2 decades, several different approaches for dissecting biological heterogeneity have emerged. Gene expression profiling (GEP) stratifies DLBCL into 3 broad groups (ABC, GCB, and DZsig/MHG), each with parallels to different normal mature B cell developmental states and prognostic implications. More recently, several different genomic approaches have been developed to categorize DLBCL based on the co-occurrence of tumor somatic mutations, identifying more granular biologically unified subgroups that complement GEP-based approaches. We review the molecular approaches and clinical evidence supporting the stratification of DLBCL patients based on tumor biology. By offering a platform for subtype-guided therapy, these divisions remain a promising avenue for improving patient outcomes, especially in subgroups with inferior outcomes with current standard-of-care therapy.</div></div>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":"60 5","pages":"Pages 267-276"},"PeriodicalIF":5.0,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138506376","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}