Seminars in hematology最新文献

{"title":"Biological, prognostic, and therapeutic impact of the epigenome in CLL","authors":"Alba Maiques-Diaz ,&nbsp;Jose Ignacio Martin-Subero","doi":"10.1053/j.seminhematol.2023.11.005","DOIUrl":"10.1053/j.seminhematol.2023.11.005","url":null,"abstract":"<div><p>Chronic lymphocytic leukemia (CLL) is characterized by widespread alterations in the genetic and epigenetic landscapes which seem to underlie the variable clinical manifestations observed in patients. Over the last decade, epigenomic studies have described the whole-genome maps of DNA methylation and chromatin features of CLL and normal B cells, identifying distinct epigenetic mechanisms operating in tumoral cells. DNA methylation analyses have identified that the CLL methylome contains imprints of the cell of origin, as well as of the proliferative history of the tumor cells, with both being strong independent prognostic predictors. Moreover, single-cell analysis revealed a higher degree of DNA methylation noise in CLL cells, which associates with transcriptional plasticity and disease aggressiveness. Integrative analysis of chromatin has uncovered chromatin signatures, as well as regulatory regions specifically active in each CLL subtype or in Richter transformed samples. Unique transcription factor (TF) binding motifs are overrepresented on those regions, suggesting that altered TF networks operate from disease initiation to progression as nongenetic factors mediating the oncogenic transcriptional profiles. Multiomics analysis has identified that response to treatment is modulated by an epigenetic imprint, and that treatments affect chromatin through the activity of particular set of TFs. Additionally, the epigenome is an axis of therapeutic vulnerability in CLL, as it can be targeted by inhibitors of histone modifying enzymes, that have shown promising preclinical results. Altogether, this review aims at summarizing the major findings derived from published literature to distill how altered epigenomic mechanisms contribute to CLL origin, evolution, clinical behavior, and response to treatment.</p></div>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":"61 3","pages":"Pages 172-180"},"PeriodicalIF":5.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138506380","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":"Lessons learned from the Eµ-TCL1 mouse model of CLL","authors":"Alessia Floerchinger ,&nbsp;Martina Seiffert","doi":"10.1053/j.seminhematol.2024.05.002","DOIUrl":"10.1053/j.seminhematol.2024.05.002","url":null,"abstract":"<div><p>The Eµ-TCL1 mouse model has been used for over 20 years to study the pathobiology of chronic lymphocytic leukemia (CLL) and for preclinical testing of novel therapies. A CLL-like disease develops with increasing age in these mice due to a B cell specific overexpression of human <em>TCL1</em>. The reliability of this model to mirror human CLL is controversially discussed, as none of the known driver mutations identified in patients are found in Eµ-TCL1 mice. It has to be acknowledged that this mouse model was key to develop targeted therapies that aim at inhibiting the constitutive B cell receptor (BCR) signaling, a main driver of CLL. Inhibitors of BCR signaling became standard-of-care for a large proportion of patients with CLL as they are highly effective. The Eµ-TCL1 model further advanced our understanding of CLL biology owed to studies that crossed this mouse line with various transgenic mouse models and demonstrated the relevance of CLL-cell intrinsic and -extrinsic drivers of disease. These studies were instrumental in showing the relevance of the tumor microenvironment in the lymphoid tissues for disease progression and immune escape in CLL. It became clear that CLL cells shape and rely on stromal and immune cells, and that immune suppressive mechanisms and T cell exhaustion contribute to CLL progression. Based on this knowledge, new immunotherapy strategies were clinically tested for CLL, but so far with disappointing results. As some of these therapies were effective in the Eµ-TCL1 mouse model, the question arose concerning the translatability of preclinical studies in these mice. The aim of this review is to summarize lessons we have learnt over the last decades by studying CLL-like disease in the Eµ-TCL1 mouse model. The article focuses on pitfalls and limitations of the model, as well as the gained knowledge and potential of using this model for the development of novel treatment strategies to achieve the goal of curing patients with CLL.</p></div>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":"61 3","pages":"Pages 194-200"},"PeriodicalIF":5.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S003719632400060X/pdfft?md5=ff43430d75dc744267e0ad85a5990a2a&pid=1-s2.0-S003719632400060X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141040802","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":"Updates on the biology of chronic lymphocytic leukemia: introductory editorial","authors":"Elisa ten Hacken PhD ,&nbsp;Barbara Eichhorst MD","doi":"10.1053/j.seminhematol.2024.06.001","DOIUrl":"10.1053/j.seminhematol.2024.06.001","url":null,"abstract":"","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":"61 3","pages":"Pages 139-141"},"PeriodicalIF":5.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141591337","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 complexities of T-cell dysfunction in chronic lymphocytic leukemia","authors":"Elena Camerini ,&nbsp;Derk Amsen ,&nbsp;Arnon P. Kater ,&nbsp;Fleur S. Peters","doi":"10.1053/j.seminhematol.2024.04.001","DOIUrl":"10.1053/j.seminhematol.2024.04.001","url":null,"abstract":"<div><p>Chronic lymphocytic leukemia (CLL) is a B-cell malignancy characterized by profound alterations and defects in the T-cell compartment. This observation has gained renewed interest as T-cell treatment strategies, which are successfully applied in more aggressive B-cell malignancies, have yielded disappointing results in CLL. Despite ongoing efforts to understand and address the observed T-cell defects, the exact mechanisms and nature underlying this dysfunction remain largely unknown. In this review, we examine the supporting signals from T cells to CLL cells in the lymph node niche, summarize key findings on T-cell functional defects, delve into potential underlying causes, and explore novel strategies for reversing these deficiencies. Our goal is to identify strategies aimed at resolving CLL-induced T-cell dysfunction which, in the future, will enhance the efficacy of autologous T-cell-based therapies for CLL patients.</p></div>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":"61 3","pages":"Pages 163-171"},"PeriodicalIF":5.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S003719632400057X/pdfft?md5=4b2429ca9d9c5acede6a8221be854cc5&pid=1-s2.0-S003719632400057X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141088726","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":"Metabolic reprogramming in the CLL TME; potential for new therapeutic targets","authors":"Helga Simon-Molas ,&nbsp;Chiara Montironi ,&nbsp;Anna Kabanova ,&nbsp;Eric Eldering","doi":"10.1053/j.seminhematol.2024.02.001","DOIUrl":"10.1053/j.seminhematol.2024.02.001","url":null,"abstract":"<div><p>Chronic lymphocytic leukemia (CLL) cells circulate between peripheral (PB) blood and lymph node (LN) compartments, and strictly depend on microenvironmental factors for proliferation, survival and drug resistance. All cancer cells display metabolic reprogramming and CLL is no exception – though the inert status of the PB CLL cells has hampered detailed insight into these processes. We summarize previous work on reactive oxygen species (ROS), oxidative stress, and hypoxia, as well as the important roles of Myc, and PI3K/Akt/mTor pathways. In vitro co-culture systems and gene expression analyses have provided a partial picture of CLL LN metabolism. New broad omics techniques allow to obtain molecular and also single-cell level understanding of CLL plasticity and metabolic reprogramming. We summarize recent developments and describe the new concept of glutamine addiction for CLL, which may hold therapeutic promise.</p></div>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":"61 3","pages":"Pages 155-162"},"PeriodicalIF":5.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0037196324000167/pdfft?md5=a00cb9b5b0b7c8fda0a7b599ab12d564&pid=1-s2.0-S0037196324000167-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139818807","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":"B-cell receptor immunoglobulin stereotypy in chronic lymphocytic leukemia: Key to understanding disease biology and stratifying patients","authors":"Andreas Agathangelidis ,&nbsp;Thomas Chatzikonstantinou ,&nbsp;Kostas Stamatopoulos","doi":"10.1053/j.seminhematol.2023.12.005","DOIUrl":"10.1053/j.seminhematol.2023.12.005","url":null,"abstract":"<div><p><span>Sequence convergence, otherwise stereotypy, of B-cell receptor immunoglobulin (BcR IG) from unrelated patients is a distinctive feature of the IG gene repertoire in chronic lymphocytic leukemia<span> (CLL) whereby patients expressing a particular BcR IG archetype are classified into groups termed stereotyped subsets. From a biological perspective, the fact that a considerable fraction (∼41%) of patients with CLL express (quasi)identical or stereotyped BcR IG underscores the key role of antigen selection in the natural history of CLL. From a clinical perspective, at odds with the pronounced heterogeneity of CLL at large, patients belonging to the same stereotyped subset display consistent clinical presentation and outcome, including response to treatment, likely as a reflection of consistent biological background. Many major stereotyped subsets were recently shown to have satellites, that is, smaller subsets that are immunogenetically similar. Preliminary evidence supports that this similarity extends to shared biological and even clinical features, with important implications for patient stratification. Consequently, BcR IG stereotypy emerges as a powerful tool for dissecting the heterogeneity of CLL toward refined </span></span>risk stratification and, eventually, more precise therapeutic interventions.</p></div>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":"61 2","pages":"Pages 91-99"},"PeriodicalIF":3.6,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139054602","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":"Targeting the B cell receptor signaling pathway in chronic lymphocytic leukemia","authors":"John T. Patton,&nbsp;Jennifer A. Woyach","doi":"10.1053/j.seminhematol.2024.04.002","DOIUrl":"10.1053/j.seminhematol.2024.04.002","url":null,"abstract":"<div><p>Aberrant signal transduction through the B cell receptor (BCR) plays a critical role in the pathogenesis of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). BCR-dependent signaling is necessary for the growth and survival of neoplastic cells, making inhibition of down-stream pathways a logical therapeutic strategy. Indeed, selective inhibitors against Bruton's tyrosine kinase (BTK) and phosphoinositide 3-kinase (PI3K) have been shown to induce high rates of response in CLL and other B cell lymphomas. In particular, the development of BTK inhibitors revolutionized the treatment approach to CLL, demonstrating long-term efficacy. While BTK inhibitors are widely used for multiple lines of treatment, PI3K inhibitors are much less commonly utilized, mainly due to toxicities. CLL remains an incurable disease and effective treatment options after relapse or development of TKI resistance are greatly needed. This review provides an overview of BCR signaling, a summary of the current therapeutic landscape, and a discussion of the ongoing trials targeting BCR-associated kinases.</p></div>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":"61 2","pages":"Pages 100-108"},"PeriodicalIF":3.6,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140765969","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)00062-3","DOIUrl":"https://doi.org/10.1053/S0037-1963(24)00062-3","url":null,"abstract":"","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":"61 2","pages":"Page CO1"},"PeriodicalIF":3.6,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141250459","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":"Vaccinations in patients with chronic lymphocytic leukemia","authors":"Elizabeth R. Francis ,&nbsp;Jennifer Vu ,&nbsp;Catherine Ostos Perez ,&nbsp;Clare Sun","doi":"10.1053/j.seminhematol.2024.01.003","DOIUrl":"10.1053/j.seminhematol.2024.01.003","url":null,"abstract":"<div><p><span><span>Chronic lymphocytic leukemia (CLL) is characterized by immune dysfunction resulting in heightened susceptibility to infections and elevated rates of morbidity and mortality. A key strategy to mitigate infection-related complications has been immunization against common </span>pathogens. However, the immunocompromised status of CLL patients poses challenges in eliciting an adequate humoral and </span>cellular immune response<span><span> to vaccination. Most CLL-directed therapy disproportionately impairs humoral immunity. Vaccine responsiveness also depends on the phase and type of immune response triggered by immunization. In this review, we discuss the immune dysfunction, vaccine responsiveness, and considerations for optimizing vaccine response </span>in patients with CLL.</span></p></div>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":"61 2","pages":"Pages 131-138"},"PeriodicalIF":3.6,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139376220","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":"Therapeutic targeting of apoptosis in chronic lymphocytic leukemia","authors":"Inhye E. Ahn,&nbsp;Matthew S. Davids","doi":"10.1053/j.seminhematol.2024.01.015","DOIUrl":"10.1053/j.seminhematol.2024.01.015","url":null,"abstract":"<div><p>Therapeutic targeting of apoptosis with small molecule B-cell lymphoma 2 (BCL-2) inhibition with venetoclax is highly efficacious in CLL, leading to sustained deep responses, particularly among patients with treatment-naïve disease with favorable prognostic markers. Patients with unfavorable genetic characteristics such as <em>TP53</em> aberration and unmutated IGHV may also derive durable benefits, but their remission duration after time-limited venetoclax-containing combination therapy is shorter, particularly in patients with relapsed/refractory disease. Emerging data indicate that the context of disease progression after initial treatment with venetoclax may define the success of re-treatment with venetoclax. Specifically, continuous venetoclax exposure may select for resistant disease due to genetic mechanisms such as <em>BCL2</em> mutations and functional resistance mechanisms such as hyperphosphorylation of BCL-2 family proteins, which decrease the affinity of venetoclax binding to the target or lead to increased MCL-1 dependence and concomitant decrease in BCL-2 dependence. These patients may be best served by switching to a different class of targeted agents at the time of progression. In contrast, relapsed CLL that arises while being off therapy after a period of time-limited venetoclax-based regimens maintains sensitivity to re-treatment with venetoclax for the majority of patients. Novel strategies related to therapeutic targeting of apoptosis include next-generation BCL-2 inhibitors with improved potency and pharmacokinetic profiles, direct targeting of anti-apoptotic BH3 family proteins beyond BCL-2 such as MCL-1, and indirect targeting of MCL-1 through mechanisms such as small molecule cyclin-dependent kinase 9 inhibitors.</p></div>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":"61 2","pages":"Pages 109-118"},"PeriodicalIF":3.6,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139831525","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}