Blood最新文献

{"title":"A modern view of LGL leukemia.","authors":"Tony Marchand, Thierry Lamy, Thomas P Loughran","doi":"10.1182/blood.2023021790","DOIUrl":"10.1182/blood.2023021790","url":null,"abstract":"<p><strong>Abstract: </strong>Large granular lymphocytic leukemia (LGLL) is a rare lymphoproliferative chronic disorder characterized by expansion of either T or natural killer (NK) cytotoxic cells. In contrast to Epstein-Barr virus-induced aggressive NK-LGLL, chronic T-LGLL and NK-LGLL are indolent diseases affecting older patients with a median age of 66.5 years. LGLL is frequently associated with autoimmune disorders, most frequently rheumatoid arthritis. An auto-/alloantigen is tentatively implicated in disease initiation. Large granular lymphocyte expansion is then triggered by proinflammatory cytokines such as interleukin-15, macrophage inflammatory protein 1 (MIP-1), and RANTES (regulated upon activation, normal T cell expressed, and secreted). This proinflammatory environment contributes to deregulation of proliferative and apoptotic pathways. After the initial description of the JAK-STAT pathway signaling activation in the majority of patients, recurrent STAT3 gain-of-function mutations have been reported. The JAK-STAT pathway plays a key role in LGL pathogenesis by promoting survival, proliferation, and cytotoxicity. Several recent advances have been made toward understanding the molecular landscapes of T- and NK-LGLL, identifying multiple recurrent mutations affecting the epigenome, such as TET2 or KMT2D, and cross talk with the immune microenvironment, such as CCL22. Despite an indolent course, published series suggest that the majority of patients eventually need treatment. However, it is noteworthy that many patients may have a long-term observation period without ever requiring therapy. Treatments rely upon immunosuppressive drugs, namely cyclophosphamide, methotrexate, and cyclosporine. Recent advances have led to the development of targeted approaches, including JAK-STAT inhibitors, cytokine targeting, and hypomethylating agents, opening new developments in a still-incurable disease.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"1910-1923"},"PeriodicalIF":21.0,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141287748","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":"A practical approach to the modern diagnosis and classification of T- and NK-cell lymphomas.","authors":"Laurence de Leval, Philippe Gaulard, Ahmet Dogan","doi":"10.1182/blood.2023021786","DOIUrl":"10.1182/blood.2023021786","url":null,"abstract":"<p><strong>Abstract: </strong>T- and natural killer (NK)-cell lymphomas are neoplasms derived from immature T cells (lymphoblastic lymphomas), or more commonly, from mature T and NK cells (peripheral T-cell lymphomas, PTCLs). PTCLs are rare but show marked biological and clinical diversity. They are usually aggressive and may present in lymph nodes, blood, bone marrow, or other organs. More than 30 T/NK-cell-derived neoplastic entities are recognized in the International Consensus Classification and the classification of the World Health Organization (fifth edition), both published in 2022, which integrate the most recent knowledge in hematology, immunology, pathology, and genetics. In both proposals, disease definition aims to integrate clinical features, etiology, implied cell of origin, morphology, phenotype, and genetic features into biologically and clinically relevant clinicopathologic entities. Cell derivation from innate immune cells or specific functional subsets of CD4+ T cells such as follicular helper T cells is a major determinant delineating entities. Accurate diagnosis of T/NK-cell lymphoma is essential for clinical management and mostly relies on tissue biopsies. Because the histological presentation may be heterogeneous and overlaps with that of many benign lymphoid proliferations and B-cell lymphomas, the diagnosis is often challenging. Disease location, morphology, and immunophenotyping remain the main features guiding the diagnosis, often complemented by genetic analysis including clonality and high-throughput sequencing mutational studies. This review provides a comprehensive overview of the classification and diagnosis of T-cell lymphoma in the context of current concepts and scientific knowledge.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"1855-1872"},"PeriodicalIF":21.0,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140903565","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":"Forimtamig, a novel GPRC5D-targeting T-cell bispecific antibody with a 2+1 format, for the treatment of multiple myeloma.","authors":"Jan Eckmann, Tanja Fauti, Marlene Biehl, Aintzane Zabaleta, Laura Blanco, Iva Lelios, Stefan Gottwald, Richard Rae, Stefanie Lechner, Christa Bayer, Quincy Dekempe, Franz Osl, Nadège Carrié, Sahar Kassem, Stefan Lorenz, Tony Christopeit, Alejandro Carpy, Alexander Bujotzek, Ann-Marie E Bröske, Iryna Dekhtiarenko, Jan Attig, Leo Kunz, Floriana Cremasco, Roberto Adelfio, Georg Fertig, Stefan Dengl, Christian Gassner, Felix Bormann, Claudia Kirstenpfad, Thomas Emanuel Kraft, Sarah Diggelmann, Melanie Knobloch, Carina Hage, Romi Feddersen, Gordon Heidkamp, Thomas Pöschinger, Maud Lea Mayoux, Luise Bernasconi, Charles Dumontet, Felipe Prosper, Ludovic Martinet, Stephane Leclair, Wei Xu, Bruno Paiva, Christian Klein, Pablo Umaña","doi":"10.1182/blood.2024025987","DOIUrl":"https://doi.org/10.1182/blood.2024025987","url":null,"abstract":"<p><p>Despite several approved therapies, multiple myeloma (MM) remains an incurable disease with high unmet medical need. \"Off-the-shelf\" T-cell bispecific antibodies (TCBs) targeting BCMA and GPRC5D have demonstrated high objective response rates (ORR) in heavily pre-treated MM patients, however, primary resistance, short duration of response and relapse driven by antigen shift frequently occurs. Although GPRC5D represents the most selective target in MM, recent findings indicate antigen loss occurs more frequently than with BCMA. Thus, anti-GPRC5D immunotherapies must hit hard during a short period of time to kill as many myeloma cells as possible. Here, we characterize forimtamig, a novel GPRC5D-targeting TCB with 2+1 format, using preclinical models of MM. Bivalent binding of forimtamig to the N-terminus of GPRC5D confers higher affinity as compared to classical 1+1 TCB formats correlating with formation of more stable immunological synapses and higher potency in tumor cell killing and T cell activation. Using an orthotopic mouse model of MM, forimtamig recruited T effector cells to the bone marrow and induced rapid tumor killing even after the introduction of step-up dosing to mitigate cytokine release. Combination of forimtamig with standard-of-care (SoC) agents including anti-CD38 antibodies, immunomodulatory drugs and proteasome inhibitors improved depth and duration of response. The combination of forimtamig with novel therapeutic agents including BCMA-TCB and Cereblon E3 Ligase Modulatory Drugs (CELMoDs) was potent and prevented occurrence of GPRC5D-negative tumor relapse. Forimtamig is currently being evaluated in Phase 1 clinical trials in relapsed and refractory myeloma (RRMM) patients for monotherapy and in combination treatments. NCT04557150.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543580","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":"Genetic and Clinical Spectrum of SAMD9 and SAMD9L Syndromes: from Variant Interpretation to Patient Management.","authors":"Sushree S Sahoo, Miriam Erlacher, Marcin W Wlodarski","doi":"10.1182/blood.2022017717","DOIUrl":"https://doi.org/10.1182/blood.2022017717","url":null,"abstract":"<p><p>SAMD9 and SAMD9L (SAMD9/9L) are paralogous genes encoding antiviral proteins that negatively regulate cell proliferation. Heterozygous germline gain-of-function (GoF) SAMD9/9L variants cause multisystem syndromes with variable manifestations. The unifying features are cytopenia, immunodeficiency, infections, bone marrow failure (BMF), myelodysplasia (MDS) and monosomy 7. Non-hematopoietic presentations can affect almost every organ system. Growth impairment and adrenal insufficiency are typical in SAMD9, while progressive neurologic deficits characterize SAMD9L. Most patients (>90%) carry germline missense GoF variants. A subgroup of patients presenting with SAMD9L-associated inflammatory disease (SAAD) carry frameshift truncating variants that are also GoF. Somatic genetic rescue occurs in >2/3 of patients and involves monosomy 7, which may spontaneously disappear (transient monosomy 7) or progress to MDS/leukemia, and adaptive clones with somatic SAMD9/9L compensatory mutations or uniparental disomy 7q (UPD7q), both associated with remission. This manuscript examines the clinical and genetic spectrum, therapies and outcome based on 243 published patients compiled in our registry with additional genetic information on 62 unpublished cases. We consolidate the diverse clinical manifestations and diagnostic challenges of SAMD9/9L syndromes to enhance recognition and improve patient care. We highlight the knowledge gaps in pathomechanisms and emphasize the importance of genetic surveillance assessing disease remission versus disease progression. Insights are provided into variant curation and the necessity of testing for somatic SAMD9/9L mutations and UPD7q. Multidisciplinary care in specialized centers is critical to manage these complex disorders. Future natural history studies, especially in patients with monosomy 7, will help formulate evidence-based surveillance protocols and optimize transplant timing and outcomes.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543581","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":"Long term follow-up of the STOPAGO study.","authors":"Adrien Cottu, Stéphanie Guillet, Jean-François Viallard, Etienne Riviere, Stéphane Cheze, Delphine Gobert, Antoine Neel, Julie Graveleau, Jean-Pierre Marolleau, François Lefrere, Guillaume Moulis, Jean-Christophe Lega, Aline Moignet, Ailsa Robbins, Etienne Crickx, Emmanuelle Boutin, Nicolas Noel, Marion Malphettes, Lionel Galicier, Sylvain Audia, Bernard Bonnotte, Olivier Lambotte, Olivier Fain, Mathieu Gerfaud-Valentin, Louis Terriou, Nihal Martis, Anne-Sophie Morin, Antoinette Perlat, Thomas Le Gallou, Frédérique Roy-Peaud, Matthieu Puyade, Thibault Comont, Nicolas Limal, Laetitia Languille, Marc Michel, Bertrand Godeau, Matthieu Mahevas","doi":"10.1182/blood.2024025707","DOIUrl":"10.1182/blood.2024025707","url":null,"abstract":"<p><p>An open prospective, multicenter study enrolled 48 selected patients with chronic immune thrombocytopenia who achieved complete response for 1 year on thrombopoietin receptor agonists, half of the patients maintained a sustained response off treatment 4 years after treatment discontinuation. NCT03119974.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543582","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":"Current myeloproliferative neoplasm scoring systems for clinical practice.","authors":"Hélène Pasquer, Jean-Jacques Kiladjian, Lina Benajiba","doi":"10.1182/blood.2024025459","DOIUrl":"https://doi.org/10.1182/blood.2024025459","url":null,"abstract":"<p><p>BCR::ABL1-negative myeloproliferative neoplasms (MPN) are clonal hematological malignancies resulting from the proliferation of myeloid cells harboring a JAK-STAT pathway activating driver mutation. MPN management recommendations are based on the evaluation of different risks to prevent disease evolution associated events while preserving patients' quality of life. Such risks can be common across all MPN or specific to each subtype (polycythemia vera (PV), essential thrombocythemia (ET), prefibrotic myelofibrosis (pre-MF), primary myelofibrosis (PMF)). MF-patients harbor the worse prognosis and hematopoietic stem cell transplantation (HSCT) is the only curative treatment, at the expense of a high morbi-mortality. Therefore, accurate scoring systems to estimate overall survival are crucial for MF patients' management and selection for HSCT. In PV and ET, vascular events prediction is prioritized given their higher incidence and related morbi-mortality. Finally, quality of life evaluation is important for all subtypes. To predict these risks and adapt MPN therapeutic strategies, clinical risk scores have been developed over the past decades, more recently including molecular risk factors for more accurate risk stratification. The large number of scoring systems available in combination with disease heterogeneity and the necessity to predict diverse outcomes, make it difficult for clinicians to choose the most appropriate score to evaluate their patients' risk in 2024. Here, we provide an overview of MPN disease evolution associated events incidence and conduct an exhaustive comparative review of the scoring systems currently available for each risk. Finally, we propose an algorithm for the use of these scores in clinical practice in each MPN subtype.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543579","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, Minh-Hanh Thi Nguyen, Terence P Speed, Damien G Hicks, Esther Bandala-Sanchez, Hongke Peng, Stephane Chappaz, Charlotte Slade, Daniel T Utzschneider, Rachel M Koldej, David Ritchie, Andreas Strasser, Rachel Thijssen, Matthew E Ritchie, Constantine Si Lun Tam, Geoffrey J Lindeman, David Ching Siang Huang, Thomas E Lew, Mary Ann Anderson, Andrew W Roberts, Charis E Teh, Daniel H D Gray","doi":"10.1182/blood.2024024341","DOIUrl":"https://doi.org/10.1182/blood.2024024341","url":null,"abstract":"<p><p>Venetoclax, a first-in-class BH3 mimetic drug targeting BCL-2, has improved outcomes for 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. Yet, there are limited data concerning 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 five weeks of venetoclax monotherapy. At baseline, we resolved CLL heterogeneity at the single-cell level to define multiple subpopulations in all patients distinguished by proliferative, metabolic and cell survival proteins. Venetoclax induced significant reduction in all CLL subpopulations coincident with rapid upregulation of pro-survival BCL-2, BCL-XL and MCL-1 proteins in surviving cells, which had reduced sensitivity to the drug. Mouse models recapitulated the venetoclax-induced elevation of survival proteins in B cells and CLL-like cells that persisted in vivo, with genetic models demonstrating that extensive apoptosis and access to the B cell cytokine, BAFF, were essential. Accordingly, analysis of patients with CLL that were treated with venetoclax or the anti-CD20 antibody obinutuzumab exhibited marked elevation of BAFF and increased pro-survival proteins in leukemic cells that persisted. Overall, these data highlight the rapid adaptation of CLL cells to targeted therapies via homeostatic factors and support co-targeting of cytokine signals to achieve deeper and more durable long-term responses.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2024-10-29","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":"Near early T-precursor lymphoblastic leukemia with marked flower petal nuclei: blast with unique cyanthiform nucleus.","authors":"Qian Wu,Dong Chen","doi":"10.1182/blood.2024026443","DOIUrl":"https://doi.org/10.1182/blood.2024026443","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"14 1","pages":"1846"},"PeriodicalIF":20.3,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489666","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 acute venous thromboembolism in patients with brain tumors.","authors":"Avi Leader, Jessica A Wilcox, Jeffrey I Zwicker","doi":"10.1182/blood.2023023450","DOIUrl":"10.1182/blood.2023023450","url":null,"abstract":"<p><strong>Abstract: </strong>Venous thromboembolism (VTE) is a common complication in patients with brain tumors. The management of acute VTE is particularly challenging due to an elevated risk of intracranial hemorrhage (ICH). Risk of developing ICH on anticoagulation is influenced by a number of factors including tumor type, recent surgery, concomitant medications, platelet counts, and radiographic features. In patients with a heightened risk for ICH, the benefits of anticoagulation need to be balanced against a likelihood of developing major hemorrhagic complications. Management decisions include whether to administer anticoagulation, at what dose, placement of an inferior vena cava filter, monitoring for development of hemorrhage or progressive thrombus, and escalation of anticoagulant dose. This article discusses the complexities of treating acute VTE in patients with brain tumors and outlines treatment algorithms based on the presence or absence of ICH at the time of VTE diagnosis. Through case-based scenarios, we illustrate our approach to anticoagulation, emphasizing individualized risk assessments and evidence-based practices to optimize treatment outcomes while minimizing the risks of hemorrhagic events in patients with brain tumors.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"1781-1790"},"PeriodicalIF":21.0,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11530362/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142085957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Germ line ERG haploinsufficiency defines a new syndrome with cytopenia and hematological malignancy predisposition.","authors":"Jiarna R Zerella, Claire C Homan, Peer Arts, Xuzhu Lin, Sam J Spinelli, Parvathy Venugopal, Milena Babic, Peter J Brautigan, Lynda Truong, Luis Arriola-Martinez, Sarah Moore, Rachel Hollins, Wendy T Parker, Hung Nguyen, Karin S Kassahn, Susan Branford, Simone Feurstein, Lise Larcher, Flore Sicre de Fontbrune, Serwet Demirdas, Sonja de Munnik, Hélène Antoine-Poirel, Benedicte Brichard, Sahar Mansour, Kristiana Gordon, Marcin W Wlodarski, Ashwin Koppayi, Sara Dobbins, Pim G N J Mutsaers, Kim E Nichols, Ninad Oak, Desiree DeMille, Rong Mao, Ali Crawford, Julie McCarrier, Donald Basel, Josue Flores-Daboub, Michael W Drazer, Kerry Phillips, Nicola K Poplawski, Graeme M Birdsey, Daniela Pirri, Pia Ostergaard, Annet Simons, Lucy A Godley, David M Ross, Devendra K Hiwase, Jean Soulier, Anna L Brown, Catherine L Carmichael, Hamish S Scott, Christopher N Hahn","doi":"10.1182/blood.2024024607","DOIUrl":"10.1182/blood.2024024607","url":null,"abstract":"<p><strong>Abstract: </strong>The genomics era has facilitated the discovery of new genes that predispose individuals to bone marrow failure (BMF) and hematological malignancy (HM). We report the discovery of ETS-related gene (ERG), a novel, autosomal dominant BMF/HM predisposition gene. ERG is a highly constrained transcription factor that is critical for definitive hematopoiesis, stem cell function, and platelet maintenance. ERG colocalizes with other transcription factors, including RUNX family transcription factor 1 (RUNX1) and GATA binding protein 2 (GATA2), on promoters or enhancers of genes that orchestrate hematopoiesis. We identified a rare heterozygous ERG missense variant in 3 individuals with thrombocytopenia from 1 family and 14 additional ERG variants in unrelated individuals with BMF/HM, including 2 de novo cases and 3 truncating variants. Phenotypes associated with pathogenic germ line ERG variants included cytopenias (thrombocytopenia, neutropenia, and pancytopenia) and HMs (acute myeloid leukemia, myelodysplastic syndrome, and acute lymphoblastic leukemia) with onset before 40 years. Twenty ERG variants (19 missense and 1 truncating), including 3 missense population variants, were functionally characterized. Thirteen potentially pathogenic erythroblast transformation specific (ETS) domain missense variants displayed loss-of-function (LOF) characteristics, thereby disrupting transcriptional transactivation, DNA binding, and/or nuclear localization. Selected variants overexpressed in mouse fetal liver cells failed to drive myeloid differentiation and cytokine-independent growth in culture and to promote acute erythroleukemia when transplanted into mice, concordant with these being LOF variants. Four individuals displayed somatic genetic rescue by copy neutral loss of heterozygosity. Identification of predisposing germ line ERG variants has clinical implications for patient and family diagnoses, counseling, surveillance, and treatment strategies, including selection of bone marrow donors and cell or gene therapy.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"1765-1780"},"PeriodicalIF":21.0,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11530364/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141589604","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}