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The glycosyltransferase ST3GAL4 drives immune evasion in acute myeloid leukemia by synthesizing ligands for the glyco-immune checkpoint receptor Siglec-9 糖基转移酶 ST3GAL4 通过合成糖免疫检查点受体 Siglec-9 的配体来驱动急性髓性白血病的免疫逃避
IF 11.4 1区 医学
Leukemia Pub Date : 2024-11-17 DOI: 10.1038/s41375-024-02454-w
Vignesh Krishnamoorthy, John Daly, Jimmy Kim, Lidia Piatnitca, Katie A. Yuen, Bhoj Kumar, Mehrnoush Taherzadeh Ghahfarrokhi, Tom Q. T. Bui, Parastoo Azadi, Ly P. Vu, Simon Wisnovsky
{"title":"The glycosyltransferase ST3GAL4 drives immune evasion in acute myeloid leukemia by synthesizing ligands for the glyco-immune checkpoint receptor Siglec-9","authors":"Vignesh Krishnamoorthy, John Daly, Jimmy Kim, Lidia Piatnitca, Katie A. Yuen, Bhoj Kumar, Mehrnoush Taherzadeh Ghahfarrokhi, Tom Q. T. Bui, Parastoo Azadi, Ly P. Vu, Simon Wisnovsky","doi":"10.1038/s41375-024-02454-w","DOIUrl":"https://doi.org/10.1038/s41375-024-02454-w","url":null,"abstract":"<p>Immunotherapy has demonstrated promise as a treatment for acute myeloid leukemia (AML). However, there is still an urgent need to identify new molecules that inhibit the immune response to AML. Most prior research in this area has focused on protein-protein interaction interfaces. While carbohydrates also regulate immune recognition, the role of cell-surface glycans in driving AML immune evasion is comparatively understudied. The Siglecs, for example, are an important family of inhibitory, glycan-binding signaling receptors that have emerged as prime targets for cancer immunotherapy in recent years. In this study, we find that AML cells express ligands for the receptor Siglec-9 at high levels. Integrated CRISPR genomic screening and clinical bioinformatic analysis identified ST3GAL4 as a potential driver of Siglec-9 ligand expression in AML. Depletion of ST3GAL4 by CRISPR-Cas9 knockout (KO) dramatically reduced the expression of Siglec-9 ligands in AML cells. Mass spectrometry analysis of cell-surface glycosylation in ST3GAL4 KO cells revealed that Siglec-9 primarily binds N-linked sialoglycans on these cell types. Finally, we found that ST3GAL4 KO enhanced the sensitivity of AML cells to phagocytosis by Siglec-9-expressing macrophages. This work reveals a novel axis of immune evasion and implicates ST3GAL4 as a possible target for immunotherapy in AML.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"51 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142645945","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}
引用次数: 0
Correction: Aberrant BCAT1 expression augments MTOR activity and accelerates disease progression in chronic lymphocytic leukemia. 更正:BCAT1 的异常表达增强了 MTOR 的活性,加速了慢性淋巴细胞白血病的病情发展。
IF 12.8 1区 医学
Leukemia Pub Date : 2024-11-13 DOI: 10.1038/s41375-024-02472-8
Qiangqiang Shao, Jedrzej Wykretowicz, Nan Hu, Karan Bedi, Mohamed Rizk, Isabella A Malek, Surinder Kumar, David B Lombard, Kerby Shedden, David Scott, Sami N Malek
{"title":"Correction: Aberrant BCAT1 expression augments MTOR activity and accelerates disease progression in chronic lymphocytic leukemia.","authors":"Qiangqiang Shao, Jedrzej Wykretowicz, Nan Hu, Karan Bedi, Mohamed Rizk, Isabella A Malek, Surinder Kumar, David B Lombard, Kerby Shedden, David Scott, Sami N Malek","doi":"10.1038/s41375-024-02472-8","DOIUrl":"https://doi.org/10.1038/s41375-024-02472-8","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":" ","pages":""},"PeriodicalIF":12.8,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142623310","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}
引用次数: 0
A CADASIL NOTCH3 mutation leads to clonal hematopoiesis and expansion of Dnmt3a-R878H hematopoietic clones CADASIL NOTCH3 突变导致克隆造血和 Dnmt3a-R878H 造血克隆的扩增
IF 11.4 1区 医学
Leukemia Pub Date : 2024-11-13 DOI: 10.1038/s41375-024-02464-8
Raúl Sánchez-Lanzas, Justin Barclay, Alexandros Hardas, Foteini Kalampalika, Amanda Jiménez-Pompa, Paolo Gallipoli, Miguel Ganuza
{"title":"A CADASIL NOTCH3 mutation leads to clonal hematopoiesis and expansion of Dnmt3a-R878H hematopoietic clones","authors":"Raúl Sánchez-Lanzas, Justin Barclay, Alexandros Hardas, Foteini Kalampalika, Amanda Jiménez-Pompa, Paolo Gallipoli, Miguel Ganuza","doi":"10.1038/s41375-024-02464-8","DOIUrl":"https://doi.org/10.1038/s41375-024-02464-8","url":null,"abstract":"<p>Clonal hematopoiesis (CH) is nearly universal in the elderly. The molecular and cellular mechanisms driving CH and the clinical consequences of carrying clonally derived mutant mature blood cells are poorly understood. We recently identified a C223Y mutation in the extracellular domain (ECD) of NOTCH3 as a putative CH driver in mice. Provocatively, germline <i>NOTCH3</i> ECD mutations perturbing cysteine numbers cause Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), a type of vascular dementia, suggesting an unexpected link between CADASIL and CH. Here, we formally demonstrated that mouse hematopoietic stem and progenitor cells (HSPCs) expressing CADASIL-related <i>NOTCH3</i><sup><i>C455R</i></sup> exhibit a proliferative advantage resulting in robust cellular expansion in vivo and in vitro. Co-expression of <i>NOTCH3</i><sup><i>C455R</i></sup> and <i>Dnmt3a</i><sup><i>R878H</i></sup>, homologous to a frequent human CH mutation, increased the fitness of <i>NOTCH3</i><sup><i>C455R</i></sup> HSPCs, demonstrating their functional cooperation. Surprisingly, the presence of <i>NOTCH3</i><sup><i>C455R</i></sup> hematopoietic cells supported the expansion of <i>Dnmt3a</i><sup><i>R878H</i></sup> HSPCs in a non-cell autonomous fashion in vivo, strongly suggesting that CADASIL patients and asymptomatic carriers can be highly predisposed to <i>DNMT3A</i><sup><i>R882H</i></sup>-driven CH. Considering that CADASIL-related <i>NOTCH3</i> mutations are more frequent in the general population than anticipated (~1 carrier in 400 people), the effect of these <i>NOTCH3</i> mutations on CH development should be considered.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"72 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142610340","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}
引用次数: 0
Venetoclax in combination with hypomethylating agents in chronic myelomonocytic leukemia: a propensity score matched multicenter cohort study Venetoclax 联合低甲基化药物治疗慢性粒单核细胞白血病:倾向得分匹配多中心队列研究
IF 11.4 1区 医学
Leukemia Pub Date : 2024-11-12 DOI: 10.1038/s41375-024-02466-6
Douglas Tremblay, Clifford Csizmar, Courtney D. DiNardo, Somedeb Ball, Noa Rippel, Danielle Hammond, Tapan M. Kadia, Farhad Ravandi, Kelly Chien, Grace Van Hyfte, Madhu Mazumdar, Antoine Saliba, Abhishek Mangaonkar, Terra Lasho, Aref Al-Kali, Marina Kremyanskaya, Jonathan Feld, Lewis R. Silverman, Rami Komrokji, John Mascarenhas, Eric Padron, Guillermo Garcia-Manero, David A. Sallman, Mrinal M. Patnaik, Guillermo Montalban-Bravo
{"title":"Venetoclax in combination with hypomethylating agents in chronic myelomonocytic leukemia: a propensity score matched multicenter cohort study","authors":"Douglas Tremblay, Clifford Csizmar, Courtney D. DiNardo, Somedeb Ball, Noa Rippel, Danielle Hammond, Tapan M. Kadia, Farhad Ravandi, Kelly Chien, Grace Van Hyfte, Madhu Mazumdar, Antoine Saliba, Abhishek Mangaonkar, Terra Lasho, Aref Al-Kali, Marina Kremyanskaya, Jonathan Feld, Lewis R. Silverman, Rami Komrokji, John Mascarenhas, Eric Padron, Guillermo Garcia-Manero, David A. Sallman, Mrinal M. Patnaik, Guillermo Montalban-Bravo","doi":"10.1038/s41375-024-02466-6","DOIUrl":"https://doi.org/10.1038/s41375-024-02466-6","url":null,"abstract":"<p>Chronic myelomonocytic leukemia (CMML) is a rare hematologic malignancy with overlapping features of myelodysplastic neoplasm (MDS) and myeloproliferative neoplasms characterized by peripheral blood monocytosis [1]. There is a predisposition for transformation to acute myeloid leukemia (AML), termed CMML with blast transformation (CMML-BT) [2, 3]. Hypomethylating agents (HMAs) are the sole FDA approved therapy for CMML albeit without established efficacy in terms of prolonging overall survival (OS) and halting disease evolution [4,5,6]. In order to improve response rates, venetoclax (VEN) has been combined with HMAs extrapolating data from AML and MDS [7, 8]. Single centers have offered varied results on the added benefit of VEN to HMA therapy in CMML and CMML-BT [9,10,11], but these studies lack control cohorts and are limited by small sample sizes of patients evaluated in each treatment setting and disease category.</p><p>To clarify the role of upfront HMA + VEN in patients with CMML and CMML-BT, we performed a multicenter retrospective cohort study utilizing a propensity score matched (PSM) cohort of patients treated with HMA alone.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"147 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599700","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}
引用次数: 0
Endothelial heterogeneity in bone marrow: insights across development, adult life and leukemia 骨髓中的内皮异质性:对发育、成年和白血病的认识
IF 11.4 1区 医学
Leukemia Pub Date : 2024-11-11 DOI: 10.1038/s41375-024-02453-x
I. L. Boueya, L. Sandhow, J. R. P. Albuquerque, R. Znaidi, D. Passaro
{"title":"Endothelial heterogeneity in bone marrow: insights across development, adult life and leukemia","authors":"I. L. Boueya, L. Sandhow, J. R. P. Albuquerque, R. Znaidi, D. Passaro","doi":"10.1038/s41375-024-02453-x","DOIUrl":"https://doi.org/10.1038/s41375-024-02453-x","url":null,"abstract":"<p>The central role of the endothelial microenvironment in orchestrating bone marrow (BM) homeostasis and hematopoietic support has been confirmed at various developmental stages and in adult life. The BM vasculature is crucial in mediating communication between BM parenchyma and circulating blood, displaying remarkable heterogeneity in structure and function. While vascular cell diversity in other tissues has long been recognized, the molecular basis of this phenomenon in BM is just now emerging. Over the past decade, single-cell approaches and microscopic observations have expanded our understanding of BM vasculature. While solely characterized for their paracrine properties in the past, recent advances have revolutionized our perception of endothelial function, revealing distinct anatomical locations associated with diverse endothelial cell states. The identification of phenotypic differences between normal and pathological conditions has therefore deepened our understanding of vascular dynamics and their impact on hematopoiesis in health and disease. In this review, we highlight key milestones and recent advances in understanding vascular heterogeneity within BM microenvironment during development, adulthood and aging. We also explore how leukemia affects this heterogeneity and how we can take this knowledge forward to improve clinical practices. By synthesizing existing literature, we aim to address unresolved questions and outline future research directions.</p><figure></figure>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"95 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142597977","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}
引用次数: 0
Genomic profiling of circulating tumor DNA for childhood cancers 针对儿童癌症的循环肿瘤 DNA 基因组特征分析
IF 11.4 1区 医学
Leukemia Pub Date : 2024-11-10 DOI: 10.1038/s41375-024-02461-x
Shaohua Lei, Sujuan Jia, Sunitha Takalkar, Ti-Cheng Chang, Xiaotu Ma, Karol Szlachta, Ke Xu, Zhongshan Cheng, Yawei Hui, Selene C. Koo, Paul E. Mead, Qingsong Gao, Priyadarshini Kumar, Colin P. Bailey, Jobin Sunny, Alberto S. Pappo, Sara M. Federico, Giles W. Robinson, Amar Gajjar, Jeffrey E. Rubnitz, Sima Jeha, Ching-Hon Pui, Hiroto Inaba, Gang Wu, Jeffery M. Klco, Ruth G. Tatevossian, Charles G. Mullighan
{"title":"Genomic profiling of circulating tumor DNA for childhood cancers","authors":"Shaohua Lei, Sujuan Jia, Sunitha Takalkar, Ti-Cheng Chang, Xiaotu Ma, Karol Szlachta, Ke Xu, Zhongshan Cheng, Yawei Hui, Selene C. Koo, Paul E. Mead, Qingsong Gao, Priyadarshini Kumar, Colin P. Bailey, Jobin Sunny, Alberto S. Pappo, Sara M. Federico, Giles W. Robinson, Amar Gajjar, Jeffrey E. Rubnitz, Sima Jeha, Ching-Hon Pui, Hiroto Inaba, Gang Wu, Jeffery M. Klco, Ruth G. Tatevossian, Charles G. Mullighan","doi":"10.1038/s41375-024-02461-x","DOIUrl":"https://doi.org/10.1038/s41375-024-02461-x","url":null,"abstract":"<p>The utility of circulating tumor DNA (ctDNA) analysis has not been well-established for disease detection and monitoring of childhood cancers, especially leukemias. We developed PeCan-Seq, a deep sequencing method targeting diverse somatic genomic variants in cell-free samples in childhood cancer. Plasma samples were collected at diagnosis from 233 children with hematologic, solid and brain tumors. All children with hematologic malignancy (<i>n</i> = 177) had detectable ctDNA at diagnosis. The median ctDNA fraction was 0.77, and 97% of 789 expected tumor variants were identified, including sequence mutations, copy number variations, and structural variations responsible for oncogenic fusions. In contrast, ctDNA was detected in 19 of 38 solid tumor patients and 1 of 18 brain tumor patients. Somatic variants from ctDNA were correlated with minimal residual disease levels as determined by flow cytometry in serial plasma samples from patients with B-cell acute lymphoblastic leukemia (B-ALL). We showcase multi-tumor detection by ctDNA analysis for a patient with concurrent B-ALL and neuroblastoma. In conclusion, PeCan-seq sensitively identified heterogeneous ctDNA alterations from 1 mL plasma for childhood hematologic malignancies and a subset of solid tumors. PeCan-seq provides a robust, non-invasive approach to augment comprehensive genomic profiling at diagnosis and mutation-specific detection during disease monitoring.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"127 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2024-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142598088","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}
引用次数: 0
The effect of methylation on the let-7-BCL2L1-BCL2 axis and the potential use of hypomethylating and BH3 mimetic drugs in histiocytic neoplasms 甲基化对 let-7-BCL2L1-BCL2 轴的影响以及低甲基化和 BH3 拟态药物在组织细胞肿瘤中的潜在用途
IF 11.4 1区 医学
Leukemia Pub Date : 2024-11-08 DOI: 10.1038/s41375-024-02459-5
Mali Salmon-Divon, Refael Meyuchas, Ofer Shpilberg, Elimelech Okon, Jamal Benhamida, Mariko Yabe, Kseniya Petrova-Drus, Tal Zvida-Bloch, May Basood, Roei Mazor, Benjamin H. Durham, Julien Haroche, Omar Abdel-Wahab, Eli L. Diamond, Oshrat Hershkovitz-Rokah
{"title":"The effect of methylation on the let-7-BCL2L1-BCL2 axis and the potential use of hypomethylating and BH3 mimetic drugs in histiocytic neoplasms","authors":"Mali Salmon-Divon, Refael Meyuchas, Ofer Shpilberg, Elimelech Okon, Jamal Benhamida, Mariko Yabe, Kseniya Petrova-Drus, Tal Zvida-Bloch, May Basood, Roei Mazor, Benjamin H. Durham, Julien Haroche, Omar Abdel-Wahab, Eli L. Diamond, Oshrat Hershkovitz-Rokah","doi":"10.1038/s41375-024-02459-5","DOIUrl":"https://doi.org/10.1038/s41375-024-02459-5","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"6 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596944","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}
引用次数: 0
Rapid growth of acquired UBA1 mutations predisposes male patients to low-risk MDS 获得性 UBA1 突变的快速增长使男性患者易患低风险 MDS
IF 11.4 1区 医学
Leukemia Pub Date : 2024-11-08 DOI: 10.1038/s41375-024-02397-2
Peng Li, F. N. U. Alnoor, Wei Xie, Margaret Williams, Julie Feusier, Yi Ding, Xiangrong Zhao, Gang Zheng, Chen Zhao, Arthur W. Zieske, Youli Zu, Philipp W. Raess, Srinivas Tantravahi, Afaf Osman, Ami B. Patel, Tsewang Tashi, Jay L. Patel, Anna P. Matynia, Madhu P. Menon, Rodney R. Miles, Jeffrey R. Jacobsen, Tracy I. George, Douglas W. Sborov, Philippe Szankasi, Paul Rindler, Devin Close, Robert S. Ohgami
{"title":"Rapid growth of acquired UBA1 mutations predisposes male patients to low-risk MDS","authors":"Peng Li, F. N. U. Alnoor, Wei Xie, Margaret Williams, Julie Feusier, Yi Ding, Xiangrong Zhao, Gang Zheng, Chen Zhao, Arthur W. Zieske, Youli Zu, Philipp W. Raess, Srinivas Tantravahi, Afaf Osman, Ami B. Patel, Tsewang Tashi, Jay L. Patel, Anna P. Matynia, Madhu P. Menon, Rodney R. Miles, Jeffrey R. Jacobsen, Tracy I. George, Douglas W. Sborov, Philippe Szankasi, Paul Rindler, Devin Close, Robert S. Ohgami","doi":"10.1038/s41375-024-02397-2","DOIUrl":"https://doi.org/10.1038/s41375-024-02397-2","url":null,"abstract":"<p>Between June 2022 and November 2023, targeted next-generation sequencing (NGS) was performed on blood or bone marrow samples at four US medical centers. We identified 27 distinct presumably somatic <i>UBA1</i> variants in 86 patients (1%, Fig. 1A). Sixty-six patients (0.7%) carried nine different pathogenic/likely pathogenic variants (PV, Fig. 1B above the protein sequence). Most were canonical loss-of-start-codon variants: p.M41T (N = 24), p.M41L (N = 21), and p.M41V (N = 14), followed by previously reported (c.118-1 G&gt;C, N = 2) and two novel splice site variants (c.118-10_118-1 del and c.118-5_118-1 del) upstream of the p.M41 codon. Further, three VEXAS-causal missense variants p.Y55H (N = 1), p.G477A (N = 1), and p.A478S (N = 1) were also classified as PV [1, 2, 4]. An additional 18 distinct novel variants (below the protein sequence in Fig. 1B and in Supplementary Table 1), classified as variants of uncertain significance (VUS), including two recurrent variants (p.D506N and p.I890F), were identified in the remaining 20 patients (Fig. 1B, C, patients 67-86).</p><p>Thirty-one (47%) patients with <i>UBA1</i> PV exhibited at least one concomitant variant, representing a significantly lower frequency compared to VUS patients (85%, p = 0.04, Fig. 1C, D and Table 1), accompanied by a lower somatic mutation burden, defined as the number of somatic variants per patient (Fig. 1E, mean ± SEM, 2.0 ± 0.2 in PV vs. 4.0 ± 0.5 in VUS, p = 0.0001). <i>UBA1</i> clone sizes were notably larger in PV (Fig. 1F, mean ± SEM, 26.1% ± 1.5) than those in VUS (16.0% ± 3.3, p = 0.002). Fifty-five PV patients (83%) exhibited <i>UBA1</i> variant VAFs higher than those of the leading concurrent variants, if any, indicating that <i>UBA1</i> PV were the founding clones. In contrast, only 40% of VUS (Fig. 1G, p = 0.001) were the leading clones. In PV patients, <i>DNMT3A</i> was the most commonly mutated gene (23%), followed by <i>TET2</i> (12%) and <i>ASXL1</i> (6%, Fig. 1C). In VUS patients, the most prevalent concomitant variant was <i>TET2</i> (Supplementary Fig. 1A, 35%, p = 0.03), followed by <i>ASXL1</i> (25%, p = 0.02) and <i>DNMT3A</i> variants (10%, p = 0.03). Notably, variants involved in tyrosine kinase or RAS signaling pathways were significantly more prevalent in VUS patients (Supplementary Fig. 1A–C).</p><figure><figcaption><b data-test=\"table-caption\">Table 1 The clinical diagnosis, molecular and cytogenetic profiles of 86 individuals with presumed somatic UBA1 variants.</b></figcaption><span>Full size table</span><svg aria-hidden=\"true\" focusable=\"false\" height=\"16\" role=\"img\" width=\"16\"><use xlink:href=\"#icon-eds-i-chevron-right-small\" xmlns:xlink=\"http://www.w3.org/1999/xlink\"></use></svg></figure>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"61 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596946","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}
引用次数: 0
Genome-first determination of the prevalence and penetrance of eight germline myeloid malignancy predisposition genes: a study of two population-based cohorts. 通过基因组首次确定八个种系髓系恶性肿瘤易感基因的流行率和渗透率:对两个人群队列的研究。
IF 12.8 1区 医学
Leukemia Pub Date : 2024-11-06 DOI: 10.1038/s41375-024-02436-y
Rachel M Hendricks, Jung Kim, Jeremy S Haley, Mark Louie Ramos, Uyenlinh L Mirshahi, David J Carey, Douglas R Stewart, Lisa J McReynolds
{"title":"Genome-first determination of the prevalence and penetrance of eight germline myeloid malignancy predisposition genes: a study of two population-based cohorts.","authors":"Rachel M Hendricks, Jung Kim, Jeremy S Haley, Mark Louie Ramos, Uyenlinh L Mirshahi, David J Carey, Douglas R Stewart, Lisa J McReynolds","doi":"10.1038/s41375-024-02436-y","DOIUrl":"https://doi.org/10.1038/s41375-024-02436-y","url":null,"abstract":"<p><p>It is estimated that 10% of individuals with a myeloid malignancy carry a germline susceptibility. Using the genome-first approach, in which individuals were ascertained on genotype alone, rather than clinical phenotype, we quantified the prevalence and penetrance of pathogenic germline variants in eight myeloid malignancy predisposition (gMMP) genes. ANKRD26, CEBPA, DDX41, MECOM, SRP72, ETV6, RUNX1 and GATA2, were analyzed from the Geisinger MyCode DiscovEHR (n = 170,503) and the United Kingdom Biobank (UKBB, n = 469,595). We identified a high risk of myeloid malignancies (MM) (odds ratio[OR] all genes: DiscovEHR, 4.6 [95% confidential interval (CI) 2.1-9.7], p < 0.0001; UKBB, 6.0 [95% CI 4.3-8.2], p = 3.1 × 10<sup>-27</sup>), and decreased overall survival (hazard ratio [HR] DiscovEHR, 1.8 [95% CI 1.3-2.6], p = 0.00049; UKBB, 1.4 [95% CI 1.2-1.8], p = 8.4 × 10<sup>-5</sup>) amongst heterozygotes. Pathogenic DDX41 variants were the most commonly identified, and in UKBB showed a significantly increased risk of MM (OR 5.7 [95% CI 3.9-8.3], p = 6.0 × 10<sup>-20</sup>) and increased all-cause mortality (HR 1.35 [95% CI 1.1-1.7], p = 0.0063). Through a genome-first approach, this study genetically ascertained individuals with a gMMP and determined their MM risk and survival.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":" ","pages":""},"PeriodicalIF":12.8,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582994","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}
引用次数: 0
Pre-emptive therapeutic decisions based on measurable residual disease status in acute myeloid leukemia: ready for prime time? 基于急性髓性白血病可测量残留疾病状态的先期治疗决策:准备好了吗?
IF 12.8 1区 医学
Leukemia Pub Date : 2024-11-05 DOI: 10.1038/s41375-024-02458-6
Firas El Chaer, Anthony J Perissinotti, Sanam Loghavi, Amer M Zeidan
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