Blood Cancer Discovery最新文献_第7页

Transcriptional Heterogeneity Overcomes Super-Enhancer Disrupting Drug Combinations in Multiple Myeloma. 转录异质性克服了多发性骨髓瘤中破坏超级增强子的药物组合。

IF 11.5

Blood Cancer Discovery Pub Date : 2024-01-08 DOI: 10.1158/2643-3230.BCD-23-0062

Seth J Welsh, Benjamin G Barwick, Erin W Meermeier, Daniel L Riggs, Chang-Xin Shi, Yuan Xiao Zhu, Meaghen E Sharik, Megan T Du, Leslie D Abrego Rocha, Victoria M Garbitt, Caleb K Stein, Joachim L Petit, Nathalie Meurice, Yuliza Tafoya Alvarado, Rodrigo Fonseca, Kennedi T Todd, Sochilt Brown, Zachery J Hammond, Nicklus H Cuc, Courtney Wittenberg, Camille Herzog, Anna V Roschke, Yulia N Demchenko, Wei-Dong D Chen, Peng Li, Wei Liao, Warren J Leonard, Sagar Lonial, Nizar J Bahlis, Paola Neri, Lawrence H Boise, Marta Chesi, P Leif Bergsagel

{"title":"Transcriptional Heterogeneity Overcomes Super-Enhancer Disrupting Drug Combinations in Multiple Myeloma.","authors":"Seth J Welsh, Benjamin G Barwick, Erin W Meermeier, Daniel L Riggs, Chang-Xin Shi, Yuan Xiao Zhu, Meaghen E Sharik, Megan T Du, Leslie D Abrego Rocha, Victoria M Garbitt, Caleb K Stein, Joachim L Petit, Nathalie Meurice, Yuliza Tafoya Alvarado, Rodrigo Fonseca, Kennedi T Todd, Sochilt Brown, Zachery J Hammond, Nicklus H Cuc, Courtney Wittenberg, Camille Herzog, Anna V Roschke, Yulia N Demchenko, Wei-Dong D Chen, Peng Li, Wei Liao, Warren J Leonard, Sagar Lonial, Nizar J Bahlis, Paola Neri, Lawrence H Boise, Marta Chesi, P Leif Bergsagel","doi":"10.1158/2643-3230.BCD-23-0062","DOIUrl":"10.1158/2643-3230.BCD-23-0062","url":null,"abstract":"Multiple myeloma (MM) is a malignancy that is often driven by MYC and that is sustained by IRF4, which are upregulated by super-enhancers. IKZF1 and IKZF3 bind to super-enhancers and can be degraded using immunomodulatory imide drugs (IMiD). Successful IMiD responses downregulate MYC and IRF4; however, this fails in IMiD-resistant cells. MYC and IRF4 downregulation can also be achieved in IMiD-resistant tumors using inhibitors of BET and EP300 transcriptional coactivator proteins; however, in vivo these drugs have a narrow therapeutic window. By combining IMiDs with EP300 inhibition, we demonstrate greater downregulation of MYC and IRF4, synergistic killing of myeloma in vitro and in vivo, and an increased therapeutic window. Interestingly, this potent combination failed where MYC and IRF4 expression was maintained by high levels of the AP-1 factor BATF. Our results identify an effective drug combination and a previously unrecognized mechanism of IMiD resistance.Significance: These results highlight the dependence of MM on IKZF1-bound super-enhancers, which can be effectively targeted by a potent therapeutic combination pairing IMiD-mediated degradation of IKZF1 and IKZF3 with EP300 inhibition. They also identify AP-1 factors as an unrecognized mechanism of IMiD resistance in MM. See related article by Neri, Barwick, et al., p. 56. See related commentary by Yun and Cleveland, p. 5. This article is featured in Selected Articles from This Issue, p. 4.","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":null,"pages":null},"PeriodicalIF":11.5,"publicationDate":"2024-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10772542/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41170235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Criteria for Diagnosis and Molecular Monitoring of NPM1-Mutated AML. NPM1突变AML的诊断和分子监测标准。

IF 11.5

Blood Cancer Discovery Pub Date : 2024-01-08 DOI: 10.1158/2643-3230.BCD-23-0144

Brunangelo Falini, Richard Dillon

{"title":"Criteria for Diagnosis and Molecular Monitoring of NPM1-Mutated AML.","authors":"Brunangelo Falini, Richard Dillon","doi":"10.1158/2643-3230.BCD-23-0144","DOIUrl":"10.1158/2643-3230.BCD-23-0144","url":null,"abstract":"NPM1-mutated acute myeloid leukemia (AML) represents the largest molecular subgroup of adult AML. NPM1-mutated AML is recognizable by molecular techniques and immunohistochemistry, which, when combined, can solve difficult diagnostic problems (including identification of myeloid sarcoma and NPM1 mutations outside exon 12). According to updated 2022 European LeukemiaNet (ELN) guidelines, determining the mutational status of NPM1 (and FLT3) is a mandatory step for the genetic-based risk stratification of AML. Monitoring of measurable residual disease (MRD) by qRT-PCR, combined with ELN risk stratification, can guide therapeutic decisions at the post-remission stage. Here, we review the criteria for appropriate diagnosis and molecular monitoring of NPM1-mutated AML.Significance: NPM1-mutated AML represents a distinct entity in the 2022 International Consensus Classification and 5th edition of World Health Organization classifications of myeloid neoplasms. The correct diagnosis of NPM1-mutated AML and its distinction from other AML entities is extremely important because it has clinical implications for the management of AML patients, such as genetic-based risk stratification according to 2022 ELN. Monitoring of MRD by qRT-PCR, combined with ELN risk stratification, can guide therapeutic decisions at the post-remission stage, e.g., whether or not to perform allogeneic hematopoietic stem cell transplantation.","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":null,"pages":null},"PeriodicalIF":11.5,"publicationDate":"2024-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10772525/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71427418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Highlighted research articles 重点研究文章

IF 11.2

Blood Cancer Discovery Pub Date : 2024-01-08 DOI: 10.1158/2643-3230.bcd-5-1-iti

引用次数: 0

Acknowledgment to Reviewers. 感谢审稿人。

IF 11.2

Blood Cancer Discovery Pub Date : 2024-01-08 DOI: 10.1158/2643-3230.BCD-5-1-AR

引用次数: 0

IDH1-mutant preleukemic hematopoietic stem cells can be eliminated by inhibition of oxidative phosphorylation. 抑制氧化磷酸化可消除 IDH1 突变的白血病前期造血干细胞。

IF 11.5

Blood Cancer Discovery Pub Date : 2023-12-13 DOI: 10.1158/2643-3230.BCD-23-0195

Niklas Landberg, Thomas Köhnke, Yang Feng, Yusuke Nakauchi, Amy C Fan, Miles H Linde, Daiki Karigane, Kelly Lim, Rahul Sinha, Luca Malcovati, Daniel Thomas, Ravindra Majeti

{"title":"IDH1-mutant preleukemic hematopoietic stem cells can be eliminated by inhibition of oxidative phosphorylation.","authors":"Niklas Landberg, Thomas Köhnke, Yang Feng, Yusuke Nakauchi, Amy C Fan, Miles H Linde, Daiki Karigane, Kelly Lim, Rahul Sinha, Luca Malcovati, Daniel Thomas, Ravindra Majeti","doi":"10.1158/2643-3230.BCD-23-0195","DOIUrl":"10.1158/2643-3230.BCD-23-0195","url":null,"abstract":"Rare preleukemic hematopoietic stem cells (pHSCs) harboring only the initiating mutations can be detected at the time of AML diagnosis. pHSCs are the origin of leukemia and a potential reservoir for relapse. Using primary human samples and gene-editing to model isocitrate dehydrogenase 1 (IDH1) mutant pHSCs, we show epigenetic, transcriptional, and metabolic differences between pHSCs and healthy hematopoietic stem cells (HSCs). We confirm that IDH1 driven clonal hematopoiesis is associated with cytopenia, suggesting an inherent defect to fully reconstitute hematopoiesis. Despite giving rise to multilineage engraftment, IDH1-mutant pHSCs exhibited reduced proliferation, blocked differentiation, downregulation of MHC Class II genes, and reprogramming of oxidative phosphorylation metabolism. Critically, inhibition of oxidative phosphorylation resulted in complete eradication of IDH1-mutant pHSCs but not IDH2-mutant pHSCs or wildtype HSCs. Our results indicate that IDH1-mutant preleukemic clones can be targeted with complex I inhibitors, offering a potential strategy to prevent development and relapse of leukemia.","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":null,"pages":null},"PeriodicalIF":11.5,"publicationDate":"2023-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10905513/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138810547","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Highlighted research articles 重点研究文章

Blood Cancer Discovery Pub Date : 2023-11-01 DOI: 10.1158/2643-3230.bcd-4-6-iti

{"title":"Highlighted research articles","authors":"","doi":"10.1158/2643-3230.bcd-4-6-iti","DOIUrl":"https://doi.org/10.1158/2643-3230.bcd-4-6-iti","url":null,"abstract":"In This Issue| November 01 2023 Highlighted research articles Author & Article Information Online ISSN: 2643-3249 Print ISSN: 2643-3230 ©2023 American Association for Cancer Research2023American Association for Cancer Research Blood Cancer Discov (2023) 4 (6): 419. https://doi.org/10.1158/2643-3230.BCD-4-6-ITI Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn Email Tools Icon Tools Get Permissions Cite Icon Cite Search Site Article Versions Icon Versions Version of Record November 1 2023 Citation Highlighted research articles. Blood Cancer Discov 1 November 2023; 4 (6): 419. https://doi.org/10.1158/2643-3230.BCD-4-6-ITI Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest Search Advanced Search Anti-BCMA bispecific T-cell engager antibodies (BiTE) have demonstrated impressive efficacy in heavily relapsed multiple myeloma patients; however, infections remain a serious concern with these therapies. In this article, Lancman et al. demonstrate that profound and prolonged hypogammaglobulinemia is universal in patients responding to therapy and is a significant driver of infections. Intravenous immunoglobulin (IVIg) replacement mitigates the risk of serious infections ten-fold. The findings support IVIg as a primary prophylaxis throughout the duration of therapy and raise questions about the optimal schedule and duration of BiTE treatment. See article, p. 440. The combination of azacytidine with venetoclax has become the standard first-line treatment for patients with acute myeloid leukemia (AML) unable to tolerate chemotherapy. However, there is still unmet need for not only identifying poor-responding patients but also identifying effective therapeutic strategies for them. In this precision medicine proof-of-concept study, Eide, Kurtz et al. implement ex vivo screening of... You do not currently have access to this content.","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135272192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

An Embarrassment of Riches: Three FDA-Approved Bispecific Antibodies for Relapsed Refractory Multiple Myeloma. 财富的尴尬：三种美国食品药品监督管理局批准的用于复发性难治性多发性骨髓瘤的双特异性抗体。

IF 11.2

Blood Cancer Discovery Pub Date : 2023-11-01 DOI: 10.1158/2643-3230.BCD-23-0176

Ross Firestone, Alexander M Lesokhin, Saad Z Usmani

引用次数: 0

Understanding Infection Risk with Anti-BCMA Bispecific Antibodies. 了解抗BCMA双特异性抗体的感染风险。

IF 11.2

Blood Cancer Discovery Pub Date : 2023-11-01 DOI: 10.1158/2643-3230.BCD-23-0157

Alfred L Garfall, Edward A Stadtmauer

引用次数: 0

Immune Surveillance of Acute Myeloid Leukemia Is Mediated by HLA-Presented Antigens on Leukemia Progenitor Cells. 白血病祖细胞HLA抗原介导的急性粒细胞白血病免疫监测。

IF 11.2

Blood Cancer Discovery Pub Date : 2023-11-01 DOI: 10.1158/2643-3230.BCD-23-0020

Annika Nelde, Heiko Schuster, Jonas S Heitmann, Jens Bauer, Yacine Maringer, Melissa Zwick, Jens-Peter Volkmer, James Y Chen, Anna M Paczulla Stanger, Ariane Lehmann, Bismark Appiah, Melanie Märklin, Elke Rücker-Braun, Helmut R Salih, Malte Roerden, Sarah M Schroeder, Max-Felix Häring, Andreas Schlosser, Johannes Schetelig, Marc Schmitz, Melanie Boerries, Natalie Köhler, Claudia Lengerke, Ravindra Majeti, Irving L Weissman, Hans-Georg Rammensee, Juliane S Walz

{"title":"Immune Surveillance of Acute Myeloid Leukemia Is Mediated by HLA-Presented Antigens on Leukemia Progenitor Cells.","authors":"Annika Nelde, Heiko Schuster, Jonas S Heitmann, Jens Bauer, Yacine Maringer, Melissa Zwick, Jens-Peter Volkmer, James Y Chen, Anna M Paczulla Stanger, Ariane Lehmann, Bismark Appiah, Melanie Märklin, Elke Rücker-Braun, Helmut R Salih, Malte Roerden, Sarah M Schroeder, Max-Felix Häring, Andreas Schlosser, Johannes Schetelig, Marc Schmitz, Melanie Boerries, Natalie Köhler, Claudia Lengerke, Ravindra Majeti, Irving L Weissman, Hans-Georg Rammensee, Juliane S Walz","doi":"10.1158/2643-3230.BCD-23-0020","DOIUrl":"10.1158/2643-3230.BCD-23-0020","url":null,"abstract":"Therapy-resistant leukemia stem and progenitor cells (LSC) are a main cause of acute myeloid leukemia (AML) relapse. LSC-targeting therapies may thus improve outcome of patients with AML. Here we demonstrate that LSCs present HLA-restricted antigens that induce T-cell responses allowing for immune surveillance of AML. Using a mass spectrometry-based immunopeptidomics approach, we characterized the antigenic landscape of patient LSCs and identified AML- and AML/LSC-associated HLA-presented antigens absent from normal tissues comprising nonmutated peptides, cryptic neoepitopes, and neoepitopes of common AML driver mutations of NPM1 and IDH2. Functional relevance of shared AML/LSC antigens is illustrated by presence of their cognizant memory T cells in patients. Antigen-specific T-cell recognition and HLA class II immunopeptidome diversity correlated with clinical outcome. Together, these antigens shared among AML and LSCs represent prime targets for T cell-based therapies with potential of eliminating residual LSCs in patients with AML.Significance: The elimination of therapy-resistant leukemia stem and progenitor cells (LSC) remains a major challenge in the treatment of AML. This study identifies and functionally validates LSC-associated HLA class I and HLA class II-presented antigens, paving the way to the development of LSC-directed T cell-based immunotherapeutic approaches for patients with AML. See related commentary by Ritz, p. 430 . This article is featured in Selected Articles from This Issue, p. 419.","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":null,"pages":null},"PeriodicalIF":11.2,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10618727/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41239314","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Potent Personalized Venetoclax Partners for Acute Myeloid Leukemia Identified by Ex Vivo Drug Screening. 通过体外药物筛选鉴定急性髓细胞白血病的强效个性化Venetoclax伴侣。

IF 11.2

Blood Cancer Discovery Pub Date : 2023-11-01 DOI: 10.1158/2643-3230.BCD-23-0180

Pamela S Becker

引用次数: 0