Blood Cancer Discovery最新文献_第3页

Human ASXL1-Mutant Hematopoiesis Is Driven by a Truncated Protein Associated with Aberrant Deubiquitination of H2AK119. 人类 ASXL1 基因突变造血是由与 H2AK119 去泛素化异常有关的截短蛋白驱动的。

IF 11.5

Blood Cancer Discovery Pub Date : 2024-05-01 DOI: 10.1158/2643-3230.BCD-23-0235

Thomas Köhnke, Kevin A Nuno, Catherine C Alder, Eric J Gars, Paul Phan, Amy C Fan, Ravindra Majeti

{"title":"Human ASXL1-Mutant Hematopoiesis Is Driven by a Truncated Protein Associated with Aberrant Deubiquitination of H2AK119.","authors":"Thomas Köhnke, Kevin A Nuno, Catherine C Alder, Eric J Gars, Paul Phan, Amy C Fan, Ravindra Majeti","doi":"10.1158/2643-3230.BCD-23-0235","DOIUrl":"10.1158/2643-3230.BCD-23-0235","url":null,"abstract":"Mutations in additional sex combs like 1 (ASXL1) confer poor prognosis both in myeloid malignancies and in premalignant clonal hematopoiesis (CH). However, the mechanisms by which these mutations contribute to disease initiation remain unresolved, and mutation-specific targeting has remained elusive. To address this, we developed a human disease model that recapitulates the disease trajectory from ASXL1-mutant CH to lethal myeloid malignancy. We demonstrate that mutations in ASXL1 lead to the expression of a functional, truncated protein and determine that truncated ASXL1 leads to global redistribution of the repressive chromatin mark H2AK119Ub, increased transposase-accessible chromatin, and activation of both myeloid and stem cell gene-expression programs. Finally, we demonstrate that H2AK119Ub levels are tied to truncated ASXL1 expression levels and leverage this observation to demonstrate that inhibition of the PRC1 complex might be an ASXL1-mutant-specific therapeutic vulnerability in both premalignant CH and myeloid malignancy.Significance: Mutant ASXL1 is a common driver of CH and myeloid malignancy. Using primary human HSPCs, we determine that truncated ASXL1 leads to redistribution of H2AK119Ub and may affect therapeutic vulnerability to PRC1 inhibition.","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"202-223"},"PeriodicalIF":11.5,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11061584/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139742184","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

Acquired Multidrug Resistance in AML Is Caused by Low Apoptotic Priming in Relapsed Myeloblasts. 急性髓细胞性白血病的获得性多药耐药性是由复发性骨髓母细胞的低凋亡引致的。

IF 11.5

Blood Cancer Discovery Pub Date : 2024-05-01 DOI: 10.1158/2643-3230.BCD-24-0001

Elyse A Olesinski, Karanpreet Singh Bhatia, Chuqi Wang, Marissa S Pioso, Xiao Xian Lin, Ahmed M Mamdouh, Shu Xuan Ng, Vedant Sandhu, Shaista Shabbir Jasdanwala, Binyam Yilma, Stephan Bohl, Jeremy A Ryan, Disha Malani, Marlise R Luskin, Olli Kallioniemi, Kimmo Porkka, Sophia Adamia, Wee Joo Chng, Motomi Osato, David M Weinstock, Jacqueline S Garcia, Anthony Letai, Shruti Bhatt

{"title":"Acquired Multidrug Resistance in AML Is Caused by Low Apoptotic Priming in Relapsed Myeloblasts.","authors":"Elyse A Olesinski, Karanpreet Singh Bhatia, Chuqi Wang, Marissa S Pioso, Xiao Xian Lin, Ahmed M Mamdouh, Shu Xuan Ng, Vedant Sandhu, Shaista Shabbir Jasdanwala, Binyam Yilma, Stephan Bohl, Jeremy A Ryan, Disha Malani, Marlise R Luskin, Olli Kallioniemi, Kimmo Porkka, Sophia Adamia, Wee Joo Chng, Motomi Osato, David M Weinstock, Jacqueline S Garcia, Anthony Letai, Shruti Bhatt","doi":"10.1158/2643-3230.BCD-24-0001","DOIUrl":"10.1158/2643-3230.BCD-24-0001","url":null,"abstract":"In many cancers, mortality is associated with the emergence of relapse with multidrug resistance (MDR). Thus far, the investigation of cancer relapse mechanisms has largely focused on acquired genetic mutations. Using acute myeloid leukemia (AML) patient-derived xenografts (PDX), we systematically elucidated a basis of MDR and identified drug sensitivity in relapsed AML. We derived pharmacologic sensitivity for 22 AML PDX models using dynamic BH3 profiling (DBP), together with genomics and transcriptomics. Using in vivo acquired resistant PDXs, we found that resistance to unrelated, narrowly targeted agents in distinct PDXs was accompanied by broad resistance to drugs with disparate mechanisms. Moreover, baseline mitochondrial apoptotic priming was consistently reduced regardless of the class of drug-inducing selection. By applying DBP, we identified drugs showing effective in vivo activity in resistant models. This study implies evasion of apoptosis drives drug resistance and demonstrates the feasibility of the DBP approach to identify active drugs for patients with relapsed AML.Significance: Acquired resistance to targeted therapy remains challenging in AML. We found that reduction in mitochondrial priming and common transcriptomic signatures was a conserved mechanism of acquired resistance across different drug classes in vivo. Drugs active in vivo can be identified even in the multidrug resistant state by DBP.","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"180-201"},"PeriodicalIF":11.5,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11061585/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140040506","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

Round Table Discussion on Optimal Clinical Trial Design in Precursor Multiple Myeloma. 前体多发性骨髓瘤最佳临床试验设计圆桌讨论会。

IF 11.5

Blood Cancer Discovery Pub Date : 2024-05-01 DOI: 10.1158/2643-3230.BCD-24-0022

Irene M Ghobrial, Nicole Gormley, Shaji K Kumar, Maria-Victoria Mateos, P Leif Bergsagel, Marta Chesi, Madhav V Dhodapkar, Angela Dispenzieri, Rafael Fonseca, Gad Getz, Efstathios Kastritis, Sigurdur Y Kristinsson, Jose Angel Martinez-Climent, Salomon Manier, Catherine R Marinac, Francesco Maura, Gareth J Morgan, Faith E Davies, Omar Nadeem, Mario Nuvolone, Bruno Paiva, Elizabeth O'Donnell, Felipe Prosper, Urvi A Shah, Romanos Sklavenitis-Pistofidis, Adam S Sperling, George S Vassiliou, Nikhil C Munshi, Philip E Castle, Kenneth C Anderson, Jesus F San Miguel

{"title":"Round Table Discussion on Optimal Clinical Trial Design in Precursor Multiple Myeloma.","authors":"Irene M Ghobrial, Nicole Gormley, Shaji K Kumar, Maria-Victoria Mateos, P Leif Bergsagel, Marta Chesi, Madhav V Dhodapkar, Angela Dispenzieri, Rafael Fonseca, Gad Getz, Efstathios Kastritis, Sigurdur Y Kristinsson, Jose Angel Martinez-Climent, Salomon Manier, Catherine R Marinac, Francesco Maura, Gareth J Morgan, Faith E Davies, Omar Nadeem, Mario Nuvolone, Bruno Paiva, Elizabeth O'Donnell, Felipe Prosper, Urvi A Shah, Romanos Sklavenitis-Pistofidis, Adam S Sperling, George S Vassiliou, Nikhil C Munshi, Philip E Castle, Kenneth C Anderson, Jesus F San Miguel","doi":"10.1158/2643-3230.BCD-24-0022","DOIUrl":"10.1158/2643-3230.BCD-24-0022","url":null,"abstract":"Summary: While the current approach to precursor hematologic conditions is to \"watch and wait,\" this may change with the development of therapies that are safe and extend survival or delay the onset of symptomatic disease. The goal of future therapies in precursor hematologic conditions is to improve survival and prevent or delay the development of symptomatic disease while maximizing safety. Clinical trial considerations in this field include identifying an appropriate at-risk population, safety assessments, dose selection, primary and secondary trial endpoints including surrogate endpoints, control arms, and quality-of-life metrics, all of which may enable more precise benefit-risk assessment.","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"146-152"},"PeriodicalIF":11.5,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11061588/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140029182","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

"Myeloid" Mutations in ALL Are Not Uncommon: Implications for Etiology and Therapies. ALL 中的 "髓系 "突变并不罕见：对病因学和疗法的影响。

IF 11.5

Blood Cancer Discovery Pub Date : 2024-05-01 DOI: 10.1158/2643-3230.BCD-24-0015

Ilaria Iacobucci

引用次数: 0

Q&A: Owen Witte on Translational Research in Cancer. 问与答：欧文-维特（Owen Witte）谈癌症转化研究。

IF 11.2

Blood Cancer Discovery Pub Date : 2024-04-07 DOI: 10.1158/2643-3230.BCD-24-0069

引用次数: 0

Baseline Serum Inflammatory Proteins Predict Poor CAR T Outcomes in Diffuse Large B-cell Lymphoma. 基线血清炎症蛋白可预测弥漫大 B 细胞淋巴瘤 CAR T 的不良预后。

IF 11.5

Blood Cancer Discovery Pub Date : 2024-03-01 DOI: 10.1158/2643-3230.BCD-23-0056

Rawan G Faramand, Sae Bom Lee, Michael D Jain, Biwei Cao, Xuefeng Wang, Kai Rejeski, Marion Subklewe, Johannes F Fahrmann, Neeraj Y Saini, Samir M Hanash, Yun Pyo Kang, Darwin Chang, Paolo C Rodriguez, Erin A Dean, Taiga Nishihori, Bijal D Shah, Aleksandr Lazaryan, Julio Chavez, Farhad Khimani, Javier A Pinilla-Ibarz, Marian Dam, Kayla M Reid, Salvatore A Corallo, Meghan Menges, Melanie Hidalgo Vargas, Jay K Mandula, Brian A Holliday, Christina A Bachmeier, Kelly Speth, Qinghua Song, Mike Mattie, Frederick L Locke, Marco L Davila

{"title":"Baseline Serum Inflammatory Proteins Predict Poor CAR T Outcomes in Diffuse Large B-cell Lymphoma.","authors":"Rawan G Faramand, Sae Bom Lee, Michael D Jain, Biwei Cao, Xuefeng Wang, Kai Rejeski, Marion Subklewe, Johannes F Fahrmann, Neeraj Y Saini, Samir M Hanash, Yun Pyo Kang, Darwin Chang, Paolo C Rodriguez, Erin A Dean, Taiga Nishihori, Bijal D Shah, Aleksandr Lazaryan, Julio Chavez, Farhad Khimani, Javier A Pinilla-Ibarz, Marian Dam, Kayla M Reid, Salvatore A Corallo, Meghan Menges, Melanie Hidalgo Vargas, Jay K Mandula, Brian A Holliday, Christina A Bachmeier, Kelly Speth, Qinghua Song, Mike Mattie, Frederick L Locke, Marco L Davila","doi":"10.1158/2643-3230.BCD-23-0056","DOIUrl":"10.1158/2643-3230.BCD-23-0056","url":null,"abstract":"A subset of patients with diffuse large B-cell lymphoma (DLBCL) treated with CD19 chimeric antigen receptor (CAR) T-cell therapy have poor clinical outcomes. We report serum proteins associated with severe immune-mediated toxicities and inferior clinical responses in 146 patients with DLBCL treated with axicabtagene ciloleucel. We develop a simple stratification based on pre-lymphodepletion C reactive protein (CRP) and ferritin to classify patients into low-, intermediate-, and high-risk groups. We observe that patients in the high-risk category were more likely to develop grade ≥3 toxicities and had inferior overall and progression-free survival. We sought to validate our findings with two independent international cohorts demonstrating that patients classified as low-risk have excellent efficacy and safety outcomes. Based on routine and readily available laboratory tests that can be obtained prior to lymphodepleting chemotherapy, this simple risk stratification can inform patient selection for CAR T-cell therapy.Significance: CAR T-cell therapy has changed the treatment paradigm for patients with relapsed/refractory hematologic malignancies. Despite encouraging efficacy, a subset of patients have poor clinical outcomes. We show that a simple clinically applicable model using pre-lymphodepletion CRP and ferritin can identify patients at high risk of poor outcomes. This article is featured in Selected Articles from This Issue, p. 80.","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"106-113"},"PeriodicalIF":11.5,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10905320/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139404649","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

The Siren Song of Synergy. 协同作用的塞壬之歌

IF 11.5

Blood Cancer Discovery Pub Date : 2024-03-01 DOI: 10.1158/2643-3230.BCD-24-0004

Patrick D Bhola, Anthony Letai

引用次数: 0

Understanding Mechanisms of Response to CAR T-cell Therapy through Single-Cell Sequencing: Insights and Challenges. 通过单细胞测序了解 CAR T 细胞疗法的反应机制：见解与挑战。

IF 11.5

Blood Cancer Discovery Pub Date : 2024-03-01 DOI: 10.1158/2643-3230.BCD-23-0212

Nicholas J Haradhvala, Marcela V Maus

引用次数: 0

Correction: Defining an Optimal Dual-Targeted CAR T-cell Therapy Approach Simultaneously Targeting BCMA and GPRC5D to Prevent BCMA Escape-Driven Relapse in Multiple Myeloma. 更正：确定同时靶向BCMA和GPRC5D的最佳双靶向CAR T细胞疗法，预防多发性骨髓瘤BCMA逸出导致的复发。

IF 11.2

Blood Cancer Discovery Pub Date : 2024-03-01 DOI: 10.1158/2643-3230.BCD-24-0017

引用次数: 0

Altered Oxidative Phosphorylation Confers Vulnerability on IDH1-Mutant Leukemia Cells: Is This Therapeutically Tractable? 氧化磷酸化改变使 IDH1 突变的白血病细胞变得脆弱：这在治疗上可行吗？

IF 11.5

Blood Cancer Discovery Pub Date : 2024-03-01 DOI: 10.1158/2643-3230.BCD-23-0255

David P Steensma

引用次数: 0