Blood Cancer Discovery最新文献_第4页

Emerging Strategies for the Prevention of Immune Toxicities Associated with T cell-Engaging Cancer Therapies. 预防与 T 细胞激活癌症疗法相关的免疫毒性的新策略。

IF 11.5

Blood Cancer Discovery Pub Date : 2024-03-01 DOI: 10.1158/2643-3230.BCD-23-0228

Andrew Kowalski, Jill Lykon, Benjamin Diamond, David G Coffey, Marcella Kaddoura, Francesco Maura, James E Hoffman, Dickran Kazandjian, Ola Landgren

引用次数: 0

Synergistic Drug Combinations Promote the Development of Resistance in Acute Myeloid Leukemia. 协同药物组合会促进急性髓性白血病耐药性的产生。

IF 11.5

Blood Cancer Discovery Pub Date : 2024-03-01 DOI: 10.1158/2643-3230.BCD-23-0067

Emily Mason-Osann, Amy E Pomeroy, Adam C Palmer, Jerome T Mettetal

{"title":"Synergistic Drug Combinations Promote the Development of Resistance in Acute Myeloid Leukemia.","authors":"Emily Mason-Osann, Amy E Pomeroy, Adam C Palmer, Jerome T Mettetal","doi":"10.1158/2643-3230.BCD-23-0067","DOIUrl":"10.1158/2643-3230.BCD-23-0067","url":null,"abstract":"Combination therapy is an important part of cancer treatment and is often employed to overcome or prevent drug resistance. Preclinical screening strategies often prioritize synergistic drug combinations; however, studies of antibiotic combinations show that synergistic drug interactions can accelerate the emergence of resistance because resistance to one drug depletes the effect of both. In this study, we aimed to determine whether synergy drives the development of resistance in cancer cell lines using live-cell imaging. Consistent with prior models of tumor evolution, we found that when controlling for activity, drug synergy is associated with increased probability of developing drug resistance. We demonstrate that these observations are an expected consequence of synergy: the fitness benefit of resisting a drug in a combination is greater in synergistic combinations than in nonsynergistic combinations. These data have important implications for preclinical strategies aiming to develop novel combinations of cancer therapies with robust and durable efficacy.Significance: Preclinical strategies to identify combinations for cancer treatment often focus on identifying synergistic combinations. This study shows that in AML cells combinations that rely on synergy can increase the likelihood of developing resistance, suggesting that combination screening strategies may benefit from a more holistic approach rather than focusing on drug synergy. See related commentary by Bhola and Letai, p. 81. This article is featured in Selected Articles from This Issue, p. 80.","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"95-105"},"PeriodicalIF":11.5,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10905516/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139486512","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

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 11.2

Blood Cancer Discovery Pub Date : 2024-01-23 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":"https://doi.org/10.1158/2643-3230.BCD-23-0195","url":null,"abstract":"Rare preleukemic hematopoietic stem cells (pHSC) harboring only the initiating mutations can be detected at the time of acute myeloid leukemia (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 (HSC). 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 the complete eradication of IDH1-mutant pHSCs but not IDH2-mutant pHSCs or wild-type HSCs. Our results indicate that IDH1-mutant preleukemic clones can be targeted with complex I inhibitors, offering a potential strategy to prevent the development and relapse of leukemia.Significance: A high burden of pHSCs is associated with worse overall survival in AML. Using single-cell sequencing, metabolic assessment, and gene-edited human models, we find human pHSCs with IDH1 mutations to be metabolically vulnerable and sensitive to eradication by complex I inhibition. See related commentary by Steensma.","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"OF1-OF18"},"PeriodicalIF":11.2,"publicationDate":"2024-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139543189","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

ETV4-Dependent Transcriptional Plasticity Maintains MYC Expression and Results in IMiD Resistance in Multiple Myeloma. ETV4依赖性转录可塑性维持多发性骨髓瘤中MYC的表达并导致IMiD耐药性。

IF 11.2

Blood Cancer Discovery Pub Date : 2024-01-08 DOI: 10.1158/2643-3230.BCD-23-0061

Paola Neri, Benjamin G Barwick, David Jung, Jonathan C Patton, Ranjan Maity, Ines Tagoug, Caleb K Stein, Remi Tilmont, Noemie Leblay, Sungwoo Ahn, Holly Lee, Seth J Welsh, Daniel L Riggs, Nicholas Stong, Erin Flynt, Anjan Thakurta, Jonathan J Keats, Sagar Lonial, P Leif Bergsagel, Lawrence H Boise, Nizar J Bahlis

{"title":"ETV4-Dependent Transcriptional Plasticity Maintains MYC Expression and Results in IMiD Resistance in Multiple Myeloma.","authors":"Paola Neri, Benjamin G Barwick, David Jung, Jonathan C Patton, Ranjan Maity, Ines Tagoug, Caleb K Stein, Remi Tilmont, Noemie Leblay, Sungwoo Ahn, Holly Lee, Seth J Welsh, Daniel L Riggs, Nicholas Stong, Erin Flynt, Anjan Thakurta, Jonathan J Keats, Sagar Lonial, P Leif Bergsagel, Lawrence H Boise, Nizar J Bahlis","doi":"10.1158/2643-3230.BCD-23-0061","DOIUrl":"10.1158/2643-3230.BCD-23-0061","url":null,"abstract":"Immunomodulatory drugs (IMiD) are a backbone therapy for multiple myeloma (MM). Despite their efficacy, most patients develop resistance, and the mechanisms are not fully defined. Here, we show that IMiD responses are directed by IMiD-dependent degradation of IKZF1 and IKZF3 that bind to enhancers necessary to sustain the expression of MYC and other myeloma oncogenes. IMiD treatment universally depleted chromatin-bound IKZF1, but eviction of P300 and BRD4 coactivators only occurred in IMiD-sensitive cells. IKZF1-bound enhancers overlapped other transcription factor binding motifs, including ETV4. Chromatin immunoprecipitation sequencing showed that ETV4 bound to the same enhancers as IKZF1, and ETV4 CRISPR/Cas9-mediated ablation resulted in sensitization of IMiD-resistant MM. ETV4 expression is associated with IMiD resistance in cell lines, poor prognosis in patients, and is upregulated at relapse. These data indicate that ETV4 alleviates IKZF1 and IKZF3 dependency in MM by maintaining oncogenic enhancer activity and identify transcriptional plasticity as a previously unrecognized mechanism of IMiD resistance.Significance: We show that IKZF1-bound enhancers are critical for IMiD efficacy and that the factor ETV4 can bind the same enhancers and substitute for IKZF1 and mediate IMiD resistance by maintaining MYC and other oncogenes. These data implicate transcription factor redundancy as a previously unrecognized mode of IMiD resistance in MM. See related article by Welsh, Barwick, et al., p. 34. 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":" ","pages":"56-73"},"PeriodicalIF":11.2,"publicationDate":"2024-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10772538/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71486777","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

Transcriptional Plasticity Drives IMiD and p300 Inhibitor Resistance in Multiple Myeloma. 转录可塑性驱动多发性骨髓瘤的 IMiD 和 p300 抑制剂抗药性

IF 11.5

Blood Cancer Discovery Pub Date : 2024-01-08 DOI: 10.1158/2643-3230.BCD-23-0223

Seongseok Yun, John L Cleveland

引用次数: 0

Product Attributes of CAR T-cell Therapy Differentially Associate with Efficacy and Toxicity in Second-line Large B-cell Lymphoma (ZUMA-7). CAR - t细胞疗法的产品属性与二线大b细胞淋巴瘤(ZUMA-7)的疗效和毒性存在差异。

IF 11.2

Blood Cancer Discovery Pub Date : 2024-01-08 DOI: 10.1158/2643-3230.BCD-23-0112

Simone Filosto, Saran Vardhanabhuti, Miguel A Canales, Xavier Poiré, Lazaros J Lekakis, Sven de Vos, Craig A Portell, Zixing Wang, Christina To, Marco Schupp, Soumya Poddar, Tan Trinh, Carmen M Warren, Ethan G Aguilar, Justin Budka, Paul Cheng, Justin Chou, Adrian Bot, Rhine R Shen, Jason R Westin

{"title":"Product Attributes of CAR T-cell Therapy Differentially Associate with Efficacy and Toxicity in Second-line Large B-cell Lymphoma (ZUMA-7).","authors":"Simone Filosto, Saran Vardhanabhuti, Miguel A Canales, Xavier Poiré, Lazaros J Lekakis, Sven de Vos, Craig A Portell, Zixing Wang, Christina To, Marco Schupp, Soumya Poddar, Tan Trinh, Carmen M Warren, Ethan G Aguilar, Justin Budka, Paul Cheng, Justin Chou, Adrian Bot, Rhine R Shen, Jason R Westin","doi":"10.1158/2643-3230.BCD-23-0112","DOIUrl":"10.1158/2643-3230.BCD-23-0112","url":null,"abstract":"Treatment resistance and toxicities remain a risk following chimeric antigen receptor (CAR) T-cell therapy. Herein, we report pharmacokinetics, pharmacodynamics, and product and apheresis attributes associated with outcomes among patients with relapsed/refractory large B-cell lymphoma (LBCL) treated with axicabtagene ciloleucel (axi-cel) in ZUMA-7. Axi-cel peak expansion associated with clinical response and toxicity, but not response durability. In apheresis material and final product, a naive T-cell phenotype (CCR7+CD45RA+) expressing CD27 and CD28 associated with improved response durability, event-free survival, progression-free survival, and a lower number of prior therapies. This phenotype was not associated with high-grade cytokine release syndrome (CRS) or neurologic events. Higher baseline and postinfusion levels of serum inflammatory markers associated with differentiated/effector products, reduced efficacy, and increased CRS and neurologic events, thus suggesting targets for intervention. These data support better outcomes with earlier CAR T-cell intervention and may improve patient care by informing on predictive biomarkers and development of next-generation products.Significance: In ZUMA-7, the largest randomized CAR T-cell trial in LBCL, a naive T-cell product phenotype (CCR7+CD45RA+) expressing CD27 and CD28 associated with improved efficacy, decreased toxicity, and a lower number of prior therapies, supporting earlier intervention with CAR T-cell therapy. In addition, targets for improvement of therapeutic index are proposed. This article is featured in Selected Articles from This Issue, p. 4.","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"21-33"},"PeriodicalIF":11.2,"publicationDate":"2024-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10772511/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138177480","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

Retraction: In Vivo Monitoring of Polycythemia Vera Development Reveals Carbonic Anhydrase 1 as a Potent Therapeutic Target. 撤回：体内监测多发性红细胞瘤的发展发现碳酸酐酶 1 是一个有效的治疗靶点

IF 11.2

Blood Cancer Discovery Pub Date : 2024-01-08 DOI: 10.1158/2643-3230.BCD-23-0218

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":" ","pages":"8-20"},"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

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":" ","pages":"34-55"},"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

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