Pub Date : 2024-05-01DOI: 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
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.
{"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":"<p><p>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.</p><p><strong>Significance: </strong>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.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":null,"pages":null},"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}
Pub Date : 2024-05-01DOI: 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
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.
{"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":"<p><strong>Summary: </strong>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.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":null,"pages":null},"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}
Pub Date : 2024-05-01DOI: 10.1158/2643-3230.BCD-24-0015
Ilaria Iacobucci
Summary: In Blood Cancer Discovery, Saygin and colleagues report that somatic variants that are recurrent in myeloid malignancies can also occur with high frequency (16%) in adult acute lymphoblastic leukemia (ALL) where they correlate with older age, diagnosis following genotoxic therapy for a prior malignancy and worse outcome to chemotherapy. Mutations in these "myeloid" genes can precede ALL diagnosis and arise in hematopoietic stem or progenitor cells that clonally expand and differentiate into both lymphoblasts and nonmalignant myeloid cells, supporting a role for clonal hematopoiesis as premalignant state outside the context of myeloid malignancies and providing implications for both ALL etiology and therapeutic intervention. See related article by Saygin et al., p. 164 (4).
摘要: Saygin及其同事在《血癌发现》（Blood Cancer Discovery）杂志上报告说，在髓系恶性肿瘤中反复出现的体细胞变异也会高频率（16%）地出现在成人急性淋巴细胞白血病（ALL）中，这些变异与年龄偏大、之前的恶性肿瘤经基因毒性治疗后确诊以及化疗效果较差有关。这些 "髓系 "基因的突变可能发生在ALL诊断之前，并出现在造血干细胞或祖细胞中，这些细胞会克隆扩增并分化成淋巴母细胞和非恶性髓系细胞，从而支持克隆造血作为髓系恶性肿瘤之外的恶性前状态的作用，并对ALL的病因学和治疗干预产生影响。参见 Saygin 等人的相关文章，第 164 页（4）。
{"title":"\"Myeloid\" Mutations in ALL Are Not Uncommon: Implications for Etiology and Therapies.","authors":"Ilaria Iacobucci","doi":"10.1158/2643-3230.BCD-24-0015","DOIUrl":"10.1158/2643-3230.BCD-24-0015","url":null,"abstract":"<p><strong>Summary: </strong>In Blood Cancer Discovery, Saygin and colleagues report that somatic variants that are recurrent in myeloid malignancies can also occur with high frequency (16%) in adult acute lymphoblastic leukemia (ALL) where they correlate with older age, diagnosis following genotoxic therapy for a prior malignancy and worse outcome to chemotherapy. Mutations in these \"myeloid\" genes can precede ALL diagnosis and arise in hematopoietic stem or progenitor cells that clonally expand and differentiate into both lymphoblasts and nonmalignant myeloid cells, supporting a role for clonal hematopoiesis as premalignant state outside the context of myeloid malignancies and providing implications for both ALL etiology and therapeutic intervention. See related article by Saygin et al., p. 164 (4).</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":null,"pages":null},"PeriodicalIF":11.5,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11061583/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140865548","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}
Pub Date : 2024-04-22DOI: 10.1158/2643-3230.BCD-24-0057
Rebecca Austin, I. Aifantis
SUMMARY The spatial distribution of cells carrying clonal hematopoiesis mutations in the bone marrow and the potential role of interactions with the microenvironment are largely unknown. This study takes clonal evolution to the spatial level by describing a novel technique examining the spatial location of mutated clones in the bone marrow and the first evidence that mutated hematopoietic clones are spatially constrained and have heterogenous locations within millimeters of distance. See related article by Young et al., p. 153 (10).
摘要 骨髓中携带克隆造血突变的细胞的空间分布以及与微环境相互作用的潜在作用在很大程度上是未知的。这项研究将克隆进化提升到空间层面，描述了一种检查骨髓中突变克隆空间位置的新技术，并首次证明突变造血克隆受空间限制，在几毫米的距离内具有不同的位置。参见 Young 等人的相关文章，第 153 页（10）。
{"title":"Hematopoietic Clonal Evolution Goes Spatial.","authors":"Rebecca Austin, I. Aifantis","doi":"10.1158/2643-3230.BCD-24-0057","DOIUrl":"https://doi.org/10.1158/2643-3230.BCD-24-0057","url":null,"abstract":"SUMMARY\u0000The spatial distribution of cells carrying clonal hematopoiesis mutations in the bone marrow and the potential role of interactions with the microenvironment are largely unknown. This study takes clonal evolution to the spatial level by describing a novel technique examining the spatial location of mutated clones in the bone marrow and the first evidence that mutated hematopoietic clones are spatially constrained and have heterogenous locations within millimeters of distance. See related article by Young et al., p. 153 (10).","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":null,"pages":null},"PeriodicalIF":11.2,"publicationDate":"2024-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140676842","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}
Pub Date : 2024-04-17DOI: 10.1158/2643-3230.BCD-23-0182
L. Meriranta, Selma Sorri, K. Huse, Xiaonan Liu, I. Spasevska, Sadia Zafar, Iftekhar Chowdhury, O. Dufva, Eerika Sahlberg, Luka Tandaric, M. Karjalainen-Lindsberg, Marko Hyytiainen, M. Varjosalo, J. Myklebust, S. Leppa
Pathomechanisms that activate oncogenic B-cell receptor (BCR) signaling in diffuse large B-cell lymphoma (DLBCL), are largely unknown. Kelch-like family member 6 (KLHL6) encoding a substrate-adapter for Cullin-3-RING E3 ubiquitin-ligase (CRL) with poorly established targets is recurrently mutated in DLBCL. By applying high-throughput protein interactome screens and functional characterization, we discovered that KLHL6 regulates BCR by targeting its signaling subunits CD79A and CD79B. Loss of physiological KLHL6 expression pattern was frequent among the MCD/C5-like activated B-cell DLBCLs and was associated with higher CD79B levels and dismal outcome. Mutations in the BTB domain of KLHL6 disrupted its localization and heterodimerization, and increased surface BCR levels and signaling, whereas Kelch domain mutants had the opposite effect. Malfunctions of KLHL6 mutants extended beyond proximal BCR signaling with distinct phenotypes from KLHL6 silencing. Collectively, our findings uncover how recurrent mutations in KLHL6 alter BCR signaling and induce actionable phenotypic characteristics in DLBCL.
弥漫大B细胞淋巴瘤（DLBCL）中激活致癌B细胞受体（BCR）信号传导的病理机制在很大程度上尚属未知。Kelch样家族成员6（Kelch-like family member 6，KLHL6）编码Cullin-3-RING E3泛素连接酶（CRL）的底物适配器，其靶点尚未明确，在DLBCL中反复发生突变。通过应用高通量蛋白质相互作用组筛选和功能表征，我们发现KLHL6通过靶向其信号亚基CD79A和CD79B来调控BCR。在MCD/C5样活化B细胞DLBCL中，KLHL6生理表达模式的缺失很常见，并且与CD79B水平升高和预后不良有关。KLHL6的BTB结构域突变破坏了其定位和异源二聚体化，并增加了表面BCR水平和信号传导，而Kelch结构域突变体则具有相反的效果。KLHL6突变体的功能障碍超出了近端BCR信号转导，其表型与KLHL6沉默不同。总之，我们的研究结果揭示了KLHL6的复发性突变如何改变BCR信号转导并诱导DLBCL的表型特征。
{"title":"Disruption of KLHL6 Fuels Oncogenic Antigen Receptor Signaling in B-cell Lymphoma.","authors":"L. Meriranta, Selma Sorri, K. Huse, Xiaonan Liu, I. Spasevska, Sadia Zafar, Iftekhar Chowdhury, O. Dufva, Eerika Sahlberg, Luka Tandaric, M. Karjalainen-Lindsberg, Marko Hyytiainen, M. Varjosalo, J. Myklebust, S. Leppa","doi":"10.1158/2643-3230.BCD-23-0182","DOIUrl":"https://doi.org/10.1158/2643-3230.BCD-23-0182","url":null,"abstract":"Pathomechanisms that activate oncogenic B-cell receptor (BCR) signaling in diffuse large B-cell lymphoma (DLBCL), are largely unknown. Kelch-like family member 6 (KLHL6) encoding a substrate-adapter for Cullin-3-RING E3 ubiquitin-ligase (CRL) with poorly established targets is recurrently mutated in DLBCL. By applying high-throughput protein interactome screens and functional characterization, we discovered that KLHL6 regulates BCR by targeting its signaling subunits CD79A and CD79B. Loss of physiological KLHL6 expression pattern was frequent among the MCD/C5-like activated B-cell DLBCLs and was associated with higher CD79B levels and dismal outcome. Mutations in the BTB domain of KLHL6 disrupted its localization and heterodimerization, and increased surface BCR levels and signaling, whereas Kelch domain mutants had the opposite effect. Malfunctions of KLHL6 mutants extended beyond proximal BCR signaling with distinct phenotypes from KLHL6 silencing. Collectively, our findings uncover how recurrent mutations in KLHL6 alter BCR signaling and induce actionable phenotypic characteristics in DLBCL.","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":null,"pages":null},"PeriodicalIF":11.2,"publicationDate":"2024-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140693421","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}
Pub Date : 2024-04-07DOI: 10.1158/2643-3230.BCD-24-0069
{"title":"Q&A: Owen Witte on Translational Research in Cancer.","authors":"","doi":"10.1158/2643-3230.BCD-24-0069","DOIUrl":"https://doi.org/10.1158/2643-3230.BCD-24-0069","url":null,"abstract":"","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":null,"pages":null},"PeriodicalIF":11.2,"publicationDate":"2024-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140855845","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}
Pub Date : 2024-04-07DOI: 10.1158/2643-3230.BCD-24-0069
David Gennert
{"title":"Q&A: Owen Witte on Leukemia Genetics.","authors":"David Gennert","doi":"10.1158/2643-3230.BCD-24-0069","DOIUrl":"https://doi.org/10.1158/2643-3230.BCD-24-0069","url":null,"abstract":"","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":null,"pages":null},"PeriodicalIF":11.2,"publicationDate":"2024-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140733373","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}
Pub Date : 2024-03-04DOI: 10.1158/2643-3249.bcdsymp24-p36
Abou A Koundio, M. Ndour, Mame Ndella Diouf, Fatou Binetou Akonde, Awa Oumar Touré, Martine Raphael
OBJECTIVE: ALL is the most common cancer in children and the most common cause of cancer death before the age of 20. In low- and middle-income countries, ALL is associated with poor outcomes. Many constraints are at the root of management failures. Therefore, in view of the progressive improvements in the efficacy of chemotherapeutic regimens, we deemed it necessary to conduct this study, the objective of which is to evaluate the role of biology in the management of children with ALL in the Oncopediatric Unit of Dakar. METHODS: This is a prospective analytical study that started on November 15th, 2021 at the UOP in collaboration with the hematology and immunology laboratories. All newly diagnosed patients with ALL based-on cytology and/or immunophenotyping, treated according to the ALL-GFAOP protocol and registered in the REDcap database are included. RESULTS: From November, 15th 2021 to July, 31th 2023, 48 patients were diagnosed with de novo ALL. With an average age of 7.8 years, female represented the main group (52,08%). According to immunophenotyping, the B profile was found in 25.0 % and the T profile in 22.9 %. The ALL T group was older (9.2 vs 4.4 years) and have had higher platelet counts (122272.7 vs 46916.7) at diagnosis than the ALL B group. This latter had higher hemoglobin (7.4 vs 6.8), white blood cell (127296.2 vs 56511.2) and blast counts at diagnosis in peripheral blood (69.4% vs 55.1%) and also in bone marrow (84.2% vs 72.5%) and higher rate of residual blast counts at Day8 after induction (9198.4 vs 1301.4). Regarding corticosensitivity at D8 of induction, no difference was found according to the number of blasts, the hemoglobinlevel and the immunological profile at diagnosis. However, patients with hyperleukocytic ALL with a relatively higher platelet count were more sensitive to corticosteroid therapy. CONCLUSIONS: Understanding the biology of acute ALL is of major interest in the effectiveness of therapeutic approaches to this type of hematology malignancies. Citation Format: Abou A Koundio, Moussa Ndour, Mame Ndella Diouf, Fatou Binetou Akonde, Awa Oumar Toure, Martine Raphael. BIOLOGY IN ACUTE LYMPHOBLASTIC LEUKEMIA FROM DIAGNOSIS TO FOLLOW-UP: A STUDY OF 48CASES [abstract]. In: Proceedings of the Blood Cancer Discovery Symposium; 2024 Mar 4-6; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(2_Suppl):Abstract nr P36.
目的： ALL 是儿童最常见的癌症，也是 20 岁前儿童癌症死亡的最常见原因。在中低收入国家，ALL 的治疗效果不佳。许多制约因素是管理失败的根源。因此，鉴于化疗方案的疗效在逐步提高，我们认为有必要开展这项研究，目的是评估生物学在达喀尔肿瘤儿科治疗 ALL 儿童中的作用。方法：这是一项前瞻性分析研究，于2021年11月15日在UOP与血液学和免疫学实验室合作启动。研究对象包括所有根据细胞学和/或免疫分型确诊的新发 ALL 患者，这些患者均按照 ALL-GFAOP 方案接受治疗，并在 REDcap 数据库中登记。结果：2021年11月15日至2023年7月31日，48名患者被诊断为新发ALL。患者平均年龄为7.8岁，以女性为主（52.08%）。根据免疫分型，25.0%的患者为B型，22.9%为T型。与 ALL B 组相比，ALL T 组年龄更大（9.2 岁对 4.4 岁），诊断时血小板计数更高（122272.7 对 46916.7）。后者的血红蛋白（7.4 对 6.8）、白细胞（127296.2 对 56511.2）以及外周血（69.4% 对 55.1%）和骨髓（84.2% 对 72.5%）中的囊泡计数均高于前者，诱导后第 8 天的残余囊泡计数也高于前者（9198.4 对 1301.4）。关于诱导后第 8 天的皮质敏感性，与诊断时的胚泡数量、血红蛋白水平和免疫学特征没有差异。然而，血小板计数相对较高的高白细胞 ALL 患者对皮质类固醇治疗更敏感。结论：了解急性ALL的生物学特性对提高这类血液恶性肿瘤的治疗效果具有重要意义。引用格式：Abou A Koundio, Moussa Ndour, Mame Ndella Diouf, Fatou Binetou Akonde, Awa Oumar Toure, Martine Raphael.急性淋巴细胞性白血病从诊断到随访的生物学：48 例研究 [摘要]。在：血癌发现研讨会论文集》，2024 年 3 月 4-6 日，马萨诸塞州波士顿。费城（宾夕法尼亚州）：AACR; Blood Cancer Discov 2024;5(2_Suppl):Abstract nr P36.
{"title":"Abstract P36: BIOLOGY IN ACUTE LYMPHOBLASTIC LEUKEMIA FROM DIAGNOSIS TO FOLLOW-UP: A STUDY OF 48CASES","authors":"Abou A Koundio, M. Ndour, Mame Ndella Diouf, Fatou Binetou Akonde, Awa Oumar Touré, Martine Raphael","doi":"10.1158/2643-3249.bcdsymp24-p36","DOIUrl":"https://doi.org/10.1158/2643-3249.bcdsymp24-p36","url":null,"abstract":"\u0000 OBJECTIVE: ALL is the most common cancer in children and the most common cause of cancer death before the age of 20. In low- and middle-income countries, ALL is associated with poor outcomes. Many constraints are at the root of management failures. Therefore, in view of the progressive improvements in the efficacy of chemotherapeutic regimens, we deemed it necessary to conduct this study, the objective of which is to evaluate the role of biology in the management of children with ALL in the Oncopediatric Unit of Dakar. METHODS: This is a prospective analytical study that started on November 15th, 2021 at the UOP in collaboration with the hematology and immunology laboratories. All newly diagnosed patients with ALL based-on cytology and/or immunophenotyping, treated according to the ALL-GFAOP protocol and registered in the REDcap database are included. RESULTS: From November, 15th 2021 to July, 31th 2023, 48 patients were diagnosed with de novo ALL. With an average age of 7.8 years, female represented the main group (52,08%). According to immunophenotyping, the B profile was found in 25.0 % and the T profile in 22.9 %. The ALL T group was older (9.2 vs 4.4 years) and have had higher platelet counts (122272.7 vs 46916.7) at diagnosis than the ALL B group. This latter had higher hemoglobin (7.4 vs 6.8), white blood cell (127296.2 vs 56511.2) and blast counts at diagnosis in peripheral blood (69.4% vs 55.1%) and also in bone marrow (84.2% vs 72.5%) and higher rate of residual blast counts at Day8 after induction (9198.4 vs 1301.4). Regarding corticosensitivity at D8 of induction, no difference was found according to the number of blasts, the hemoglobinlevel and the immunological profile at diagnosis. However, patients with hyperleukocytic ALL with a relatively higher platelet count were more sensitive to corticosteroid therapy. CONCLUSIONS: Understanding the biology of acute ALL is of major interest in the effectiveness of therapeutic approaches to this type of hematology malignancies.\u0000 Citation Format: Abou A Koundio, Moussa Ndour, Mame Ndella Diouf, Fatou Binetou Akonde, Awa Oumar Toure, Martine Raphael. BIOLOGY IN ACUTE LYMPHOBLASTIC LEUKEMIA FROM DIAGNOSIS TO FOLLOW-UP: A STUDY OF 48CASES [abstract]. In: Proceedings of the Blood Cancer Discovery Symposium; 2024 Mar 4-6; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(2_Suppl):Abstract nr P36.","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":null,"pages":null},"PeriodicalIF":11.2,"publicationDate":"2024-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140266375","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}
Pub Date : 2024-03-04DOI: 10.1158/2643-3249.bcdsymp24-p26
S. Chaudhry, Felipe Beckedorff, S. Jasdanwala, T. Totiger, Maurizio Affer, Nidhi Hariramani, Olivia Tonini, Stephan Noudali, Alexandra Chirino, Alyssa Cornista, S. Montoya, Daniel Bilbao, J. Afaghani, Josean Rodriguez, Shruti Bhatt, Eric Wang, Justin Taylor
SF3B1 mutations, the most frequent spliceosomal alterations across cancers, occur in 25% of myelodysplastic syndromes (MDS) patients yet lack effective therapies. Two phase 2 clinical trials with the XPO1 inhibitors in high-risk MDS revealed increased activity in patients with SF3B1 mutations. XPO1 (Exportin-1) plays a role in the transport of multiple RNA species, including small nuclear RNAs (snRNAs) out of the nucleus. Given the role of XPO1 in exporting snRNAs, which form the catalytic portion of the spliceosome, we hypothesized that XPO1 inhibition may preferentially affect SF3B1-mutant cells and that SF3B1-mutant high-risk MDS patients would have a better response to rational targeted drug combinations with XPO1 inhibitors. To evaluate the mechanism underlying the preferential sensitivity of SF3B1-mutant cells to XPO1 inhibition, we conducted subcellular RNA sequencing before and after XPO1 inhibition in SF3B1 wildtype and mutant cells. Transcriptomic analysis revealed increased global retention of RNA transcripts and elevated snRNAs in the nucleus after XPO1 inhibition in the SF3B1 mutant cell line. Global RNA expression and splicing analysis revealed increased alternative splicing in SF3B1 mutant cells after XPO1 inhibition. These results suggest that the preferential sensitivity of SF3B1 mutant cells to nuclear export inhibition arises through increased nuclear retention of spliceosomal snRNAs and select mRNAs that results in perturbation of apoptotic pathways. Despite the promising efficacy of XPO1 inhibition in SF3B1-mutated MDS, dose escalation is limited by toxicity. In order to identify novel drug combination targets with lower XPO1 inhibitor doses, we employed whole genome CRISPR screens in two acute myeloid leukemia (AML) cell lines treated with XPO1 inhibitor. We identified two drug targets that greatly synergized with eltanexor specifically in the SF3B1 mutant cell lines: venetoclax (a BCL2 inhibitor), and A1331852 (a BCL-XL inhibitor). In addition, BH3 profiling demonstrated increased priming of the BCL2 and BCL-XL in SF3B1 mutant cells. We further validated these combinations in vivo using competitive transplant assays in Sf3b1 K700E conditional knock-in mice. The combination of eltanexor with venetoclax and eltanexor with A1331852 showed a significant decrease in the Sf3b1-mutant burden in the peripheral blood and bone marrow progenitor compartments, suggesting a preferential sensitivity of the combinations for SF3B1 mutant cells. Although A1331852 exhibited similar results to venetoclax, there was increased weight loss and decrease in hemoglobin associated with BCLXL inhibition. In conclusion, our study provides insight on the mechanisms underlying the heightened sensitivity of XPO1 inhibition in SF3B1-mutant MDS/AML. The identification of BCL2 and BCL-XL as synergistic targets with XPO1 inhibitors, validated by in vivo testing, BH3 profiling, and RNA sequencing, highlights the potential for therapeutic combinations. Speci
SF3B1突变是癌症中最常见的剪接体改变，25%的骨髓增生异常综合征（MDS）患者会出现这种突变，但却缺乏有效的治疗方法。XPO1抑制剂在高风险MDS中的两项2期临床试验显示，SF3B1突变患者的活性增加。XPO1（Exportin-1）在将多种 RNA（包括小核 RNA（snRNA））转运出细胞核的过程中发挥作用。鉴于 XPO1 在导出 snRNA（形成剪接体的催化部分）中的作用，我们假设 XPO1 抑制可能会优先影响 SF3B1 突变细胞，SF3B1 突变的高风险 MDS 患者对 XPO1 抑制剂的合理靶向药物组合会有更好的反应。为了评估SF3B1突变细胞对XPO1抑制剂更敏感的机制，我们在SF3B1野生型和突变细胞中进行了XPO1抑制前后的亚细胞RNA测序。转录组分析表明，在SF3B1突变体细胞系中，XPO1抑制后，RNA转录本在细胞核中的全局保留增加，snRNA升高。全局 RNA 表达和剪接分析表明，在 XPO1 受抑制后，SF3B1 突变体细胞中的替代剪接增加。这些结果表明，SF3B1突变体细胞对核输出抑制的优先敏感性是通过剪接体snRNA和选择性mRNA的核保留增加而产生的，这导致了细胞凋亡途径的干扰。尽管抑制XPO1对SF3B1突变的MDS具有良好疗效，但剂量升级受到毒性的限制。为了在XPO1抑制剂剂量较低的情况下发现新的药物组合靶点，我们在用XPO1抑制剂治疗的两种急性髓性白血病（AML）细胞系中采用了全基因组CRISPR筛选。在 SF3B1 突变细胞系中，我们发现了两个能与 eltanexor 产生巨大协同作用的药物靶点：venetoclax（一种 BCL2 抑制剂）和 A1331852（一种 BCL-XL 抑制剂）。此外，BH3分析表明，在SF3B1突变细胞中，BCL2和BCL-XL的引物增加。我们通过在 Sf3b1 K700E 条件性基因敲入小鼠中进行竞争性移植试验，进一步在体内验证了这些组合。eltanexor与venetoclax的组合以及eltanexor与A1331852的组合显示，外周血和骨髓祖细胞中的Sf3b1突变负荷显著下降，这表明这些组合对SF3B1突变细胞具有优先敏感性。虽然A1331852的结果与venetoclax相似，但体重减轻和血红蛋白降低与BCLXL抑制有关。总之，我们的研究深入揭示了在SF3B1突变的MDS/AML中XPO1抑制的敏感性提高的机制。BCL2和BCL-XL被鉴定为与XPO1抑制剂协同作用的靶点，并通过体内测试、BH3图谱分析和RNA测序进行了验证，这凸显了联合治疗的潜力。具体来说，eltanexor和venetoclax的组合可能是一种很有前景的SF3B1特异性疗法。引用格式：Sana Chaudhry, Felipe Beckedorff, Shaista Shabbir Jasdanwala, Tulasigeri M Totiger, Maurizio Affer, Nidhi Hariramani, Olivia Tonini, Stephan Noudali, Alexandra Chirino, Alyssa Cornista, Skye Montoya, Daniel Bilbao, Jumana Afaghani, Jose Antonio Rodríguez, Shruti Bhatt, Eric Wang, Justin Taylor.SF3B1突变型MDS中改变的RNA输出对核输出抑制敏感[摘要]。In：血癌发现研讨会论文集；2024 年 3 月 4-6 日；马萨诸塞州波士顿。费城（宾夕法尼亚州）：AACR; Blood Cancer Discov 2024;5(2_Suppl):Abstract nr P26.
{"title":"Abstract P26: Altered RNA Export Sensitizes to Nuclear Export Inhibition in SF3B1 Mutant MDS","authors":"S. Chaudhry, Felipe Beckedorff, S. Jasdanwala, T. Totiger, Maurizio Affer, Nidhi Hariramani, Olivia Tonini, Stephan Noudali, Alexandra Chirino, Alyssa Cornista, S. Montoya, Daniel Bilbao, J. Afaghani, Josean Rodriguez, Shruti Bhatt, Eric Wang, Justin Taylor","doi":"10.1158/2643-3249.bcdsymp24-p26","DOIUrl":"https://doi.org/10.1158/2643-3249.bcdsymp24-p26","url":null,"abstract":"\u0000 SF3B1 mutations, the most frequent spliceosomal alterations across cancers, occur in 25% of myelodysplastic syndromes (MDS) patients yet lack effective therapies. Two phase 2 clinical trials with the XPO1 inhibitors in high-risk MDS revealed increased activity in patients with SF3B1 mutations. XPO1 (Exportin-1) plays a role in the transport of multiple RNA species, including small nuclear RNAs (snRNAs) out of the nucleus. Given the role of XPO1 in exporting snRNAs, which form the catalytic portion of the spliceosome, we hypothesized that XPO1 inhibition may preferentially affect SF3B1-mutant cells and that SF3B1-mutant high-risk MDS patients would have a better response to rational targeted drug combinations with XPO1 inhibitors. To evaluate the mechanism underlying the preferential sensitivity of SF3B1-mutant cells to XPO1 inhibition, we conducted subcellular RNA sequencing before and after XPO1 inhibition in SF3B1 wildtype and mutant cells. Transcriptomic analysis revealed increased global retention of RNA transcripts and elevated snRNAs in the nucleus after XPO1 inhibition in the SF3B1 mutant cell line. Global RNA expression and splicing analysis revealed increased alternative splicing in SF3B1 mutant cells after XPO1 inhibition. These results suggest that the preferential sensitivity of SF3B1 mutant cells to nuclear export inhibition arises through increased nuclear retention of spliceosomal snRNAs and select mRNAs that results in perturbation of apoptotic pathways. Despite the promising efficacy of XPO1 inhibition in SF3B1-mutated MDS, dose escalation is limited by toxicity. In order to identify novel drug combination targets with lower XPO1 inhibitor doses, we employed whole genome CRISPR screens in two acute myeloid leukemia (AML) cell lines treated with XPO1 inhibitor. We identified two drug targets that greatly synergized with eltanexor specifically in the SF3B1 mutant cell lines: venetoclax (a BCL2 inhibitor), and A1331852 (a BCL-XL inhibitor). In addition, BH3 profiling demonstrated increased priming of the BCL2 and BCL-XL in SF3B1 mutant cells. We further validated these combinations in vivo using competitive transplant assays in Sf3b1 K700E conditional knock-in mice. The combination of eltanexor with venetoclax and eltanexor with A1331852 showed a significant decrease in the Sf3b1-mutant burden in the peripheral blood and bone marrow progenitor compartments, suggesting a preferential sensitivity of the combinations for SF3B1 mutant cells. Although A1331852 exhibited similar results to venetoclax, there was increased weight loss and decrease in hemoglobin associated with BCLXL inhibition. In conclusion, our study provides insight on the mechanisms underlying the heightened sensitivity of XPO1 inhibition in SF3B1-mutant MDS/AML. The identification of BCL2 and BCL-XL as synergistic targets with XPO1 inhibitors, validated by in vivo testing, BH3 profiling, and RNA sequencing, highlights the potential for therapeutic combinations. Speci","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":null,"pages":null},"PeriodicalIF":11.2,"publicationDate":"2024-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140266927","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}
Pub Date : 2024-03-04DOI: 10.1158/2643-3249.bcdsymp24-p27
Shih-Chun Alec Chu, Yi-Wan Hsiao, Yamei Deng, Chenwei Wang, Jennifer Kyle, Yongchao Dou, James C. Pino, Camilo Posso, Leanne Henry, Ginny Li, Li Ding, Lijun Chen, Mamie Lih, Y. Geffen, Gilbert Omenn, Chandan Kumar, S. Dhanasekaran, Fengchao Yu, E. Traer, J. Tyner, Hui Zhang, Tao Liu, Sara J. C. Gosline, Bing Zhang, A. Chinnaiyan, Alexey I. Nesvizhskii, Marcin Cieslik
Acute myeloid leukemia (AML) is a blood malignancy of poor prognosis with marked heterogeneity. To elucidate the underlying mechanisms that drive AML as part of the Clinical Proteomic Tumor Analysis Consortium (CPTAC) effort, we performed large scale comprehensive genomics, transcriptomics, proteomics including multiple post-translational modifications (phosphorylation, acetylation, and glycosylation), metabolomics, and lipidomics characterization of 173 treatment-naïve AML patients. Applying the similarity network fusion method on both transcriptomics and proteomics data, we identified 8 proteogenomic clusters. These clusters recapitulate specific recurrent mutations, fusions, structural variants, and established clinical subtypes available within the cohort, as well as reveal new cluster-specific phenotypes within other multi-omic datasets. We used single-cell RNAseq data as a reference to perform immune component analysis for collected bulk samples. The result reveals that our proteogenomic clustering also captures the variations of AML differentiation hierarchies including CD14+ monocyte-like and GMP-like AML. To assess the complex disease nature of AML, we performed functional analysis for each cluster to reveal interplay between multiple genomic aberrations such as NPM1, FLT3-ITD, DNMT3A mutations, complex chromosomal alterations, and the leukemia cell differentiation. Additionally, the multi-omics analysis performed not only connects previously identified molecular drivers and cell differentiation variations within AML, but also links them with observed cancer metabolomic reprogramming alongside differences in MTOR signaling, MYC activities, mitochondrial activities, and drug responses. Moreover, our study also identified site-specific post-translational modifications previously not known in AML, highlighting the valuable insights and clinical relevance of these newly identified clusters. Citation Format: Shih-Chun Alec Chu, Yi Hsiao, Yamei Deng, Chenwei Wang, Jennifer Kyle, Yongchao Dou, James Pino, Camilo Posso, Leanne Henry, Ginny Li, Li Ding, Lijun Chen, Mamie Lih, Yifat Geffen, Gilbert Omenn, Chandan Kumar, Saravana Dhanasekaran, Fengchao Yu, Elie Traer, Jeffrey W. Tyner, Hui Zhang, Tao Liu, Sara Gosline, Bing Zhang, Arul Chinnaiyan, Alexey I Nesvizhskii, Marcin Cieslik. Proteogenomic and metabolomic analysis of acute myeloid leukemia reveals molecular and functional underpinnings of cellular and clinical phenotypes [abstract]. In: Proceedings of the Blood Cancer Discovery Symposium; 2024 Mar 4-6; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(2_Suppl):Abstract nr P27.
{"title":"Abstract P27: Proteogenomic and metabolomic analysis of acute myeloid leukemia reveals molecular and functional underpinnings of cellular and clinical phenotypes","authors":"Shih-Chun Alec Chu, Yi-Wan Hsiao, Yamei Deng, Chenwei Wang, Jennifer Kyle, Yongchao Dou, James C. Pino, Camilo Posso, Leanne Henry, Ginny Li, Li Ding, Lijun Chen, Mamie Lih, Y. Geffen, Gilbert Omenn, Chandan Kumar, S. Dhanasekaran, Fengchao Yu, E. Traer, J. Tyner, Hui Zhang, Tao Liu, Sara J. C. Gosline, Bing Zhang, A. Chinnaiyan, Alexey I. Nesvizhskii, Marcin Cieslik","doi":"10.1158/2643-3249.bcdsymp24-p27","DOIUrl":"https://doi.org/10.1158/2643-3249.bcdsymp24-p27","url":null,"abstract":"\u0000 Acute myeloid leukemia (AML) is a blood malignancy of poor prognosis with marked heterogeneity. To elucidate the underlying mechanisms that drive AML as part of the Clinical Proteomic Tumor Analysis Consortium (CPTAC) effort, we performed large scale comprehensive genomics, transcriptomics, proteomics including multiple post-translational modifications (phosphorylation, acetylation, and glycosylation), metabolomics, and lipidomics characterization of 173 treatment-naïve AML patients. Applying the similarity network fusion method on both transcriptomics and proteomics data, we identified 8 proteogenomic clusters. These clusters recapitulate specific recurrent mutations, fusions, structural variants, and established clinical subtypes available within the cohort, as well as reveal new cluster-specific phenotypes within other multi-omic datasets. We used single-cell RNAseq data as a reference to perform immune component analysis for collected bulk samples. The result reveals that our proteogenomic clustering also captures the variations of AML differentiation hierarchies including CD14+ monocyte-like and GMP-like AML. To assess the complex disease nature of AML, we performed functional analysis for each cluster to reveal interplay between multiple genomic aberrations such as NPM1, FLT3-ITD, DNMT3A mutations, complex chromosomal alterations, and the leukemia cell differentiation. Additionally, the multi-omics analysis performed not only connects previously identified molecular drivers and cell differentiation variations within AML, but also links them with observed cancer metabolomic reprogramming alongside differences in MTOR signaling, MYC activities, mitochondrial activities, and drug responses. Moreover, our study also identified site-specific post-translational modifications previously not known in AML, highlighting the valuable insights and clinical relevance of these newly identified clusters.\u0000 Citation Format: Shih-Chun Alec Chu, Yi Hsiao, Yamei Deng, Chenwei Wang, Jennifer Kyle, Yongchao Dou, James Pino, Camilo Posso, Leanne Henry, Ginny Li, Li Ding, Lijun Chen, Mamie Lih, Yifat Geffen, Gilbert Omenn, Chandan Kumar, Saravana Dhanasekaran, Fengchao Yu, Elie Traer, Jeffrey W. Tyner, Hui Zhang, Tao Liu, Sara Gosline, Bing Zhang, Arul Chinnaiyan, Alexey I Nesvizhskii, Marcin Cieslik. Proteogenomic and metabolomic analysis of acute myeloid leukemia reveals molecular and functional underpinnings of cellular and clinical phenotypes [abstract]. In: Proceedings of the Blood Cancer Discovery Symposium; 2024 Mar 4-6; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(2_Suppl):Abstract nr P27.","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":null,"pages":null},"PeriodicalIF":11.2,"publicationDate":"2024-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140080771","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}
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