Pub Date : 2024-09-11DOI: 10.1038/s41375-024-02379-4
Daniel Hägerstrand, Blaž Oder, Diego Cortese, Ying Qu, Amrei Binzer-Panchal, Cecilia Österholm, Teresa Del Peso Santos, Leily Rabbani, Hassan Foroughi Asl, Aron Skaftason, Viktor Ljungström, August Lundholm, Maria Koutroumani, Zahra Haider, Cecilia Jylhä, John Mollstedt, Larry Mansouri, Karla Plevova, Andreas Agathangelidis, Lydia Scarfò, Marine Armand, Alice F. Muggen, Neil E. Kay, Tait Shanafelt, Davide Rossi, Lukas M. Orre, Sarka Pospisilova, Konstantin Barylyuk, Frederic Davi, Mattias Vesterlund, Anton W. Langerak, Janne Lehtiö, Paolo Ghia, Kostas Stamatopoulos, Lesley-Ann Sutton, Richard Rosenquist
SF3B1 mutations are recurrent in chronic lymphocytic leukemia (CLL), particularly enriched in clinically aggressive stereotyped subset #2. To investigate their impact, we conducted RNA-sequencing of 18 SF3B1MUT and 17 SF3B1WT subset #2 cases and identified 80 significant alternative splicing events (ASEs). Notable ASEs concerned exon inclusion in the non-canonical BAF (ncBAF) chromatin remodeling complex subunit, BRD9, and splice variants in eight additional ncBAF complex interactors. Long-read RNA-sequencing confirmed the presence of splice variants, and extended analysis of 139 CLL cases corroborated their association with SF3B1 mutations. Overexpression of SF3B1K700E induced exon inclusion in BRD9, resulting in a novel splice isoform with an alternative C-terminus. Protein interactome analysis of the BRD9 splice isoform revealed augmented ncBAF complex interaction, while exhibiting decreased binding of auxiliary proteins, including SPEN, BRCA2, and CHD9. Additionally, integrative multi-omics analysis identified a ncBAF complex-bound gene quartet on chromosome 1 with higher expression levels and more accessible chromatin in SF3B1MUT CLL. Finally, Cancer Dependency Map analysis and BRD9 inhibition displayed BRD9 dependency and sensitivity in cell lines and primary CLL cells. In conclusion, spliceosome dysregulation caused by SF3B1 mutations leads to multiple ASEs and an altered ncBAF complex interactome, highlighting a novel pathobiological mechanism in SF3B1MUT CLL.
{"title":"The non-canonical BAF chromatin remodeling complex is a novel target of spliceosome dysregulation in SF3B1-mutated chronic lymphocytic leukemia","authors":"Daniel Hägerstrand, Blaž Oder, Diego Cortese, Ying Qu, Amrei Binzer-Panchal, Cecilia Österholm, Teresa Del Peso Santos, Leily Rabbani, Hassan Foroughi Asl, Aron Skaftason, Viktor Ljungström, August Lundholm, Maria Koutroumani, Zahra Haider, Cecilia Jylhä, John Mollstedt, Larry Mansouri, Karla Plevova, Andreas Agathangelidis, Lydia Scarfò, Marine Armand, Alice F. Muggen, Neil E. Kay, Tait Shanafelt, Davide Rossi, Lukas M. Orre, Sarka Pospisilova, Konstantin Barylyuk, Frederic Davi, Mattias Vesterlund, Anton W. Langerak, Janne Lehtiö, Paolo Ghia, Kostas Stamatopoulos, Lesley-Ann Sutton, Richard Rosenquist","doi":"10.1038/s41375-024-02379-4","DOIUrl":"10.1038/s41375-024-02379-4","url":null,"abstract":"SF3B1 mutations are recurrent in chronic lymphocytic leukemia (CLL), particularly enriched in clinically aggressive stereotyped subset #2. To investigate their impact, we conducted RNA-sequencing of 18 SF3B1MUT and 17 SF3B1WT subset #2 cases and identified 80 significant alternative splicing events (ASEs). Notable ASEs concerned exon inclusion in the non-canonical BAF (ncBAF) chromatin remodeling complex subunit, BRD9, and splice variants in eight additional ncBAF complex interactors. Long-read RNA-sequencing confirmed the presence of splice variants, and extended analysis of 139 CLL cases corroborated their association with SF3B1 mutations. Overexpression of SF3B1K700E induced exon inclusion in BRD9, resulting in a novel splice isoform with an alternative C-terminus. Protein interactome analysis of the BRD9 splice isoform revealed augmented ncBAF complex interaction, while exhibiting decreased binding of auxiliary proteins, including SPEN, BRCA2, and CHD9. Additionally, integrative multi-omics analysis identified a ncBAF complex-bound gene quartet on chromosome 1 with higher expression levels and more accessible chromatin in SF3B1MUT CLL. Finally, Cancer Dependency Map analysis and BRD9 inhibition displayed BRD9 dependency and sensitivity in cell lines and primary CLL cells. In conclusion, spliceosome dysregulation caused by SF3B1 mutations leads to multiple ASEs and an altered ncBAF complex interactome, highlighting a novel pathobiological mechanism in SF3B1MUT CLL.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"38 11","pages":"2429-2442"},"PeriodicalIF":12.8,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02379-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142166197","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-10DOI: 10.1038/s41375-024-02386-5
Janine Stutterheim, Rachella van der Waarden, Hester A. de Groot-Kruseman, Edwin Sonneveld, Valérie de Haas, Rana Dandis, C. Ellen van der Schoot, Vincent H. J. van der Velden, Rob Pieters
Measurable residual disease (MRD) is regularly tested at later timepoints after the end of first consolidation (EOC) in children with acute lymphoblastic leukemia (ALL). The question remains whether this is useful for detecting (molecular) relapse. We investigated the clinical relevance of MRD after EOC in intermediate risk patients treated on DCOG-ALL-10 (n = 271) and DCOG-ALL-9 (n = 122), with MRD <0.05% at EOC. EOC MRD-negative patients (n = 178) had excellent outcomes, irrespective of MRD results at later timepoints; 6-year cumulative incidence of relapse (6-y CIR) of 7.4% (95% CI, 3.9%–12.3%) for those with MRD negativity at all later timepoints compared to 3.8% (95% CI, 0.3%–16.8%) for those with one or more later timepoints being positive (p = 0.51). Patients with positive EOC MRD (n = 91) of whom the subsequent timepoints were MRD negative (n = 43), had comparable good outcomes, 6-y CIR of 7.0% (95% CI, 1.8%–17.2%). In contrast, patients being MRD positive at EOC and MRD positive at one or more subsequent timepoints (n = 48) had a higher risk of relapse, 6-y CIR 29.4% (95% CI, 17.2%–42.8%), p < 0.001. These findings were confirmed in the validation cohort of ALL-9 as well as using the updated EuroMRD guidelines. In EOC MRD-negative patients, subsequent MRD measurements can be abandoned. For EOC MRD-positive patients the subsequent MRD measurement might be informative for further risk stratification.
{"title":"Are measurable residual disease results after consolidation therapy useful in children with acute lymphoblastic leukemia?","authors":"Janine Stutterheim, Rachella van der Waarden, Hester A. de Groot-Kruseman, Edwin Sonneveld, Valérie de Haas, Rana Dandis, C. Ellen van der Schoot, Vincent H. J. van der Velden, Rob Pieters","doi":"10.1038/s41375-024-02386-5","DOIUrl":"10.1038/s41375-024-02386-5","url":null,"abstract":"Measurable residual disease (MRD) is regularly tested at later timepoints after the end of first consolidation (EOC) in children with acute lymphoblastic leukemia (ALL). The question remains whether this is useful for detecting (molecular) relapse. We investigated the clinical relevance of MRD after EOC in intermediate risk patients treated on DCOG-ALL-10 (n = 271) and DCOG-ALL-9 (n = 122), with MRD <0.05% at EOC. EOC MRD-negative patients (n = 178) had excellent outcomes, irrespective of MRD results at later timepoints; 6-year cumulative incidence of relapse (6-y CIR) of 7.4% (95% CI, 3.9%–12.3%) for those with MRD negativity at all later timepoints compared to 3.8% (95% CI, 0.3%–16.8%) for those with one or more later timepoints being positive (p = 0.51). Patients with positive EOC MRD (n = 91) of whom the subsequent timepoints were MRD negative (n = 43), had comparable good outcomes, 6-y CIR of 7.0% (95% CI, 1.8%–17.2%). In contrast, patients being MRD positive at EOC and MRD positive at one or more subsequent timepoints (n = 48) had a higher risk of relapse, 6-y CIR 29.4% (95% CI, 17.2%–42.8%), p < 0.001. These findings were confirmed in the validation cohort of ALL-9 as well as using the updated EuroMRD guidelines. In EOC MRD-negative patients, subsequent MRD measurements can be abandoned. For EOC MRD-positive patients the subsequent MRD measurement might be informative for further risk stratification.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"38 11","pages":"2376-2381"},"PeriodicalIF":12.8,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02386-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142160574","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-09DOI: 10.1038/s41375-024-02407-3
Tanxin Liu, Keren Xu, Anmol Pardeshi, Swe Swe Myint, Alice Y. Kang, Libby M. Morimoto, Michael R. Lieber, Joseph L. Wiemels, Scott C. Kogan, Catherine Metayer, Adam J. de Smith
{"title":"Early-life tobacco exposure is causally implicated in aberrant RAG-mediated recombination in childhood acute lymphoblastic leukemia","authors":"Tanxin Liu, Keren Xu, Anmol Pardeshi, Swe Swe Myint, Alice Y. Kang, Libby M. Morimoto, Michael R. Lieber, Joseph L. Wiemels, Scott C. Kogan, Catherine Metayer, Adam J. de Smith","doi":"10.1038/s41375-024-02407-3","DOIUrl":"10.1038/s41375-024-02407-3","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"38 11","pages":"2492-2496"},"PeriodicalIF":12.8,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02407-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142158811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-09DOI: 10.1038/s41375-024-02406-4
Austin Boucher, Josiah Murray, Sridhar Rao
The cohesin complex, encoded by SMC3, SMC1A, RAD21, and STAG2, is a critical regulator of DNA-looping and gene expression. Over a decade has passed since recurrent mutations affecting cohesin subunits were first identified in myeloid malignancies such as Acute Myeloid Leukemia (AML). Since that time there has been tremendous progress in our understanding of chromatin structure and cohesin biology, but critical questions remain because of the multiple critical functions the cohesin complex is responsible for. Recent findings have been particularly noteworthy with the identification of crosstalk between DNA-looping and chromatin domains, a deeper understanding of how cohesin establishes sister chromatid cohesion, a renewed interest in cohesin’s role for DNA damage response, and work demonstrating cohesin’s importance for Polycomb repression. Despite these exciting findings, the role of cohesin in normal hematopoiesis, and the precise mechanisms by which cohesin mutations promote cancer, remain poorly understood. This review discusses what is known about the role of cohesin in normal hematopoiesis, and how recent findings could shed light on the mechanisms through which cohesin mutations promote leukemic transformation. Important unanswered questions in the field, such as whether cohesin plays a role in HSC heterogeneity, and the mechanisms by which it regulates gene expression at a molecular level, will also be discussed. Particular attention will be given to the potential therapeutic vulnerabilities of leukemic cells with cohesin subunit mutations.
由 SMC3、SMC1A、RAD21 和 STAG2 编码的凝聚素复合体是 DNA 循环和基因表达的关键调节因子。自首次在急性髓性白血病（AML）等髓系恶性肿瘤中发现影响凝聚素亚基的复发性突变以来，十多年过去了。从那时起，我们对染色质结构和凝聚素生物学的认识取得了巨大进步，但由于凝聚素复合物具有多种关键功能，因此仍然存在一些关键问题。最近的研究成果尤其值得关注：DNA环路和染色质结构域之间的串扰被发现；人们对凝聚素如何建立姐妹染色单体内聚力有了更深入的了解；人们对凝聚素在 DNA 损伤反应中的作用重新产生了兴趣；还有研究证明了凝聚素对多聚酶抑制的重要性。尽管有这些令人兴奋的发现，但人们对凝聚素在正常造血过程中的作用以及凝聚素突变致癌的确切机制仍然知之甚少。本综述将讨论目前已知的凝聚素在正常造血过程中的作用，以及最新发现如何揭示凝聚素突变促进白血病转化的机制。此外，还将讨论该领域的重要未解之谜，如凝聚素是否在造血干细胞异质性中发挥作用，以及凝聚素在分子水平上调控基因表达的机制。还将特别关注具有凝聚素亚基突变的白血病细胞的潜在治疗弱点。
{"title":"Cohesin mutations in acute myeloid leukemia","authors":"Austin Boucher, Josiah Murray, Sridhar Rao","doi":"10.1038/s41375-024-02406-4","DOIUrl":"10.1038/s41375-024-02406-4","url":null,"abstract":"The cohesin complex, encoded by SMC3, SMC1A, RAD21, and STAG2, is a critical regulator of DNA-looping and gene expression. Over a decade has passed since recurrent mutations affecting cohesin subunits were first identified in myeloid malignancies such as Acute Myeloid Leukemia (AML). Since that time there has been tremendous progress in our understanding of chromatin structure and cohesin biology, but critical questions remain because of the multiple critical functions the cohesin complex is responsible for. Recent findings have been particularly noteworthy with the identification of crosstalk between DNA-looping and chromatin domains, a deeper understanding of how cohesin establishes sister chromatid cohesion, a renewed interest in cohesin’s role for DNA damage response, and work demonstrating cohesin’s importance for Polycomb repression. Despite these exciting findings, the role of cohesin in normal hematopoiesis, and the precise mechanisms by which cohesin mutations promote cancer, remain poorly understood. This review discusses what is known about the role of cohesin in normal hematopoiesis, and how recent findings could shed light on the mechanisms through which cohesin mutations promote leukemic transformation. Important unanswered questions in the field, such as whether cohesin plays a role in HSC heterogeneity, and the mechanisms by which it regulates gene expression at a molecular level, will also be discussed. Particular attention will be given to the potential therapeutic vulnerabilities of leukemic cells with cohesin subunit mutations.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"38 11","pages":"2318-2328"},"PeriodicalIF":12.8,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02406-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142158810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-07DOI: 10.1038/s41375-024-02398-1
Sian Faustini, Y. L. Tracey Chan, Lilli Evans, Emily Collman, Alec Rapson, Claire Backhouse, Annabelle Emery, John P. Campbell, Sally Moore, Alex Richter, Guy Pratt, Mark T. Drayson, Jennifer L. J. Heaney
{"title":"Plasma cell disorders supress mucosal anti-bacterial immunity: another dimension of immunoparesis in plasma cell neoplasms","authors":"Sian Faustini, Y. L. Tracey Chan, Lilli Evans, Emily Collman, Alec Rapson, Claire Backhouse, Annabelle Emery, John P. Campbell, Sally Moore, Alex Richter, Guy Pratt, Mark T. Drayson, Jennifer L. J. Heaney","doi":"10.1038/s41375-024-02398-1","DOIUrl":"10.1038/s41375-024-02398-1","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"38 11","pages":"2501-2504"},"PeriodicalIF":12.8,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02398-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142144317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-07DOI: 10.1038/s41375-024-02388-3
Daniel C. Choi, Nassima Messali, Narasimha Rao Uda, Ghaith Abu-Zeinah, Pouneh Kermani, Maria Mia Yabut, Heidi E. L. Lischer, Franco Castillo Tokumori, Katie Erdos, Thomas Lehmann, Marta Sobas, Tata Nageswara Rao, Joseph M. Scandura
{"title":"JAK2V617F impairs lymphoid differentiation in myeloproliferative neoplasms","authors":"Daniel C. Choi, Nassima Messali, Narasimha Rao Uda, Ghaith Abu-Zeinah, Pouneh Kermani, Maria Mia Yabut, Heidi E. L. Lischer, Franco Castillo Tokumori, Katie Erdos, Thomas Lehmann, Marta Sobas, Tata Nageswara Rao, Joseph M. Scandura","doi":"10.1038/s41375-024-02388-3","DOIUrl":"10.1038/s41375-024-02388-3","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"38 11","pages":"2487-2491"},"PeriodicalIF":12.8,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142144316","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}
Pub Date : 2024-09-05DOI: 10.1038/s41375-024-02382-9
Jianxiang Wang, Bin Jiang, Jian Li, Ligen Liu, Xin Du, Hao Jiang, Jianda Hu, Menghe Yuan, Taishi Sakatani, Takeshi Kadokura, Masato Takeuchi, Masanori Kosako, Xiao Ma, Larisa Girshova, Jerome Tan, Sergey Bondarenko, Lily Wong Lee Lee, Archrob Khuhapinant, Elena Martynova, Nahla Hasabou
The phase 3 COMMODORE trial evaluated gilteritinib versus salvage chemotherapy (SC) in a predominantly Asian relapsed/refractory (R/R) FLT3-mutated (FLT3mut+) acute myeloid leukemia (AML) patient population. The primary endpoint was overall survival (OS); secondary endpoints included event-free survival (EFS) and complete remission (CR) rate. As of June 30, 2020 (interim analysis: 32.2 months after study initiation), 234 patients were randomized (gilteritinib, n = 116; SC, n = 118). Median OS was significantly longer with gilteritinib versus SC (9.6 vs. 5.0 months; HR 0.566 [95% CI: 0.392, 0.818]; p = 0.00211) with a median follow-up of 10.3 months. Median EFS was also significantly longer with gilteritinib (2.8 vs. 0.6 months; HR 0.551 [95% CI: 0.395, 0.769]; p = 0.00004). CR rates with gilteritinib and SC were 16.4% and 10.2%, respectively; composite CR rates were 50.0% and 20.3%, respectively. Exposure-adjusted grade ≥3 adverse event (AE) rates were lower with gilteritinib (58.38 events/patient-year [E/PY]) versus SC (168.30 E/PY). Common AEs with gilteritinib were anemia (77.9%) and thrombocytopenia (45.1%). Gilteritinib plasma concentration peaked ~4 h postdose; ~3-fold accumulation occurred with multiple dosing. The COMMODORE trial demonstrated that gilteritinib significantly improved OS and EFS in predominantly Asian patients, validating the outcomes of gilteritinib from the ADMIRAL trial in R/R FLT3mut+ AML.
{"title":"Phase 3 study of gilteritinib versus salvage chemotherapy in predominantly Asian patients with relapsed/refractory FLT3-mutated acute myeloid leukemia","authors":"Jianxiang Wang, Bin Jiang, Jian Li, Ligen Liu, Xin Du, Hao Jiang, Jianda Hu, Menghe Yuan, Taishi Sakatani, Takeshi Kadokura, Masato Takeuchi, Masanori Kosako, Xiao Ma, Larisa Girshova, Jerome Tan, Sergey Bondarenko, Lily Wong Lee Lee, Archrob Khuhapinant, Elena Martynova, Nahla Hasabou","doi":"10.1038/s41375-024-02382-9","DOIUrl":"10.1038/s41375-024-02382-9","url":null,"abstract":"The phase 3 COMMODORE trial evaluated gilteritinib versus salvage chemotherapy (SC) in a predominantly Asian relapsed/refractory (R/R) FLT3-mutated (FLT3mut+) acute myeloid leukemia (AML) patient population. The primary endpoint was overall survival (OS); secondary endpoints included event-free survival (EFS) and complete remission (CR) rate. As of June 30, 2020 (interim analysis: 32.2 months after study initiation), 234 patients were randomized (gilteritinib, n = 116; SC, n = 118). Median OS was significantly longer with gilteritinib versus SC (9.6 vs. 5.0 months; HR 0.566 [95% CI: 0.392, 0.818]; p = 0.00211) with a median follow-up of 10.3 months. Median EFS was also significantly longer with gilteritinib (2.8 vs. 0.6 months; HR 0.551 [95% CI: 0.395, 0.769]; p = 0.00004). CR rates with gilteritinib and SC were 16.4% and 10.2%, respectively; composite CR rates were 50.0% and 20.3%, respectively. Exposure-adjusted grade ≥3 adverse event (AE) rates were lower with gilteritinib (58.38 events/patient-year [E/PY]) versus SC (168.30 E/PY). Common AEs with gilteritinib were anemia (77.9%) and thrombocytopenia (45.1%). Gilteritinib plasma concentration peaked ~4 h postdose; ~3-fold accumulation occurred with multiple dosing. The COMMODORE trial demonstrated that gilteritinib significantly improved OS and EFS in predominantly Asian patients, validating the outcomes of gilteritinib from the ADMIRAL trial in R/R FLT3mut+ AML.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"38 11","pages":"2410-2418"},"PeriodicalIF":12.8,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02382-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142138026","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-04DOI: 10.1038/s41375-024-02403-7
Cédric G. van der Ham, Lianne C. Suurenbroek, Michelle M. Kleisman, Željko Antić, Stefan H. Lelieveld, Marley Yeong, Liset Westera, Edwin Sonneveld, Peter M. Hoogerbrugge, Vincent H. J. van der Velden, Frank N. van Leeuwen, Roland P. Kuiper
Pediatric acute lymphoblastic leukemia (ALL) is marked by low mutational load at initial diagnosis, which increases at relapse. To determine which processes are active in (relapsed) ALL and how they behave during disease progression before and after therapy, we performed whole genome sequencing on 97 tumor samples of 29 multiply relapsed ALL patients. Mutational load increased upon relapse in 28 patients and upon every subsequent relapse in 22 patients. In addition to two clock-like mutational processes, we identified UV-like damage, APOBEC activity, reactive oxygen species, thiopurine-associated damage and an unknown therapy component as drivers of mutagenesis. Mutational processes often affected patients over longer time periods, but could also occur in isolated events, suggesting the requirement of additional triggers. Thiopurine exposure was the most prominent source of new mutations in relapse, affecting over half of the studied patients in first and/or later relapse and causing potential relapse-driving mutations in multiple patients. Our data demonstrate that multiple mutational processes frequently act in parallel as prominent secondary drivers with dynamic activity during ALL development and progression.
小儿急性淋巴细胞白血病（ALL）的特点是初诊时突变负荷低，复发时突变负荷增加。为了确定哪些过程在（复发）ALL 中处于活跃状态，以及它们在治疗前后疾病进展过程中的表现，我们对 29 名多次复发的 ALL 患者的 97 份肿瘤样本进行了全基因组测序。结果显示，28 名患者的复发和 22 名患者的每次复发都会增加突变负荷。除了两个时钟样突变过程外，我们还发现紫外线样损伤、APOBEC活性、活性氧、硫嘌呤相关损伤和一种未知的治疗成分是诱变的驱动因素。突变过程对患者的影响往往持续较长时间，但也可能发生在孤立的事件中，这表明需要额外的触发因素。硫嘌呤暴露是复发中新突变的最主要来源，影响了半数以上首次复发和/或后期复发的患者，并在多名患者中引起潜在的复发驱动突变。我们的数据表明，在 ALL 的发生和发展过程中，多种突变过程经常作为显著的次要驱动因素并行作用，并具有动态活性。
{"title":"Mutational mechanisms in multiply relapsed pediatric acute lymphoblastic leukemia","authors":"Cédric G. van der Ham, Lianne C. Suurenbroek, Michelle M. Kleisman, Željko Antić, Stefan H. Lelieveld, Marley Yeong, Liset Westera, Edwin Sonneveld, Peter M. Hoogerbrugge, Vincent H. J. van der Velden, Frank N. van Leeuwen, Roland P. Kuiper","doi":"10.1038/s41375-024-02403-7","DOIUrl":"10.1038/s41375-024-02403-7","url":null,"abstract":"Pediatric acute lymphoblastic leukemia (ALL) is marked by low mutational load at initial diagnosis, which increases at relapse. To determine which processes are active in (relapsed) ALL and how they behave during disease progression before and after therapy, we performed whole genome sequencing on 97 tumor samples of 29 multiply relapsed ALL patients. Mutational load increased upon relapse in 28 patients and upon every subsequent relapse in 22 patients. In addition to two clock-like mutational processes, we identified UV-like damage, APOBEC activity, reactive oxygen species, thiopurine-associated damage and an unknown therapy component as drivers of mutagenesis. Mutational processes often affected patients over longer time periods, but could also occur in isolated events, suggesting the requirement of additional triggers. Thiopurine exposure was the most prominent source of new mutations in relapse, affecting over half of the studied patients in first and/or later relapse and causing potential relapse-driving mutations in multiple patients. Our data demonstrate that multiple mutational processes frequently act in parallel as prominent secondary drivers with dynamic activity during ALL development and progression.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"38 11","pages":"2366-2375"},"PeriodicalIF":12.8,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02403-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142133167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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