Pub Date : 2024-09-16DOI: 10.1038/s41375-024-02401-9
Brandon S. Willis, Kevin Mongeon, Hannah Dry, India L. Neveras, Nadezda Bryan, Meghana Pandya, Justine Roderick-Richardson, Wendan Xu, Li Yang, Alan Rosen, Corinne Reimer, Liliana Tuskova, Pavel Klener, Jerome T. Mettetal, Georg Lenz, Simon T. Barry
The therapeutic potential of targeting PI3K/AKT/PTEN signalling in B-cell malignancies remains attractive. Whilst PI3K-α/δ inhibitors demonstrate clinical benefit in certain B-cell lymphomas, PI3K signalling inhibitors have been inadequate in relapsed/refractory diffuse large B-cell lymphoma (DLBCL) in part, due to treatment related toxicities. Clinically, AKT inhibitors exhibit a differentiated tolerability profile offering an alternative approach for treating patients with B-cell malignancies. To explore how AKT inhibition complements other potential therapeutics in the treatment of DLBCL patients, an in vitro combination screen was conducted across a panel of DLCBL cell lines. The AKT inhibitor, capivasertib, in combination with the BCL-2 inhibitor, venetoclax, produced notable therapeutic benefit in preclinical models of DLBCL. Capivasertib and venetoclax rapidly induced caspase and PARP cleavage in GCB-DLBCL PTEN wildtype cell lines and those harbouring PTEN mutations or reduced PTEN protein, driving prolonged tumour growth inhibition in DLBCL cell line and patient derived xenograft lymphoma models. The addition of the rituximab further deepened the durability of capivasertib and venetoclax responses in a RCHOP refractory DLBCL in vivo models. These findings provide preclinical evidence for the rational treatment combination of AKT and BCL-2 inhibitors using capivasertib and venetoclax respectively alongside anti-CD20 antibody supplementation for treatment of patients with DLBCL.
针对 B 细胞恶性肿瘤中的 PI3K/AKT/PTEN 信号的治疗潜力仍然很有吸引力。虽然 PI3K-α/δ 抑制剂对某些 B 细胞淋巴瘤有临床疗效,但 PI3K 信号抑制剂对复发/难治性弥漫大 B 细胞淋巴瘤(DLBCL)的疗效不佳,部分原因是治疗相关毒性。在临床上,AKT 抑制剂表现出不同的耐受性,为治疗 B 细胞恶性肿瘤患者提供了另一种方法。为了探索 AKT 抑制如何与治疗 DLBCL 患者的其他潜在疗法相辅相成,我们对一组 DLCBL 细胞系进行了体外联合筛选。AKT抑制剂capivasertib与BCL-2抑制剂venetoclax联用,在DLBCL临床前模型中产生了显著的治疗效果。Capivasertib 和 venetoclax 能迅速诱导 GCB-DLBCL PTEN 野生型细胞系和那些携带 PTEN 突变或 PTEN 蛋白减少的细胞系中的 Caspase 和 PARP 分裂,从而延长 DLBCL 细胞系和患者异种移植淋巴瘤模型中的肿瘤生长抑制。在RCHOP难治性DLBCL体内模型中,加入利妥昔单抗进一步加深了capivasertib和venetoclax反应的持久性。这些发现为分别使用capivasertib和venetoclax的AKT和BCL-2抑制剂与抗CD20抗体辅助治疗DLBCL患者提供了合理的临床前证据。
{"title":"Potent combination benefit of the AKT inhibitor capivasertib and the BCL-2 inhibitor venetoclax in diffuse large B cell lymphoma","authors":"Brandon S. Willis, Kevin Mongeon, Hannah Dry, India L. Neveras, Nadezda Bryan, Meghana Pandya, Justine Roderick-Richardson, Wendan Xu, Li Yang, Alan Rosen, Corinne Reimer, Liliana Tuskova, Pavel Klener, Jerome T. Mettetal, Georg Lenz, Simon T. Barry","doi":"10.1038/s41375-024-02401-9","DOIUrl":"https://doi.org/10.1038/s41375-024-02401-9","url":null,"abstract":"<p>The therapeutic potential of targeting PI3K/AKT/PTEN signalling in B-cell malignancies remains attractive. Whilst PI3K-α/δ inhibitors demonstrate clinical benefit in certain B-cell lymphomas, PI3K signalling inhibitors have been inadequate in relapsed/refractory diffuse large B-cell lymphoma (DLBCL) in part, due to treatment related toxicities. Clinically, AKT inhibitors exhibit a differentiated tolerability profile offering an alternative approach for treating patients with B-cell malignancies. To explore how AKT inhibition complements other potential therapeutics in the treatment of DLBCL patients, an in vitro combination screen was conducted across a panel of DLCBL cell lines. The AKT inhibitor, capivasertib, in combination with the BCL-2 inhibitor, venetoclax, produced notable therapeutic benefit in preclinical models of DLBCL. Capivasertib and venetoclax rapidly induced caspase and PARP cleavage in GCB-DLBCL <i>PTEN</i> wildtype cell lines and those harbouring <i>PTEN</i> mutations or reduced PTEN protein, driving prolonged tumour growth inhibition in DLBCL cell line and patient derived xenograft lymphoma models. The addition of the rituximab further deepened the durability of capivasertib and venetoclax responses in a RCHOP refractory DLBCL in vivo models. These findings provide preclinical evidence for the rational treatment combination of AKT and BCL-2 inhibitors using capivasertib and venetoclax respectively alongside anti-CD20 antibody supplementation for treatment of patients with DLBCL.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142234434","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 : 2024-09-16DOI: 10.1038/s41375-024-02375-8
Mouhamad Khouja, Linmiao Jiang, Karol Pal, Peter James Stewart, Binaya Regmi, Martin Schwarz, Wolfram Klapper, Stefan K. Alig, Nikos Darzentas, Hanneke C. Kluin-Nelemans, Olivier Hermine, Martin Dreyling, David Gonzalez de Castro, Eva Hoster, Christiane Pott
Recent studies highlighted genetic aberrations associated with prognosis in Mantle Cell lymphoma (MCL), yet comprehensive testing is not implemented in clinical routine. We conducted a comprehensive genomic characterization of 180 patients from the European MCL network trials by targeted sequencing of peripheral blood DNA using the EuroClonality(EC)-NDC assay. The IGH::CCND1 fusion was identified in 94% of patients, clonal IGH-V-(D)-J rearrangements in all, and 79% had ≥1 somatic gene mutation. The top mutated genes were ATM, TP53, KMT2D, SAMHD1, BIRC3 and NFKBIE. Copy number variations (CNVs) were detected in 83% of patients with RB1, ATM, CDKN2A/B and TP53 being the most frequently deleted and KLF2, CXCR4, CCND1, MAP2K1 and MYC the top amplified genes. CNVs and mutations were more frequently observed in older patients with adverse impact on prognosis. TP53mut, NOTCH1mut, FAT1mutTRAF2del, CDKN2A/Bdel and MAP2K1amp were linked to inferior failure-free (FFS) and overall survival (OS), while TRAF2mut, EGR2del and BCL2amp related to inferior OS only. Genetic complexity (≥3 CNVs) observed in 51% of analysed patients was significantly associated with impaired FFS and OS. We demonstrate that targeted sequencing from peripheral blood and bone marrow reliably detects diagnostically and prognostically important genetic factors in MCL patients, facilitating genetic characterization in clinical routine.
{"title":"Comprehensive genetic analysis by targeted sequencing identifies risk factors and predicts patient outcome in Mantle Cell Lymphoma: results from the EU-MCL network trials","authors":"Mouhamad Khouja, Linmiao Jiang, Karol Pal, Peter James Stewart, Binaya Regmi, Martin Schwarz, Wolfram Klapper, Stefan K. Alig, Nikos Darzentas, Hanneke C. Kluin-Nelemans, Olivier Hermine, Martin Dreyling, David Gonzalez de Castro, Eva Hoster, Christiane Pott","doi":"10.1038/s41375-024-02375-8","DOIUrl":"https://doi.org/10.1038/s41375-024-02375-8","url":null,"abstract":"<p>Recent studies highlighted genetic aberrations associated with prognosis in Mantle Cell lymphoma (MCL), yet comprehensive testing is not implemented in clinical routine. We conducted a comprehensive genomic characterization of 180 patients from the European MCL network trials by targeted sequencing of peripheral blood DNA using the EuroClonality(EC)-NDC assay. The <i>IGH::CCND1</i> fusion was identified in 94% of patients, clonal IGH-V-(D)-J rearrangements in all, and 79% had ≥1 somatic gene mutation. The top mutated genes were <i>ATM</i>, <i>TP53</i>, <i>KMT2D</i>, <i>SAMHD1</i>, <i>BIRC3</i> and <i>NFKBIE</i>. Copy number variations (CNVs) were detected in 83% of patients with <i>RB1</i>, <i>ATM</i>, <i>CDKN2A/B</i> and <i>TP53</i> being the most frequently deleted and <i>KLF2</i>, <i>CXCR4</i>, <i>CCND1</i>, <i>MAP2K1</i> and <i>MYC</i> the top amplified genes. CNVs and mutations were more frequently observed in older patients with adverse impact on prognosis. <i>TP53</i><sup><i>mut</i></sup>, <i>NOTCH1</i><sup><i>mut</i></sup><i>, FAT1</i><sup><i>mut</i></sup> <i>TRAF2</i><sup>del</sup>, <i>CDKN2A/B</i><sup><i>del</i></sup> and <i>MAP2K1</i><sup><i>amp</i></sup> were linked to inferior failure-free (FFS) and overall survival (OS), while <i>TRAF2</i><sup>mut</sup>, <i>EGR2</i><sup><i>del</i></sup> and <i>BCL2</i><sup><i>amp</i></sup> related to inferior OS only. Genetic complexity (≥3 CNVs) observed in 51% of analysed patients was significantly associated with impaired FFS and OS. We demonstrate that targeted sequencing from peripheral blood and bone marrow reliably detects diagnostically and prognostically important genetic factors in MCL patients, facilitating genetic characterization in clinical routine.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142234502","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}
Acute erythroleukemia (AEL) is a rare subtype of acute myeloid leukemia with a poor prognosis. In this study, we established a novel murine AEL model with Trp53 depletion and ERG overexpression. ERG overexpression in Trp53-deficient mouse bone marrow cells, but not in wild-type bone marrow cells, leads to AEL development within two months after transplantation with 100% penetrance. The established mouse AEL cells expressing Cas9 can be cultured in vitro, induce AEL in vivo even in unirradiated recipient mice, and enable efficient gene ablation using the CRISPR/Cas9 system. We also confirmed the cooperation between ERG overexpression and TP53 inactivation in promoting the growth of immature erythroid cells in human cord blood cells. Mechanistically, ERG antagonizes KLF1 and inhibits erythroid maturation, whereas TP53 deficiency promotes proliferation of erythroid progenitors. Furthermore, we identified HDAC7 as a specific susceptibility in AEL by the DepMap-based two-group comparison analysis. HDAC7 promotes the growth of human and mouse AEL cells both in vitro and in vivo through its non-enzymatic functions. Our study provides experimental evidence that TP53 deficiency and ERG overexpression are necessary and sufficient for the development of AEL and highlights HDAC7 as a promising therapeutic target for this disease.
{"title":"HDAC7 is a potential therapeutic target in acute erythroid leukemia","authors":"Wenyu Zhang, Keita Yamamoto, Yu-Hsuan Chang, Tomohiro Yabushita, Yangying Hao, Ruka Shimura, Jakushin Nakahara, Shiori Shikata, Kohei Iida, Qianyi Chen, Xichen Zhang, Toshio Kitamura, Susumu Goyama","doi":"10.1038/s41375-024-02394-5","DOIUrl":"https://doi.org/10.1038/s41375-024-02394-5","url":null,"abstract":"<p>Acute erythroleukemia (AEL) is a rare subtype of acute myeloid leukemia with a poor prognosis. In this study, we established a novel murine AEL model with <i>Trp53</i> depletion and ERG overexpression. ERG overexpression in <i>Trp53</i>-deficient mouse bone marrow cells, but not in wild-type bone marrow cells, leads to AEL development within two months after transplantation with 100% penetrance. The established mouse AEL cells expressing Cas9 can be cultured in vitro, induce AEL in vivo even in unirradiated recipient mice, and enable efficient gene ablation using the CRISPR/Cas9 system. We also confirmed the cooperation between ERG overexpression and TP53 inactivation in promoting the growth of immature erythroid cells in human cord blood cells. Mechanistically, ERG antagonizes KLF1 and inhibits erythroid maturation, whereas TP53 deficiency promotes proliferation of erythroid progenitors. Furthermore, we identified HDAC7 as a specific susceptibility in AEL by the DepMap-based two-group comparison analysis. HDAC7 promotes the growth of human and mouse AEL cells both in vitro and in vivo through its non-enzymatic functions. Our study provides experimental evidence that TP53 deficiency and ERG overexpression are necessary and sufficient for the development of AEL and highlights HDAC7 as a promising therapeutic target for this disease.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142233498","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 : 2024-09-12DOI: 10.1038/s41375-024-02338-z
Bo Liu, Xianli Zhang, Yuanyuan Zhou, Haiping Liu, Zhenkun Wang, Yuting Fu, Qiongdan Gao, Xiang Cheng, Qingyuan Sun, Zhenyu Ju
Enhanced ribosome biogenesis and protein synthesis are required for cell proliferation. During hematopoietic regeneration, hematopoietic stem cells (HSCs) proliferate rapidly to replenish the hematopoietic system. How HSCs respond and regulate ribosome biogenesis and protein synthesis during regeneration remains unclear. Here, we analyzed the expression of a series of ubiquitin-specific-proteases (USPs) during HSC regeneration. We found USP4 expression is significantly increased in proliferating HSCs. Further functional and mechanistic investigations revealed a crucial regulatory function of USP4 in HSC regeneration and leukemia progression by modulating ribosome biogenesis and protein synthesis. USP4 deubiquitinates and stabilizes PES1 to facilitate ribosome biogenesis and protein synthesis in proliferative HSCs and leukemic cells. Usp4 deletion significantly decreases protein synthesis, proliferation and reconstitution capacity of HSCs. Usp4 inhibition suppresses ribosome biogenesis and proliferation of leukemic cells, and prolongs the survival of AML (Acute myeloid leukemia) mice. These findings provide a new insight into the response mechanism of ribosome biogenesis and protein synthesis in HSCs, and their contribution to leukemia progression.
{"title":"USP4 regulates ribosome biogenesis and protein synthesis for hematopoietic stem cell regeneration and leukemia progression","authors":"Bo Liu, Xianli Zhang, Yuanyuan Zhou, Haiping Liu, Zhenkun Wang, Yuting Fu, Qiongdan Gao, Xiang Cheng, Qingyuan Sun, Zhenyu Ju","doi":"10.1038/s41375-024-02338-z","DOIUrl":"https://doi.org/10.1038/s41375-024-02338-z","url":null,"abstract":"<p>Enhanced ribosome biogenesis and protein synthesis are required for cell proliferation. During hematopoietic regeneration, hematopoietic stem cells (HSCs) proliferate rapidly to replenish the hematopoietic system. How HSCs respond and regulate ribosome biogenesis and protein synthesis during regeneration remains unclear. Here, we analyzed the expression of a series of ubiquitin-specific-proteases (USPs) during HSC regeneration. We found USP4 expression is significantly increased in proliferating HSCs. Further functional and mechanistic investigations revealed a crucial regulatory function of USP4 in HSC regeneration and leukemia progression by modulating ribosome biogenesis and protein synthesis. USP4 deubiquitinates and stabilizes PES1 to facilitate ribosome biogenesis and protein synthesis in proliferative HSCs and leukemic cells. <i>Usp4</i> deletion significantly decreases protein synthesis, proliferation and reconstitution capacity of HSCs. <i>Usp4</i> inhibition suppresses ribosome biogenesis and proliferation of leukemic cells, and prolongs the survival of AML (Acute myeloid leukemia) mice. These findings provide a new insight into the response mechanism of ribosome biogenesis and protein synthesis in HSCs, and their contribution to leukemia progression.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142171066","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 : 2024-09-12DOI: 10.1038/s41375-024-02402-8
Florence Rabian, Sylvie Chevret, Bérengère Gruson, Sylvain Thépot, Anouk Walter-Petrich, Thorsten Braun, Norbert Vey, José Miguel Torregrosa-Diaz, Pierre Peterlin, Andrea Toma, Maud D’Aveni, Jacques Delaunay, Laurence Legros, Nathalie Droin, Fatiha Chermat, Daniel Lusina, Lionel Adès, Rosa Sapena, Eric Solary, Pierre Fenaux, Raphael Itzykson
Severe thrombocytopenia (<50 ×109/L) occurs in 10–30% of Chronic Myelomonocytic Leukemias (CMML) and leads to significant mortality through increased risk of bleeding and disease progression [1]. Its management is ill codified [2].
The thrombopoietin receptor agonist Eltrombopag improves platelet counts in lower-risk myelodysplastic syndromes [3]. Its activity in CMML has been investigated in retrospective case series of up to eleven patients [4,5,6], or as part of a phase I MDS trial [7].
{"title":"Eltrombopag in chronic myelomonocytic leukemia with severe thrombocytopenia. A Groupe Francophone des Myélodysplasies (GFM) study","authors":"Florence Rabian, Sylvie Chevret, Bérengère Gruson, Sylvain Thépot, Anouk Walter-Petrich, Thorsten Braun, Norbert Vey, José Miguel Torregrosa-Diaz, Pierre Peterlin, Andrea Toma, Maud D’Aveni, Jacques Delaunay, Laurence Legros, Nathalie Droin, Fatiha Chermat, Daniel Lusina, Lionel Adès, Rosa Sapena, Eric Solary, Pierre Fenaux, Raphael Itzykson","doi":"10.1038/s41375-024-02402-8","DOIUrl":"https://doi.org/10.1038/s41375-024-02402-8","url":null,"abstract":"<p>Severe thrombocytopenia (<50 ×10<sup>9</sup>/L) occurs in 10–30% of Chronic Myelomonocytic Leukemias (CMML) and leads to significant mortality through increased risk of bleeding and disease progression [1]. Its management is ill codified [2].</p><p>The thrombopoietin receptor agonist Eltrombopag improves platelet counts in lower-risk myelodysplastic syndromes [3]. Its activity in CMML has been investigated in retrospective case series of up to eleven patients [4,5,6], or as part of a phase I MDS trial [7].</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142171065","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 : 2024-09-11DOI: 10.1038/s41375-024-02326-3
Jan Korbecki, Mateusz Bosiacki, Patrycja Kupnicka, Katarzyna Barczak, Dariusz Chlubek, Irena Baranowska-Bosiacka
Extensive research on the CXCL12-CXCR4 axis in acute myeloid leukemia (AML) has resulted in the incorporation of novel anti-leukemia drugs targeting this axis into therapeutic strategies. However, despite this progress, a comprehensive and up-to-date review addressing the role of the CXCL12-CXCR4 axis in AML’s oncogenic processes is lacking. In this review, we examine its molecular aspects influencing cancer progression, such as its impact on autonomous proliferation, apoptotic regulation, chemoresistance mechanisms, and interactions with non-leukemic cells such as MSCs and Treg cells. Additionally, we explore clinical implications, including prognosis, correlation with WBC count, blast count in the bone marrow and peripheral blood, as well as its association with FLT3-ITD, NPM1 mutations, and FAB classification. Finally, this paper extensively discusses drugs that specifically target the CXCL12-CXCR4 axis, including plerixafor/AMD3100, ulocuplumab, peptide E5, and motixafortide, shedding light on their potential therapeutic value in the treatment of AML.
{"title":"CXCR4 as a therapeutic target in acute myeloid leukemia","authors":"Jan Korbecki, Mateusz Bosiacki, Patrycja Kupnicka, Katarzyna Barczak, Dariusz Chlubek, Irena Baranowska-Bosiacka","doi":"10.1038/s41375-024-02326-3","DOIUrl":"https://doi.org/10.1038/s41375-024-02326-3","url":null,"abstract":"<p>Extensive research on the CXCL12-CXCR4 axis in acute myeloid leukemia (AML) has resulted in the incorporation of novel anti-leukemia drugs targeting this axis into therapeutic strategies. However, despite this progress, a comprehensive and up-to-date review addressing the role of the CXCL12-CXCR4 axis in AML’s oncogenic processes is lacking. In this review, we examine its molecular aspects influencing cancer progression, such as its impact on autonomous proliferation, apoptotic regulation, chemoresistance mechanisms, and interactions with non-leukemic cells such as MSCs and T<sub>reg</sub> cells. Additionally, we explore clinical implications, including prognosis, correlation with WBC count, blast count in the bone marrow and peripheral blood, as well as its association with <i>FLT3</i>-ITD, <i>NPM1</i> mutations, and FAB classification. Finally, this paper extensively discusses drugs that specifically target the CXCL12-CXCR4 axis, including plerixafor/AMD3100, ulocuplumab, peptide E5, and motixafortide, shedding light on their potential therapeutic value in the treatment of AML.</p><figure></figure>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142166536","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 : 2024-09-11DOI: 10.1038/s41375-024-02395-4
Susan R. Rheingold, Deepa Bhojwani, Lingyun Ji, Xinxin Xu, Meenakshi Devidas, John A. Kairalla, Mary Shago, Nyla A. Heerema, Andrew J. Carroll, Heather Breidenbach, Michael Borowitz, Brent L. Wood, Anne L. Angiolillo, Barbara L. Asselin, W. Paul Bowman, Patrick Brown, ZoAnn E. Dreyer, Kimberly P. Dunsmore, Joanne M. Hilden, Eric Larsen, Kelly Maloney, Yousif Matloub, Leonard A. Mattano, Stuart S. Winter, Lia Gore, Naomi J. Winick, William L. Carroll, Stephen P. Hunger, Elizabeth A. Raetz, Mignon L. Loh
Limited prognostic factors have been associated with overall survival (OS) post-relapse in childhood Acute Lymphoblastic Leukemia (ALL). Patients enrolled on 12 Children’s Oncology Group frontline ALL trials (1996–2014) were analyzed to assess for additional prognostic factors associated with OS post-relapse. Among 16,115 patients, 2053 (12.7%) relapsed. Relapse rates were similar for B-ALL (12.5%) and T-ALL (11.2%) while higher for infants (34.2%). Approximately 50% of B-ALL relapses occurred late (≥36 months) and 72.5% involved the marrow. Conversely, 64.8% of T-ALL relapses occurred early (<18 months) and 47.1% involved the central nervous system. The 5-year OS post-relapse for the entire cohort was 48.9 ± 1.2%; B-ALL:52.5 ± 1.3%, T-ALL:35.5 ± 3.3%, and infant ALL:21.5 ± 3.9%. OS varied by early, intermediate and late time-to-relapse; 25.8 ± 2.4%, 49.5 ± 2.2%, and 66.4 ± 1.8% respectively for B-ALL and 29.8 ± 3.9%, 33.3 ± 7.6%, 58 ± 9.8% for T-ALL. Patients with ETV6::RUNX1 or Trisomy 4 + 10 had median time-to-relapse of 43 months and higher OS post-relapse 74.4 ± 3.1% and 70.2 ± 3.6%, respectively. Patients with hypodiploidy, KMT2A-rearrangement, and TCF3::PBX1 had short median time-to-relapse (12.5-18 months) and poor OS post-relapse (14.2 ± 6.1%, 31.9 ± 7.7%, 36.8 ± 6.6%). Site-of-relapse varied by cytogenetic subtype. This large dataset provided the opportunity to identify risk factors for OS post-relapse to inform trial design and highlight populations with dismal outcomes post-relapse.
{"title":"Determinants of survival after first relapse of acute lymphoblastic leukemia: a Children’s Oncology Group study","authors":"Susan R. Rheingold, Deepa Bhojwani, Lingyun Ji, Xinxin Xu, Meenakshi Devidas, John A. Kairalla, Mary Shago, Nyla A. Heerema, Andrew J. Carroll, Heather Breidenbach, Michael Borowitz, Brent L. Wood, Anne L. Angiolillo, Barbara L. Asselin, W. Paul Bowman, Patrick Brown, ZoAnn E. Dreyer, Kimberly P. Dunsmore, Joanne M. Hilden, Eric Larsen, Kelly Maloney, Yousif Matloub, Leonard A. Mattano, Stuart S. Winter, Lia Gore, Naomi J. Winick, William L. Carroll, Stephen P. Hunger, Elizabeth A. Raetz, Mignon L. Loh","doi":"10.1038/s41375-024-02395-4","DOIUrl":"https://doi.org/10.1038/s41375-024-02395-4","url":null,"abstract":"<p>Limited prognostic factors have been associated with overall survival (OS) post-relapse in childhood Acute Lymphoblastic Leukemia (ALL). Patients enrolled on 12 Children’s Oncology Group frontline ALL trials (1996–2014) were analyzed to assess for additional prognostic factors associated with OS post-relapse. Among 16,115 patients, 2053 (12.7%) relapsed. Relapse rates were similar for B-ALL (12.5%) and T-ALL (11.2%) while higher for infants (34.2%). Approximately 50% of B-ALL relapses occurred late (≥36 months) and 72.5% involved the marrow. Conversely, 64.8% of T-ALL relapses occurred early (<18 months) and 47.1% involved the central nervous system. The 5-year OS post-relapse for the entire cohort was 48.9 ± 1.2%; B-ALL:52.5 ± 1.3%, T-ALL:35.5 ± 3.3%, and infant ALL:21.5 ± 3.9%. OS varied by early, intermediate and late time-to-relapse; 25.8 ± 2.4%, 49.5 ± 2.2%, and 66.4 ± 1.8% respectively for B-ALL and 29.8 ± 3.9%, 33.3 ± 7.6%, 58 ± 9.8% for T-ALL. Patients with <i>ETV6::RUNX1</i> or Trisomy 4 + 10 had median time-to-relapse of 43 months and higher OS post-relapse 74.4 ± 3.1% and 70.2 ± 3.6%, respectively. Patients with hypodiploidy, <i>KMT2A</i>-rearrangement, and <i>TCF3::PBX1</i> had short median time-to-relapse (12.5-18 months) and poor OS post-relapse (14.2 ± 6.1%, 31.9 ± 7.7%, 36.8 ± 6.6%). Site-of-relapse varied by cytogenetic subtype. This large dataset provided the opportunity to identify risk factors for OS post-relapse to inform trial design and highlight populations with dismal outcomes post-relapse.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142166196","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 : 2024-09-11DOI: 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":"https://doi.org/10.1038/s41375-024-02379-4","url":null,"abstract":"<p><i>SF3B1</i> 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 <i>SF3B1</i><sup><i>MUT</i></sup> and 17 <i>SF3B1</i><sup><i>WT</i></sup> 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, <i>BRD9</i>, 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 <i>SF3B1</i> mutations. Overexpression of <i>SF3B1</i><sup><i>K700E</i></sup> induced exon inclusion in <i>BRD9</i>, 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 <i>SF3B1</i><sup><i>MUT</i></sup> 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 <i>SF3B1</i> mutations leads to multiple ASEs and an altered ncBAF complex interactome, highlighting a novel pathobiological mechanism in <i>SF3B1</i><sup><i>MUT</i></sup> CLL.</p><figure></figure>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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":"https://doi.org/10.1038/s41375-024-02386-5","url":null,"abstract":"<p>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 (<i>n</i> = 271) and DCOG-ALL-9 (<i>n</i> = 122), with MRD <0.05% at EOC. EOC MRD-negative patients (<i>n</i> = 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 (<i>p</i> = 0.51). Patients with positive EOC MRD (<i>n</i> = 91) of whom the subsequent timepoints were MRD negative (<i>n</i> = 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 (<i>n</i> = 48) had a higher risk of relapse, 6-y CIR 29.4% (95% CI, 17.2%–42.8%), <i>p</i> < 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.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}