Pub Date : 2024-08-22DOI: 10.1038/s41375-024-02387-4
Maryam Kazerani, Anetta Marcinek, Nora Philipp, Bettina Brauchle, Jonathan Jonas Taylor, Helena Domínguez Moreno, Andrea Terrasi, Benjamin Tast, Lisa Rohrbacher, Yingshuai Wang, Maximilian Warm, Alica-Joana Emhardt, Giulia Magno, Karsten Spiekermann, Tobias Herold, Tobias Straub, Sebastian Theurich, Gunnar Schotta, Roman Kischel, Veit L. Bücklein, Marion Subklewe
{"title":"Evolution of T-cell fitness through AML progression: enhanced bispecific T-cell engager-mediated function of bone marrow T cells at remission compared to initial diagnosis and relapse","authors":"Maryam Kazerani, Anetta Marcinek, Nora Philipp, Bettina Brauchle, Jonathan Jonas Taylor, Helena Domínguez Moreno, Andrea Terrasi, Benjamin Tast, Lisa Rohrbacher, Yingshuai Wang, Maximilian Warm, Alica-Joana Emhardt, Giulia Magno, Karsten Spiekermann, Tobias Herold, Tobias Straub, Sebastian Theurich, Gunnar Schotta, Roman Kischel, Veit L. Bücklein, Marion Subklewe","doi":"10.1038/s41375-024-02387-4","DOIUrl":"10.1038/s41375-024-02387-4","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02387-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142021855","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 : 2024-08-21DOI: 10.1038/s41375-024-02378-5
Eduardo Rodríguez-Arbolí, Megan Othus, Sylvie D. Freeman, Francesco Buccisano, Lok Lam Ngai, Ian Thomas, Raffaele Palmieri, Jacqueline Cloos, Sean Johnson, Elisa Meddi, Nigel H. Russell, Adriano Venditti, Patrycja Gradowska, Gert J. Ossenkoppele, Bob Löwenberg, Roland B. Walter
{"title":"Optimal prognostic threshold for measurable residual disease positivity by multiparameter flow cytometry in acute myeloid leukemia (AML)","authors":"Eduardo Rodríguez-Arbolí, Megan Othus, Sylvie D. Freeman, Francesco Buccisano, Lok Lam Ngai, Ian Thomas, Raffaele Palmieri, Jacqueline Cloos, Sean Johnson, Elisa Meddi, Nigel H. Russell, Adriano Venditti, Patrycja Gradowska, Gert J. Ossenkoppele, Bob Löwenberg, Roland B. Walter","doi":"10.1038/s41375-024-02378-5","DOIUrl":"10.1038/s41375-024-02378-5","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142013838","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 : 2024-08-21DOI: 10.1038/s41375-024-02358-9
Héléna Boutzen, Alex Murison, Alexa Oriecuia, Suraj Bansal, Christopher Arlidge, Jean C. Y. Wang, Mathieu Lupien, Kerstin B. Kaufmann, John E. Dick
The leukemia stem cell (LSC) compartment is a complex reservoir fueling disease progression in acute myeloid leukemia (AML). The existence of heterogeneity within this compartment is well documented but prior studies have focused on genetic heterogeneity without being able to address functional heterogeneity. Understanding this heterogeneity is critical for the informed design of therapies targeting LSC, but has been hampered by LSC scarcity and the lack of reliable cell surface markers for viable LSC isolation. To overcome these challenges, we turned to the patient-derived OCI-AML22 cell model. This model includes functionally, transcriptionally and epigenetically characterized LSC broadly representative of LSC found in primary AML samples. Focusing on the pool of LSC, we used an integrated approach combining xenograft assays with single-cell analysis to identify two LSC subtypes with distinct transcriptional, epigenetic and functional properties. These LSC subtypes differed in depth of quiescence, differentiation potential, repopulation capacity, sensitivity to chemotherapy and could be isolated based on CD112 expression. A majority of AML patient samples had transcriptional signatures reflective of either LSC subtype, and some even showed coexistence within an individual sample. This work provides a framework for investigating the LSC compartment and designing combinatorial therapeutic strategies in AML.
急性髓性白血病（AML）中，白血病干细胞（LSC）区是一个复杂的储库，对疾病进展起着推波助澜的作用。这一区室中存在的异质性已得到充分证实，但之前的研究主要集中在遗传异质性上，而无法解决功能异质性问题。了解这种异质性对于设计针对造血干细胞的知情疗法至关重要，但造血干细胞的稀缺性和缺乏可靠的细胞表面标志物来分离有活力的造血干细胞一直阻碍着研究的进行。为了克服这些挑战，我们转而使用源自患者的 OCI-AML22 细胞模型。该模型包括具有功能、转录和表观遗传特征的 LSC，广泛代表了原发性 AML 样本中发现的 LSC。我们以LSC池为重点，采用异种移植检测与单细胞分析相结合的综合方法，鉴定出两种具有不同转录、表观遗传和功能特性的LSC亚型。这些LSC亚型在静止深度、分化潜能、再繁殖能力、对化疗的敏感性等方面存在差异，并可根据CD112的表达进行分离。大多数急性髓细胞性白血病患者样本的转录特征反映了其中任何一种 LSC 亚型，有些甚至在单个样本中显示出共存性。这项工作为研究 LSC 区系和设计 AML 组合治疗策略提供了一个框架。
{"title":"Identification of leukemia stem cell subsets with distinct transcriptional, epigenetic and functional properties","authors":"Héléna Boutzen, Alex Murison, Alexa Oriecuia, Suraj Bansal, Christopher Arlidge, Jean C. Y. Wang, Mathieu Lupien, Kerstin B. Kaufmann, John E. Dick","doi":"10.1038/s41375-024-02358-9","DOIUrl":"10.1038/s41375-024-02358-9","url":null,"abstract":"The leukemia stem cell (LSC) compartment is a complex reservoir fueling disease progression in acute myeloid leukemia (AML). The existence of heterogeneity within this compartment is well documented but prior studies have focused on genetic heterogeneity without being able to address functional heterogeneity. Understanding this heterogeneity is critical for the informed design of therapies targeting LSC, but has been hampered by LSC scarcity and the lack of reliable cell surface markers for viable LSC isolation. To overcome these challenges, we turned to the patient-derived OCI-AML22 cell model. This model includes functionally, transcriptionally and epigenetically characterized LSC broadly representative of LSC found in primary AML samples. Focusing on the pool of LSC, we used an integrated approach combining xenograft assays with single-cell analysis to identify two LSC subtypes with distinct transcriptional, epigenetic and functional properties. These LSC subtypes differed in depth of quiescence, differentiation potential, repopulation capacity, sensitivity to chemotherapy and could be isolated based on CD112 expression. A majority of AML patient samples had transcriptional signatures reflective of either LSC subtype, and some even showed coexistence within an individual sample. This work provides a framework for investigating the LSC compartment and designing combinatorial therapeutic strategies in AML.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02358-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142013836","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 : 2024-08-20DOI: 10.1038/s41375-024-02372-x
Carlo Gambacorti-Passerini, Tim H. Brümmendorf, Elisabetta Abruzzese, Kevin R. Kelly, Vivian G. Oehler, Valentín García-Gutiérrez, Henrik Hjorth-Hansen, Thomas Ernst, Eric Leip, Simon Purcell, Gerald Luscan, Andrea Viqueira, Francis J. Giles, Andreas Hochhaus
This final analysis from the phase 4 BYOND trial reports outcomes with bosutinib in patients with previously treated chronic myeloid leukemia (CML); 163 patients with CML resistant/intolerant to previous tyrosine kinase inhibitors received bosutinib (starting dose: 500 mg QD). At study completion (median follow-up, 47.8 months), 48.1% (n = 75/156) of patients with Philadelphia chromosome–positive chronic phase CML were still receiving treatment. Among evaluable patients, 71.8% (95% CI, 63.9–78.9) and 59.7% (95% CI, 51.4–67.7) attained or maintained major molecular response (MMR) and molecular response (MR)4, respectively, at any time on treatment. The majority of patients achieved a deeper molecular response relative to baseline while on bosutinib. Kaplan-Meier probabilities (95% CI) of maintaining MMR and MR4 at 36 months were 87.2% (78.0–92.7) and 80.7% (69.4–88.1), respectively. At 48 months, the Kaplan-Meier overall survival rate was 88.3% (95% CI, 81.8–92.6); there were 17 deaths, including 2 that were considered CML related. Long-term adverse events (AEs) were consistent with the known safety profile of bosutinib, and no new safety issues were identified. The management of AEs through dose reduction maintained efficacy while improving tolerability. These results support the use of bosutinib in patients with previously treated CML. ClinicalTrials.gov, NCT02228382
{"title":"Efficacy and safety of bosutinib in previously treated patients with chronic myeloid leukemia: final results from the BYOND trial","authors":"Carlo Gambacorti-Passerini, Tim H. Brümmendorf, Elisabetta Abruzzese, Kevin R. Kelly, Vivian G. Oehler, Valentín García-Gutiérrez, Henrik Hjorth-Hansen, Thomas Ernst, Eric Leip, Simon Purcell, Gerald Luscan, Andrea Viqueira, Francis J. Giles, Andreas Hochhaus","doi":"10.1038/s41375-024-02372-x","DOIUrl":"10.1038/s41375-024-02372-x","url":null,"abstract":"This final analysis from the phase 4 BYOND trial reports outcomes with bosutinib in patients with previously treated chronic myeloid leukemia (CML); 163 patients with CML resistant/intolerant to previous tyrosine kinase inhibitors received bosutinib (starting dose: 500 mg QD). At study completion (median follow-up, 47.8 months), 48.1% (n = 75/156) of patients with Philadelphia chromosome–positive chronic phase CML were still receiving treatment. Among evaluable patients, 71.8% (95% CI, 63.9–78.9) and 59.7% (95% CI, 51.4–67.7) attained or maintained major molecular response (MMR) and molecular response (MR)4, respectively, at any time on treatment. The majority of patients achieved a deeper molecular response relative to baseline while on bosutinib. Kaplan-Meier probabilities (95% CI) of maintaining MMR and MR4 at 36 months were 87.2% (78.0–92.7) and 80.7% (69.4–88.1), respectively. At 48 months, the Kaplan-Meier overall survival rate was 88.3% (95% CI, 81.8–92.6); there were 17 deaths, including 2 that were considered CML related. Long-term adverse events (AEs) were consistent with the known safety profile of bosutinib, and no new safety issues were identified. The management of AEs through dose reduction maintained efficacy while improving tolerability. These results support the use of bosutinib in patients with previously treated CML. ClinicalTrials.gov, NCT02228382","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02372-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142007633","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 : 2024-08-20DOI: 10.1038/s41375-024-02380-x
Tinatin Muradashvili, Mansen Yu, Sabrina L. Browning, Noffar Bar, Elan Gorshein, Terri L. Parker, Natalia Neparidze
{"title":"Prevalence of metabolic comorbidities and viral co-infections in monoclonal gammopathy: a retrospective analysis","authors":"Tinatin Muradashvili, Mansen Yu, Sabrina L. Browning, Noffar Bar, Elan Gorshein, Terri L. Parker, Natalia Neparidze","doi":"10.1038/s41375-024-02380-x","DOIUrl":"10.1038/s41375-024-02380-x","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142007639","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 : 2024-08-17DOI: 10.1038/s41375-024-02334-3
John Alan Gambril, Sanam M. Ghazi, Stephen Sansoterra, Mussammat Ferdousi, Onaopepo Kola-Kehinde, Patrick Ruz, Adam S. Kittai, Kerry Rogers, Michael Grever, Seema Bhat, Tracy Wiczer, John C. Byrd, Jennifer Woyach, Daniel Addison
Bruton’s tyrosine kinase inhibitors (BTKi) have dramatic efficacy against B-cell malignancies, but link with cardiotoxicity, including atrial fibrillation (AF). Burden, severity, and implications of BTKi-related AF are unknown. Leveraging a large-cohort of consecutive B-cell malignancy patients initiated on BTKi from 2009–2020, we identified patients with extended ambulatory rhythm monitoring. The primary outcome was AF burden after BTKi-initiation. Secondary outcomes included ventricular arrhythmia burden and other arrhythmias. Observed incident-AF rates and burden with next-generation BTKi’s were compared to ibrutinib. Multivariable regression defined association between rhythm measures and major adverse cardiac events (MACE), and mortality. There were 98 BTKi-treated patients [38.8% next-generation BTKi’s, 14.3% prior-AF], with 28,224 h of monitoring. Median duration BTKi-use was 34 months. Over mean duration 12 days monitoring, 72.4% developed arrhythmias (16.3% incident-AF, 31.6% other SVTs, 14.3% ventricular tachycardia). 14.3% had high AF-burden. AF-burden was similar between ibrutinib and next-generation BTKi’s. No single antiarrhythmic-therapy prevented BTKi-related AF. However, antiarrhythmic initiation associated with reduction in arrhythmic burden (P = 0.009). In a multivariable model accounting for traditional cardiovascular risk factors, prior-AF associated with increased post-BTKi AF-burden. In follow-up, high AF burden associated with MACE (HR 3.12, P = 0.005) and mortality (HR 2.97, P = 0.007). Among BTKi-treated patients, high AF burden prognosticates future MACE and mortality risk.
{"title":"Atrial fibrillation burden and clinical outcomes following BTK inhibitor initiation","authors":"John Alan Gambril, Sanam M. Ghazi, Stephen Sansoterra, Mussammat Ferdousi, Onaopepo Kola-Kehinde, Patrick Ruz, Adam S. Kittai, Kerry Rogers, Michael Grever, Seema Bhat, Tracy Wiczer, John C. Byrd, Jennifer Woyach, Daniel Addison","doi":"10.1038/s41375-024-02334-3","DOIUrl":"10.1038/s41375-024-02334-3","url":null,"abstract":"Bruton’s tyrosine kinase inhibitors (BTKi) have dramatic efficacy against B-cell malignancies, but link with cardiotoxicity, including atrial fibrillation (AF). Burden, severity, and implications of BTKi-related AF are unknown. Leveraging a large-cohort of consecutive B-cell malignancy patients initiated on BTKi from 2009–2020, we identified patients with extended ambulatory rhythm monitoring. The primary outcome was AF burden after BTKi-initiation. Secondary outcomes included ventricular arrhythmia burden and other arrhythmias. Observed incident-AF rates and burden with next-generation BTKi’s were compared to ibrutinib. Multivariable regression defined association between rhythm measures and major adverse cardiac events (MACE), and mortality. There were 98 BTKi-treated patients [38.8% next-generation BTKi’s, 14.3% prior-AF], with 28,224 h of monitoring. Median duration BTKi-use was 34 months. Over mean duration 12 days monitoring, 72.4% developed arrhythmias (16.3% incident-AF, 31.6% other SVTs, 14.3% ventricular tachycardia). 14.3% had high AF-burden. AF-burden was similar between ibrutinib and next-generation BTKi’s. No single antiarrhythmic-therapy prevented BTKi-related AF. However, antiarrhythmic initiation associated with reduction in arrhythmic burden (P = 0.009). In a multivariable model accounting for traditional cardiovascular risk factors, prior-AF associated with increased post-BTKi AF-burden. In follow-up, high AF burden associated with MACE (HR 3.12, P = 0.005) and mortality (HR 2.97, P = 0.007). Among BTKi-treated patients, high AF burden prognosticates future MACE and mortality risk.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02334-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141996099","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 : 2024-08-16DOI: 10.1038/s41375-024-02371-y
Fabian Frontzek, Loïc Renaud, Ulrich Dührsen, Viola Poeschel, Sophie Bernard, Loïc Chartier, Nicolas Ketterer, Christian Récher, Olivier Fitoussi, Gerhard Held, Olivier Casasnovas, Corinne Haioun, Nicolas Mounier, Hervé Tilly, Franck Morschhauser, Steven Le Gouill, Imke E. Karsten, Gerben Duns, Christian Steidl, David W. Scott, Wolfram Klapper, Andreas Rosenwald, German Ott, Thierry Molina, Georg Lenz, Marita Ziepert, Bettina Altmann, Catherine Thieblemont, Norbert Schmitz
Progression or relapse in the central nervous system (CNS) remains a rare but mostly fatal event for patients with diffuse large B-cell lymphoma (DLBCL). In a retrospective analysis of 5189 patients treated within 19 prospective German and French phase 2/3 trials, we identified 159 patients experiencing a CNS event (relapse: 62%, progression: 38%). Intracerebral, meningeal, intraspinal, or combined involvement was reported in 44%, 31%, 3%, and 22% of patients, respectively. 62 of 155 evaluable patients (40%) showed concurrent systemic progression/ relapse. 82% of all CNS events occurred within two years after study inclusion or randomization. 87% of patients showed extranodal involvement outside the CNS. Patients generally had poor outcomes with a median overall survival (OS) of 3.4 months (95% CI 2.9–4.2) and a 2-year OS of 15% (10–22%). Outcomes did not differ depending on the site or time point of CNS events. Patients with isolated CNS events demonstrated significantly better OS (p = 0.023). Twenty-five patients were consolidated with autologous or allogeneic stem cell transplantation and achieved a 3-year OS of 36% (20–66%). This large study including more than 5000 DLBCL patients highlights the unmet medical need to improve the outcome of DLBCL patients suffering from CNS relapse.
对于弥漫大 B 细胞淋巴瘤（DLBCL）患者来说，中枢神经系统（CNS）的进展或复发仍然罕见，但大多是致命的。在对19项德国和法国前瞻性2/3期试验中接受治疗的5189名患者进行的回顾性分析中，我们发现159名患者出现了中枢神经系统事件（复发：62%，进展：38%）。脑内、脑膜、椎管内或合并受累的患者比例分别为 44%、31%、3% 和 22%。在 155 例可评估的患者中，62 例（40%）同时出现全身进展/复发。82%的中枢神经系统事件发生在纳入研究或随机分配后两年内。87%的患者出现中枢神经系统以外的结节外受累。患者的预后普遍较差，中位总生存期（OS）为3.4个月（95% CI为2.9-4.2），2年OS为15%（10-22%）。中枢神经系统事件发生的部位或时间点不同，结果也不尽相同。发生孤立中枢神经系统事件的患者的 OS 明显更好（p = 0.023）。25名患者接受了自体或异体干细胞移植，3年生存率为36%（20-66%）。这项包括5000多名DLBCL患者的大型研究强调，改善中枢神经系统复发的DLBCL患者预后的医疗需求尚未得到满足。
{"title":"Identification, risk factors, and clinical course of CNS relapse in DLBCL patients across 19 prospective phase 2 and 3 trials—a LYSA and GLA/ DSHNHL collaboration","authors":"Fabian Frontzek, Loïc Renaud, Ulrich Dührsen, Viola Poeschel, Sophie Bernard, Loïc Chartier, Nicolas Ketterer, Christian Récher, Olivier Fitoussi, Gerhard Held, Olivier Casasnovas, Corinne Haioun, Nicolas Mounier, Hervé Tilly, Franck Morschhauser, Steven Le Gouill, Imke E. Karsten, Gerben Duns, Christian Steidl, David W. Scott, Wolfram Klapper, Andreas Rosenwald, German Ott, Thierry Molina, Georg Lenz, Marita Ziepert, Bettina Altmann, Catherine Thieblemont, Norbert Schmitz","doi":"10.1038/s41375-024-02371-y","DOIUrl":"10.1038/s41375-024-02371-y","url":null,"abstract":"Progression or relapse in the central nervous system (CNS) remains a rare but mostly fatal event for patients with diffuse large B-cell lymphoma (DLBCL). In a retrospective analysis of 5189 patients treated within 19 prospective German and French phase 2/3 trials, we identified 159 patients experiencing a CNS event (relapse: 62%, progression: 38%). Intracerebral, meningeal, intraspinal, or combined involvement was reported in 44%, 31%, 3%, and 22% of patients, respectively. 62 of 155 evaluable patients (40%) showed concurrent systemic progression/ relapse. 82% of all CNS events occurred within two years after study inclusion or randomization. 87% of patients showed extranodal involvement outside the CNS. Patients generally had poor outcomes with a median overall survival (OS) of 3.4 months (95% CI 2.9–4.2) and a 2-year OS of 15% (10–22%). Outcomes did not differ depending on the site or time point of CNS events. Patients with isolated CNS events demonstrated significantly better OS (p = 0.023). Twenty-five patients were consolidated with autologous or allogeneic stem cell transplantation and achieved a 3-year OS of 36% (20–66%). This large study including more than 5000 DLBCL patients highlights the unmet medical need to improve the outcome of DLBCL patients suffering from CNS relapse.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141991809","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 : 2024-08-15DOI: 10.1038/s41375-024-02342-3
Eloïne Bestion, Régis Costello, Soraya Mezouar, Philippe Halfon
{"title":"Autophagy in cancer resistance: New combinatorial strategy for cancer therapy","authors":"Eloïne Bestion, Régis Costello, Soraya Mezouar, Philippe Halfon","doi":"10.1038/s41375-024-02342-3","DOIUrl":"10.1038/s41375-024-02342-3","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141988230","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 : 2024-08-14DOI: 10.1038/s41375-024-02376-7
Erika Tissino, Annalisa Gaglio, Antonella Nicolò, Federico Pozzo, Tamara Bittolo, Francesca Maria Rossi, Riccardo Bomben, Paola Nanni, Ilaria Cattarossi, Eva Zaina, Anna Maria Zimbo, Giulia Ianna, Guido Capasso, Gabriela Forestieri, Riccardo Moia, Moumita Datta, Andrea Härzschel, Jacopo Olivieri, Giovanni D’Arena, Luca Laurenti, Francesco Zaja, Annalisa Chiarenza, Giuseppe A. Palumbo, Enrica Antonia Martino, Massimo Gentile, Davide Rossi, Gianluca Gaidano, Giovanni Del Poeta, Roberta Laureana, Maria Ilaria Del Principe, Palash C. Maity, Hassan Jumaa, Tanja Nicole Hartmann, Antonella Zucchetto, Valter Gattei
In chronic lymphocytic leukemia (CLL), survival of neoplastic cells depends on microenvironmental signals at lymphoid sites where the crosstalk between the integrin VLA-4 (CD49d/CD29), expressed in ~40% of CLL, and the B-cell receptor (BCR) occurs. Here, BCR engagement inside–out activates VLA-4, thus enhancing VLA-4-mediated adhesion of CLL cells, which in turn obtain pro-survival signals from the surrounding microenvironment. We report that the BCR is also able to effectively inside–out activate the VLA-4 integrin in circulating CD49d-expressing CLL cells through an autonomous antigen-independent BCR signaling. As a consequence, circulating CLL cells exhibiting activated VLA-4 express markers of BCR pathway activation (phospho-BTK and phospho-PLC-γ2) along with higher levels of phospho-ERK and phospho-AKT indicating parallel activation of downstream pathways. Moreover, circulating CLL cells expressing activated VLA-4 bind soluble blood-borne VCAM-1 leading to increased VLA-4-dependent actin polymerization/re-organization and ERK phosphorylation. Finally, evidence is provided that ibrutinib treatment, by affecting autonomous BCR signaling, impairs the constitutive VLA-4 activation eventually decreasing soluble VCAM-1 binding and reducing downstream ERK phosphorylation by circulating CLL cells. This study describes a novel anchor-independent mechanism occurring in circulating CLL cells involving the BCR and the VLA-4 integrin, which help to unravel the peculiar biological and clinical features of CD49d+ CLL.
{"title":"The VLA-4 integrin is constitutively active in circulating chronic lymphocytic leukemia cells via BCR autonomous signaling: a novel anchor-independent mechanism exploiting soluble blood-borne ligands","authors":"Erika Tissino, Annalisa Gaglio, Antonella Nicolò, Federico Pozzo, Tamara Bittolo, Francesca Maria Rossi, Riccardo Bomben, Paola Nanni, Ilaria Cattarossi, Eva Zaina, Anna Maria Zimbo, Giulia Ianna, Guido Capasso, Gabriela Forestieri, Riccardo Moia, Moumita Datta, Andrea Härzschel, Jacopo Olivieri, Giovanni D’Arena, Luca Laurenti, Francesco Zaja, Annalisa Chiarenza, Giuseppe A. Palumbo, Enrica Antonia Martino, Massimo Gentile, Davide Rossi, Gianluca Gaidano, Giovanni Del Poeta, Roberta Laureana, Maria Ilaria Del Principe, Palash C. Maity, Hassan Jumaa, Tanja Nicole Hartmann, Antonella Zucchetto, Valter Gattei","doi":"10.1038/s41375-024-02376-7","DOIUrl":"10.1038/s41375-024-02376-7","url":null,"abstract":"In chronic lymphocytic leukemia (CLL), survival of neoplastic cells depends on microenvironmental signals at lymphoid sites where the crosstalk between the integrin VLA-4 (CD49d/CD29), expressed in ~40% of CLL, and the B-cell receptor (BCR) occurs. Here, BCR engagement inside–out activates VLA-4, thus enhancing VLA-4-mediated adhesion of CLL cells, which in turn obtain pro-survival signals from the surrounding microenvironment. We report that the BCR is also able to effectively inside–out activate the VLA-4 integrin in circulating CD49d-expressing CLL cells through an autonomous antigen-independent BCR signaling. As a consequence, circulating CLL cells exhibiting activated VLA-4 express markers of BCR pathway activation (phospho-BTK and phospho-PLC-γ2) along with higher levels of phospho-ERK and phospho-AKT indicating parallel activation of downstream pathways. Moreover, circulating CLL cells expressing activated VLA-4 bind soluble blood-borne VCAM-1 leading to increased VLA-4-dependent actin polymerization/re-organization and ERK phosphorylation. Finally, evidence is provided that ibrutinib treatment, by affecting autonomous BCR signaling, impairs the constitutive VLA-4 activation eventually decreasing soluble VCAM-1 binding and reducing downstream ERK phosphorylation by circulating CLL cells. This study describes a novel anchor-independent mechanism occurring in circulating CLL cells involving the BCR and the VLA-4 integrin, which help to unravel the peculiar biological and clinical features of CD49d+ CLL.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02376-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141980816","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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