Pub Date : 2024-08-13DOI: 10.1038/s41375-024-02367-8
Sarada Ketharnathan, Sujata Pokharel, Sergey V. Prykhozhij, Anna Cordeiro-Santanach, Kevin Ban, Serkan Dogan, Huy-Dung Hoang, Mira F. Liebman, Elaine Leung, Tommy Alain, Irina Alecu, Steffany A. L. Bennett, Miroslava Čuperlović-Culf, Yigal Dror, Jason N. Berman
Mutations in the DNAJC21 gene were recently described in Shwachman–Diamond syndrome (SDS), a bone marrow failure syndrome with high predisposition for myeloid malignancies. To study the underlying biology in hematopoiesis regulation and disease, we generated the first in vivo model of Dnajc21 deficiency using the zebrafish. Zebrafish dnajc21 mutants phenocopy key SDS patient phenotypes such as cytopenia, reduced growth, and defective protein synthesis. We show that cytopenia results from impaired hematopoietic differentiation, accumulation of DNA damage, and reduced cell proliferation. The introduction of a biallelic tp53 mutation in the dnajc21 mutants leads to the development of myelodysplastic neoplasia-like features defined by abnormal erythroid morphology and expansion of hematopoietic progenitors. Using transcriptomic and metabolomic analyses, we uncover a novel role for Dnajc21 in nucleotide metabolism. Exogenous nucleoside supplementation restores neutrophil counts, revealing an association between nucleotide imbalance and neutrophil differentiation, suggesting a novel mechanism in dnajc21-mutant SDS biology.
{"title":"Loss of Dnajc21 leads to cytopenia and altered nucleotide metabolism in zebrafish","authors":"Sarada Ketharnathan, Sujata Pokharel, Sergey V. Prykhozhij, Anna Cordeiro-Santanach, Kevin Ban, Serkan Dogan, Huy-Dung Hoang, Mira F. Liebman, Elaine Leung, Tommy Alain, Irina Alecu, Steffany A. L. Bennett, Miroslava Čuperlović-Culf, Yigal Dror, Jason N. Berman","doi":"10.1038/s41375-024-02367-8","DOIUrl":"10.1038/s41375-024-02367-8","url":null,"abstract":"Mutations in the DNAJC21 gene were recently described in Shwachman–Diamond syndrome (SDS), a bone marrow failure syndrome with high predisposition for myeloid malignancies. To study the underlying biology in hematopoiesis regulation and disease, we generated the first in vivo model of Dnajc21 deficiency using the zebrafish. Zebrafish dnajc21 mutants phenocopy key SDS patient phenotypes such as cytopenia, reduced growth, and defective protein synthesis. We show that cytopenia results from impaired hematopoietic differentiation, accumulation of DNA damage, and reduced cell proliferation. The introduction of a biallelic tp53 mutation in the dnajc21 mutants leads to the development of myelodysplastic neoplasia-like features defined by abnormal erythroid morphology and expansion of hematopoietic progenitors. Using transcriptomic and metabolomic analyses, we uncover a novel role for Dnajc21 in nucleotide metabolism. Exogenous nucleoside supplementation restores neutrophil counts, revealing an association between nucleotide imbalance and neutrophil differentiation, suggesting a novel mechanism in dnajc21-mutant SDS biology.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02367-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141973875","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 : 2024-08-08DOI: 10.1038/s41375-024-02325-4
Michael Y. He, Kit I. Tong, Ting Liu, Ryder Whittaker Hawkins, Victoria Shelton, Yong Zeng, Mehran Bakhtiari, Yufeng Xiao, Guangrong Zheng, Ali Sakhdari, Lin Yang, Wenxi Xu, David G. Brooks, Rob C. Laister, Housheng Hansen He, Robert Kridel
Despite selective HDAC3 inhibition showing promise in a subset of lymphomas with CREBBP mutations, wild-type tumors generally exhibit resistance. Here, using unbiased genome-wide CRISPR screening, we identify GNAS knockout (KO) as a sensitizer of resistant lymphoma cells to HDAC3 inhibition. Mechanistically, GNAS KO-induced sensitization is independent of the canonical G-protein activities but unexpectedly mediated by viral mimicry-related interferon (IFN) responses, characterized by TBK1 and IRF3 activation, double-stranded RNA formation, and transposable element (TE) expression. GNAS KO additionally synergizes with HDAC3 inhibition to enhance CD8+ T cell-induced cytotoxicity. Moreover, we observe in human lymphoma patients that low GNAS expression is associated with high baseline TE expression and upregulated IFN signaling and shares common disrupted biological activities with GNAS KO in histone modification, mRNA processing, and transcriptional regulation. Collectively, our findings establish an unprecedented link between HDAC3 inhibition and viral mimicry in lymphoma. We suggest low GNAS expression as a potential biomarker that reflects viral mimicry priming for enhanced response to HDAC3 inhibition in the clinical treatment of lymphoma, especially the CREBBP wild-type cases.
尽管选择性 HDAC3 抑制在 CREBBP 突变的淋巴瘤亚群中显示出前景，但野生型肿瘤通常表现出耐药性。在这里，我们利用无偏见的全基因组CRISPR筛选，确定了GNAS基因敲除（KO）是抗性淋巴瘤细胞对HDAC3抑制的增敏剂。从机理上讲，GNAS KO诱导的增敏作用与典型的G蛋白活性无关，而是意外地由病毒模拟相关的干扰素（IFN）反应介导，其特征是TBK1和IRF3活化、双链RNA形成和转座元件（TE）表达。GNAS KO 还能与 HDAC3 抑制协同增强 CD8+ T 细胞诱导的细胞毒性。此外，我们在人类淋巴瘤患者中观察到，GNAS 的低表达与基线 TE 的高表达和 IFN 信号的上调有关，并且与 GNAS KO 在组蛋白修饰、mRNA 处理和转录调控方面具有共同的生物活性。总之，我们的研究结果在淋巴瘤的 HDAC3 抑制和病毒模仿之间建立了前所未有的联系。我们建议将 GNAS 的低表达作为一种潜在的生物标志物，它反映了在淋巴瘤（尤其是 CREBBP 野生型病例）的临床治疗中，病毒模仿会增强对 HDAC3 抑制的反应。
{"title":"GNAS knockout potentiates HDAC3 inhibition through viral mimicry-related interferon responses in lymphoma","authors":"Michael Y. He, Kit I. Tong, Ting Liu, Ryder Whittaker Hawkins, Victoria Shelton, Yong Zeng, Mehran Bakhtiari, Yufeng Xiao, Guangrong Zheng, Ali Sakhdari, Lin Yang, Wenxi Xu, David G. Brooks, Rob C. Laister, Housheng Hansen He, Robert Kridel","doi":"10.1038/s41375-024-02325-4","DOIUrl":"10.1038/s41375-024-02325-4","url":null,"abstract":"Despite selective HDAC3 inhibition showing promise in a subset of lymphomas with CREBBP mutations, wild-type tumors generally exhibit resistance. Here, using unbiased genome-wide CRISPR screening, we identify GNAS knockout (KO) as a sensitizer of resistant lymphoma cells to HDAC3 inhibition. Mechanistically, GNAS KO-induced sensitization is independent of the canonical G-protein activities but unexpectedly mediated by viral mimicry-related interferon (IFN) responses, characterized by TBK1 and IRF3 activation, double-stranded RNA formation, and transposable element (TE) expression. GNAS KO additionally synergizes with HDAC3 inhibition to enhance CD8+ T cell-induced cytotoxicity. Moreover, we observe in human lymphoma patients that low GNAS expression is associated with high baseline TE expression and upregulated IFN signaling and shares common disrupted biological activities with GNAS KO in histone modification, mRNA processing, and transcriptional regulation. Collectively, our findings establish an unprecedented link between HDAC3 inhibition and viral mimicry in lymphoma. We suggest low GNAS expression as a potential biomarker that reflects viral mimicry priming for enhanced response to HDAC3 inhibition in the clinical treatment of lymphoma, especially the CREBBP wild-type cases.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02325-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141904298","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 : 2024-08-05DOI: 10.1038/s41375-024-02360-1
Elena Crisà, Elvira Mora, Ulrich Germing, Cecile Bally, Maria Diez Campelo, Mikko Myllymäki, Martin Jädersten, Rami Komrokji, Uwe Platzbecker, Detlef Haase, Wolf-Karsten Hofmann, Najla H. Al Ali, Daniela Barraco, Juan José Bargay, Teresa Bernal, Felix López Cadenas, Anna Calvisi, Isabella Capodanno, Marco Cerrano, Rosanna Ciancia, Monica Crugnola, Andrea Kündgen, Carlo Finelli, Claudio Fozza, Chiara Frairia, Ebeling Freja, Christina Ganster, Anne Sophie Kubasch, Maria Jose Jimenez, Roberto Latagliata, Francisca Hernandez Mohedo, Antonieta Molero, Miriam Vara Pampliega, Clara Aparicio Perez, Giuseppe Pietrantuono, Antonella Poloni, Helena Pomares, Valle Recasens, Axel Rüfer, Alessio Signori, Eva Hellstrom-Lindberg, Pierre Fenaux, Guillermo Sanz, Valeria Santini
Lenalidomide (LEN) can induce red blood cell-transfusion independence (RBC-TI) in 60–70% of del(5q) myelodysplastic neoplasm (MDS) patients. Current recommendation is to continue LEN in responding patients until failure or progression, with likelihood of toxicity and a high cost for healthcare systems. This HARMONY Alliance study investigated the outcome of MDS del(5q) patients who discontinued LEN while RBC-transfusion independent. We enrolled 118 patients with IPSS-R low-intermediate risk. Seventy patients (59%) discontinued LEN for intolerance, 38 (32%) per their physician decision, nine (8%) per their own decision and one (1%) for unknown reasons. After a median follow-up of 49 months from discontinuation, 50/118 patients lost RBC-TI and 22/30 who underwent cytogenetic re-evaluation lost complete cytogenetic response. The median RBC-TI duration was 56 months. In multivariate analysis, RBC-TI duration after LEN discontinuation correlated with low transfusion burden before LEN therapy, treatment ≥ 12 LEN cycles, younger age and higher Hb level at LEN withdrawal. Forty-eight patients were re-treated with LEN for loss of response and 28 achieved again RBC-TI. These data show that stopping LEN therapy in MDS del(5q) patients who reached RBC-TI allows prolonged maintenance of TI in a large subset of patients.
来那度胺（LEN）可使60%-70%的del(5q)骨髓增生异常肿瘤（MDS）患者摆脱红细胞输血（RBC-TI）。目前的建议是继续对有反应的患者进行 LEN 治疗，直到失败或病情恶化，但这样做可能会产生毒性，而且会给医疗系统带来高昂的成本。这项 HARMONY 联盟研究调查了停用 LEN 且不依赖红细胞输注的 MDS del(5q) 患者的预后。我们招募了 118 名 IPSS-R 低中危患者。70名患者（59%）因不耐受而停用LEN，38名患者（32%）根据医生的决定停用，9名患者（8%）根据自己的决定停用，1名患者（1%）原因不明。在停药后中位随访49个月后，50/118名患者失去了RBC-TI，22/30名接受细胞遗传学再评估的患者失去了完全细胞遗传学反应。中位 RBC-TI 持续时间为 56 个月。在多变量分析中，LEN停药后RBC-TI持续时间与LEN治疗前输血负担低、LEN治疗周期≥12个、年龄较小及LEN停药时Hb水平较高相关。48例患者因反应消失而再次接受LEN治疗，其中28例再次实现了RBC-TI。这些数据表明，对达到RBC-TI的MDS del(5q)患者停止LEN治疗可使一大部分患者的TI得到长期维持。
{"title":"Transfusion independence after lenalidomide discontinuation in patients with del(5q) myelodysplastic neoplasm: a HARMONY Alliance study","authors":"Elena Crisà, Elvira Mora, Ulrich Germing, Cecile Bally, Maria Diez Campelo, Mikko Myllymäki, Martin Jädersten, Rami Komrokji, Uwe Platzbecker, Detlef Haase, Wolf-Karsten Hofmann, Najla H. Al Ali, Daniela Barraco, Juan José Bargay, Teresa Bernal, Felix López Cadenas, Anna Calvisi, Isabella Capodanno, Marco Cerrano, Rosanna Ciancia, Monica Crugnola, Andrea Kündgen, Carlo Finelli, Claudio Fozza, Chiara Frairia, Ebeling Freja, Christina Ganster, Anne Sophie Kubasch, Maria Jose Jimenez, Roberto Latagliata, Francisca Hernandez Mohedo, Antonieta Molero, Miriam Vara Pampliega, Clara Aparicio Perez, Giuseppe Pietrantuono, Antonella Poloni, Helena Pomares, Valle Recasens, Axel Rüfer, Alessio Signori, Eva Hellstrom-Lindberg, Pierre Fenaux, Guillermo Sanz, Valeria Santini","doi":"10.1038/s41375-024-02360-1","DOIUrl":"10.1038/s41375-024-02360-1","url":null,"abstract":"Lenalidomide (LEN) can induce red blood cell-transfusion independence (RBC-TI) in 60–70% of del(5q) myelodysplastic neoplasm (MDS) patients. Current recommendation is to continue LEN in responding patients until failure or progression, with likelihood of toxicity and a high cost for healthcare systems. This HARMONY Alliance study investigated the outcome of MDS del(5q) patients who discontinued LEN while RBC-transfusion independent. We enrolled 118 patients with IPSS-R low-intermediate risk. Seventy patients (59%) discontinued LEN for intolerance, 38 (32%) per their physician decision, nine (8%) per their own decision and one (1%) for unknown reasons. After a median follow-up of 49 months from discontinuation, 50/118 patients lost RBC-TI and 22/30 who underwent cytogenetic re-evaluation lost complete cytogenetic response. The median RBC-TI duration was 56 months. In multivariate analysis, RBC-TI duration after LEN discontinuation correlated with low transfusion burden before LEN therapy, treatment ≥ 12 LEN cycles, younger age and higher Hb level at LEN withdrawal. Forty-eight patients were re-treated with LEN for loss of response and 28 achieved again RBC-TI. These data show that stopping LEN therapy in MDS del(5q) patients who reached RBC-TI allows prolonged maintenance of TI in a large subset of patients.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141893777","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 : 2024-08-04DOI: 10.1038/s41375-024-02365-w
Nataly Cruz-Rodriguez, Hua Tang, Benjamin Bateman, Weiping Tang, Michael Deininger
BCR::ABL1 tyrosine kinase inhibitors (TKIs) have turned chronic myeloid leukemia (CML) from a lethal condition into a chronic ailment. With optimal management, the survival of CML patients diagnosed in the chronic phase is approaching that of age-matched controls. However, only one-third of patients can discontinue TKIs and enter a state of functional cure termed treatment-free remission (TFR), while the remainder require life-long TKI therapy to avoid the recurrence of active leukemia. Approximately 10% of patients exhibit primary or acquired TKI resistance and eventually progress to the blast phase. It is thought that recurrence after attempted TFR originates from CML stem cells (LSCs) surviving despite continued suppression of BCR::ABL1 kinase. Although kinase activity is indispensable for induction of overt CML, kinase-independent scaffold functions of BCR::ABL1 are known to contribute to leukemogenesis, raising the intriguing but as yet hypothetical possibility, that degradation of BCR::ABL1 protein may accomplish what TKIs fail to achieve – eliminate residual LSCs to turn functional into real cures. The advent of BCR::ABL1 proteolysis targeting chimeras (PROTACs), heterobifunctional molecules linking a TKI-based warhead to an E3 ligase recruiter, has moved clinical protein degradation into the realm of the possible. Here we examine the molecular rationale as well as pros and cons of degrading BCR::ABL1 protein. We review reported BCR::ABL1 PROTACs, point out limitations of available data and compounds and suggest directions for future research. Ultimately, clinical testing of a potent and specific BCR::ABL1 degrader will be required to determine the efficacy and tolerability of this approach.
{"title":"BCR::ABL1 Proteolysis-targeting chimeras (PROTACs): The new frontier in the treatment of Ph+ leukemias?","authors":"Nataly Cruz-Rodriguez, Hua Tang, Benjamin Bateman, Weiping Tang, Michael Deininger","doi":"10.1038/s41375-024-02365-w","DOIUrl":"10.1038/s41375-024-02365-w","url":null,"abstract":"BCR::ABL1 tyrosine kinase inhibitors (TKIs) have turned chronic myeloid leukemia (CML) from a lethal condition into a chronic ailment. With optimal management, the survival of CML patients diagnosed in the chronic phase is approaching that of age-matched controls. However, only one-third of patients can discontinue TKIs and enter a state of functional cure termed treatment-free remission (TFR), while the remainder require life-long TKI therapy to avoid the recurrence of active leukemia. Approximately 10% of patients exhibit primary or acquired TKI resistance and eventually progress to the blast phase. It is thought that recurrence after attempted TFR originates from CML stem cells (LSCs) surviving despite continued suppression of BCR::ABL1 kinase. Although kinase activity is indispensable for induction of overt CML, kinase-independent scaffold functions of BCR::ABL1 are known to contribute to leukemogenesis, raising the intriguing but as yet hypothetical possibility, that degradation of BCR::ABL1 protein may accomplish what TKIs fail to achieve – eliminate residual LSCs to turn functional into real cures. The advent of BCR::ABL1 proteolysis targeting chimeras (PROTACs), heterobifunctional molecules linking a TKI-based warhead to an E3 ligase recruiter, has moved clinical protein degradation into the realm of the possible. Here we examine the molecular rationale as well as pros and cons of degrading BCR::ABL1 protein. We review reported BCR::ABL1 PROTACs, point out limitations of available data and compounds and suggest directions for future research. Ultimately, clinical testing of a potent and specific BCR::ABL1 degrader will be required to determine the efficacy and tolerability of this approach.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02365-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141887417","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 : 2024-08-03DOI: 10.1038/s41375-024-02351-2
Daniel Atar, Lara Ruoff, Anna-Sophia Mast, Simon Krost, Moustafa Moustafa-Oglou, Sophia Scheuermann, Beate Kristmann, Maximilian Feige, Aysegül Canak, Kathrin Wolsing, Lennart Schlager, Karin Schilbach, Latifa Zekri, Martin Ebinger, Daniel Nixdorf, Marion Subklewe, Johannes Schulte, Claudia Lengerke, Irmela Jeremias, Niels Werchau, Joerg Mittelstaet, Peter Lang, Rupert Handgretinger, Patrick Schlegel, Christian M. Seitz
Targeting AML by chimeric antigen receptor T-cells (CAR-T) is challenging due to the promiscuous expression of AML-associated antigens in healthy hematopoiesis and high degree of inter- and intratumoral heterogeneity. Here, we present single-cell expression data of AML-associated antigens in 30 primary pediatric AML samples. We identified CD33, CD38, CD371, IL1RAP and CD123 as the most frequently expressed. Notably, high variability was observed not only across the different patient samples but also among leukemic cells of the same patient suggesting the necessity of multiplexed targeting approaches. To address this need, we utilized our modular Adapter CAR (AdCAR) platform, enabling precise qualitative and quantitative control over CAR-T-cell function. We show highly efficient and target-specific activity for newly generated adapter molecules (AMs) against CD33, CD38, CD123, CD135 and CD371, both in vitro and in vivo. We reveal that inherent intratumoral heterogeneity in antigen expression translates into antigen escape and therapy failure to monotargeted CAR-T therapy. Further, we demonstrate in PDX models that rational combinatorial targeting by AdCAR-T-cells can cure heterogenic disease. In conclusion, we elucidate the clinical relevance of heterogeneity in antigen expression in pediatric AML and present a novel concept for precision immunotherapy by combinatorial targeting utilizing the AdCAR platform.
{"title":"Rational combinatorial targeting by adapter CAR-T-cells (AdCAR-T) prevents antigen escape in acute myeloid leukemia","authors":"Daniel Atar, Lara Ruoff, Anna-Sophia Mast, Simon Krost, Moustafa Moustafa-Oglou, Sophia Scheuermann, Beate Kristmann, Maximilian Feige, Aysegül Canak, Kathrin Wolsing, Lennart Schlager, Karin Schilbach, Latifa Zekri, Martin Ebinger, Daniel Nixdorf, Marion Subklewe, Johannes Schulte, Claudia Lengerke, Irmela Jeremias, Niels Werchau, Joerg Mittelstaet, Peter Lang, Rupert Handgretinger, Patrick Schlegel, Christian M. Seitz","doi":"10.1038/s41375-024-02351-2","DOIUrl":"10.1038/s41375-024-02351-2","url":null,"abstract":"Targeting AML by chimeric antigen receptor T-cells (CAR-T) is challenging due to the promiscuous expression of AML-associated antigens in healthy hematopoiesis and high degree of inter- and intratumoral heterogeneity. Here, we present single-cell expression data of AML-associated antigens in 30 primary pediatric AML samples. We identified CD33, CD38, CD371, IL1RAP and CD123 as the most frequently expressed. Notably, high variability was observed not only across the different patient samples but also among leukemic cells of the same patient suggesting the necessity of multiplexed targeting approaches. To address this need, we utilized our modular Adapter CAR (AdCAR) platform, enabling precise qualitative and quantitative control over CAR-T-cell function. We show highly efficient and target-specific activity for newly generated adapter molecules (AMs) against CD33, CD38, CD123, CD135 and CD371, both in vitro and in vivo. We reveal that inherent intratumoral heterogeneity in antigen expression translates into antigen escape and therapy failure to monotargeted CAR-T therapy. Further, we demonstrate in PDX models that rational combinatorial targeting by AdCAR-T-cells can cure heterogenic disease. In conclusion, we elucidate the clinical relevance of heterogeneity in antigen expression in pediatric AML and present a novel concept for precision immunotherapy by combinatorial targeting utilizing the AdCAR platform.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02351-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141878965","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 : 2024-08-02DOI: 10.1038/s41375-024-02366-9
Wenqiang Yan, Lihui Shi, Jingyu Xu, Lingna Li, Jian Cui, Yuntong Liu, Jieqiong Zhou, Chenxing Du, Tengteng Yu, Shuaishuai Zhang, Rui Lv, Weiwei Sui, Shuhui Deng, Xiaoqing Li, Xin Du, Yan Xu, Dehui Zou, Lugui Qiu, Mu Hao, Gang An
Residual normal plasma cells (NPCs), which compete with tumor plasma cells, play an important role in multiple myeloma. However, large-scale cohort studies investigating residual NPCs, especially at the minimal residual disease (MRD) phase, are currently lacking. In this study, we conducted a comprehensive investigation into the clinical significance of residual NPCs throughout the entire disease course in 1363 myeloma patients from the NICHE cohort (NCT04645199). Our results revealed that myeloma patients with high baseline NPCs ratio (≥5%) exhibited distinct indolent features, characterized by lower tumor burden, reduced frequencies of cytopenia, immunoparesis, and high-risk cytogenetics. Importantly, high residual NPCs ratio at diagnosis or relapse was independently associated with favorable survival. High absolute percentages of NPCs at undetectable MRD were related with superior clinical benefit and immune reconstitution. At MRD-positive phases, grouping based on NPCs ratio (<50%, 50–90%, ≥90%) demonstrated better risk stratification compared to residual tumor log levels. Based on the time-dependent NPCs ratio trend, we developed a dynamic MRD model that classifies patients into three groups with diverse longitudinal trends, leading to distinct prognoses. Collectively, residual NPCs serves not only as a valuable complementary biomarker for risk stratification but also provides valuable insights on reclassifications and kinetics of MRD.
{"title":"Clinical implications of residual normal plasma cells within bone marrow across various disease stages in multiple myeloma","authors":"Wenqiang Yan, Lihui Shi, Jingyu Xu, Lingna Li, Jian Cui, Yuntong Liu, Jieqiong Zhou, Chenxing Du, Tengteng Yu, Shuaishuai Zhang, Rui Lv, Weiwei Sui, Shuhui Deng, Xiaoqing Li, Xin Du, Yan Xu, Dehui Zou, Lugui Qiu, Mu Hao, Gang An","doi":"10.1038/s41375-024-02366-9","DOIUrl":"10.1038/s41375-024-02366-9","url":null,"abstract":"Residual normal plasma cells (NPCs), which compete with tumor plasma cells, play an important role in multiple myeloma. However, large-scale cohort studies investigating residual NPCs, especially at the minimal residual disease (MRD) phase, are currently lacking. In this study, we conducted a comprehensive investigation into the clinical significance of residual NPCs throughout the entire disease course in 1363 myeloma patients from the NICHE cohort (NCT04645199). Our results revealed that myeloma patients with high baseline NPCs ratio (≥5%) exhibited distinct indolent features, characterized by lower tumor burden, reduced frequencies of cytopenia, immunoparesis, and high-risk cytogenetics. Importantly, high residual NPCs ratio at diagnosis or relapse was independently associated with favorable survival. High absolute percentages of NPCs at undetectable MRD were related with superior clinical benefit and immune reconstitution. At MRD-positive phases, grouping based on NPCs ratio (<50%, 50–90%, ≥90%) demonstrated better risk stratification compared to residual tumor log levels. Based on the time-dependent NPCs ratio trend, we developed a dynamic MRD model that classifies patients into three groups with diverse longitudinal trends, leading to distinct prognoses. Collectively, residual NPCs serves not only as a valuable complementary biomarker for risk stratification but also provides valuable insights on reclassifications and kinetics of MRD.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02366-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141878964","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 : 2024-07-31DOI: 10.1038/s41375-024-02353-0
Ariel Leyte-Vidal, RosaAnna DeFilippis, Ian R. Outhwaite, Isabelle Kwan, Ji Young Lee, Carlyn Leavitt, Kaeli B. Miller, Delphine Rea, Aziz M. Rangwala, Kevin Lou, Suhana Patel, Ailin Alvarez, Kevan M. Shokat, Ivet Bahar, Markus A. Seeliger, Neil P. Shah
{"title":"Absence of ABL1 exon 2-encoded SH3 residues in BCR::ABL1 destabilizes the autoinhibited kinase conformation and confers resistance to asciminib","authors":"Ariel Leyte-Vidal, RosaAnna DeFilippis, Ian R. Outhwaite, Isabelle Kwan, Ji Young Lee, Carlyn Leavitt, Kaeli B. Miller, Delphine Rea, Aziz M. Rangwala, Kevin Lou, Suhana Patel, Ailin Alvarez, Kevan M. Shokat, Ivet Bahar, Markus A. Seeliger, Neil P. Shah","doi":"10.1038/s41375-024-02353-0","DOIUrl":"10.1038/s41375-024-02353-0","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02353-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141857797","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 : 2024-07-30DOI: 10.1038/s41375-024-02349-w
Xueshuai Han, Jingru Sui, Kui Nie, Yang Zhao, Xuan Lv, Jindou Xie, Leonard Tan, Rex K. H. Au-Yeung, Jiao Ma, Giorgio Inghirami, Olivier Elemento, Wayne Tam, Zhaoqi Liu
{"title":"Tumor evolution analysis uncovered immune-escape related mutations in relapse of diffuse large B-cell lymphoma","authors":"Xueshuai Han, Jingru Sui, Kui Nie, Yang Zhao, Xuan Lv, Jindou Xie, Leonard Tan, Rex K. H. Au-Yeung, Jiao Ma, Giorgio Inghirami, Olivier Elemento, Wayne Tam, Zhaoqi Liu","doi":"10.1038/s41375-024-02349-w","DOIUrl":"10.1038/s41375-024-02349-w","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141855912","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 : 2024-07-30DOI: 10.1038/s41375-024-02362-z
Ye Jin Lee, Seo Yun Lee, Soomi Kim, Soo-Hyun Kim, Soo Hyeon Lee, Sungho Park, Jae Jin Kim, Dong-Wook Kim, Hongtae Kim
Chronic myeloid leukemia (CML), caused by BCR::ABL1 fusion gene, is known to regulate disease progression by altering the expression of genes. However, the molecular mechanisms underlying these changes are largely unknown. In this study, we identified RNA Exonuclease 5 (REXO5/LOC81691) as a novel gene with elevated mRNA expression levels in chronic myeloid leukemia (CML) patients. Additionally, using the REXO5 knockout (KO) K562 cell lines, we revealed a novel role for REXO5 in the DNA damage response (DDR). Compared to wild-type (WT) cells, REXO5 KO cells showed an accumulation of R-loops and increased DNA damage. We demonstrated that REXO5 translocates to sites of DNA damage through its RNA recognition motif (RRM) and selectively binds to R loops. Interestingly, we identified that REXO5 regulates R-loop levels by degrading mRNA within R-loop using its exonuclease domain. REXO5 KO showed ATR-CHK1 activation. Collectively, we demonstrated that REXO5 plays a key role in the physiological control of R-loops using its exonuclease domain. These findings may provide novel insights into how REXO5 expression changes contribute to CML pathogenesis.
众所周知，由 BCR::ABL1 融合基因引起的慢性髓性白血病（CML）会通过改变基因的表达来调控疾病的进展。然而，这些变化的分子机制在很大程度上还不为人知。在这项研究中，我们发现 RNA Exonuclease 5 (REXO5/LOC81691) 是慢性髓性白血病（CML）患者中 mRNA 表达水平升高的新基因。此外，我们利用 REXO5 基因敲除（KO）K562 细胞系，揭示了 REXO5 在 DNA 损伤应答（DDR）中的新作用。与野生型（WT）细胞相比，REXO5 KO细胞显示出R环的积累和DNA损伤的增加。我们证实，REXO5通过其RNA识别基序（RRM）转运到DNA损伤位点，并选择性地与R环结合。有趣的是，我们发现 REXO5 通过利用其外切酶结构域降解 R 环内的 mRNA 来调节 R 环水平。REXO5 KO显示了ATR-CHK1的激活。总之，我们证明了 REXO5 利用其外切酶结构域在 R 环的生理调控中发挥着关键作用。这些发现可能为了解 REXO5 表达变化如何导致 CML 发病提供了新的见解。
{"title":"REXO5 promotes genomic integrity through regulating R-loop using its exonuclease activity","authors":"Ye Jin Lee, Seo Yun Lee, Soomi Kim, Soo-Hyun Kim, Soo Hyeon Lee, Sungho Park, Jae Jin Kim, Dong-Wook Kim, Hongtae Kim","doi":"10.1038/s41375-024-02362-z","DOIUrl":"10.1038/s41375-024-02362-z","url":null,"abstract":"Chronic myeloid leukemia (CML), caused by BCR::ABL1 fusion gene, is known to regulate disease progression by altering the expression of genes. However, the molecular mechanisms underlying these changes are largely unknown. In this study, we identified RNA Exonuclease 5 (REXO5/LOC81691) as a novel gene with elevated mRNA expression levels in chronic myeloid leukemia (CML) patients. Additionally, using the REXO5 knockout (KO) K562 cell lines, we revealed a novel role for REXO5 in the DNA damage response (DDR). Compared to wild-type (WT) cells, REXO5 KO cells showed an accumulation of R-loops and increased DNA damage. We demonstrated that REXO5 translocates to sites of DNA damage through its RNA recognition motif (RRM) and selectively binds to R loops. Interestingly, we identified that REXO5 regulates R-loop levels by degrading mRNA within R-loop using its exonuclease domain. REXO5 KO showed ATR-CHK1 activation. Collectively, we demonstrated that REXO5 plays a key role in the physiological control of R-loops using its exonuclease domain. These findings may provide novel insights into how REXO5 expression changes contribute to CML pathogenesis.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02362-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141855911","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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