Leukemia最新文献_第4页

Early-life tobacco exposure is causally implicated in aberrant RAG-mediated recombination in childhood acute lymphoblastic leukemia 早期烟草暴露与儿童急性淋巴细胞白血病中 RAG 介导的异常重组有因果关系

IF 11.4 1区医学

Leukemia Pub Date : 2024-09-09 DOI: 10.1038/s41375-024-02407-3

Tanxin Liu, Keren Xu, Anmol Pardeshi, Swe Swe Myint, Alice Y. Kang, Libby M. Morimoto, Michael R. Lieber, Joseph L. Wiemels, Scott C. Kogan, Catherine Metayer, Adam J. de Smith

引用次数: 0

Cohesin mutations in acute myeloid leukemia 急性髓性白血病中的凝聚素突变

IF 11.4 1区医学

Leukemia Pub Date : 2024-09-09 DOI: 10.1038/s41375-024-02406-4

Austin Boucher, Josiah Murray, Sridhar Rao

{"title":"Cohesin mutations in acute myeloid leukemia","authors":"Austin Boucher, Josiah Murray, Sridhar Rao","doi":"10.1038/s41375-024-02406-4","DOIUrl":"https://doi.org/10.1038/s41375-024-02406-4","url":null,"abstract":"The cohesin complex, encoded by SMC3, SMC1A, RAD21, and STAG2, is a critical regulator of DNA-looping and gene expression. Over a decade has passed since recurrent mutations affecting cohesin subunits were first identified in myeloid malignancies such as Acute Myeloid Leukemia (AML). Since that time there has been tremendous progress in our understanding of chromatin structure and cohesin biology, but critical questions remain because of the multiple critical functions the cohesin complex is responsible for. Recent findings have been particularly noteworthy with the identification of crosstalk between DNA-looping and chromatin domains, a deeper understanding of how cohesin establishes sister chromatid cohesion, a renewed interest in cohesin’s role for DNA damage response, and work demonstrating cohesin’s importance for Polycomb repression. Despite these exciting findings, the role of cohesin in normal hematopoiesis, and the precise mechanisms by which cohesin mutations promote cancer, remain poorly understood. This review discusses what is known about the role of cohesin in normal hematopoiesis, and how recent findings could shed light on the mechanisms through which cohesin mutations promote leukemic transformation. Important unanswered questions in the field, such as whether cohesin plays a role in HSC heterogeneity, and the mechanisms by which it regulates gene expression at a molecular level, will also be discussed. Particular attention will be given to the potential therapeutic vulnerabilities of leukemic cells with cohesin subunit mutations.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142158810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Plasma cell disorders supress mucosal anti-bacterial immunity: another dimension of immunoparesis in plasma cell neoplasms 浆细胞紊乱抑制粘膜抗菌免疫：浆细胞肿瘤免疫排斥的另一个层面

IF 11.4 1区医学

Leukemia Pub Date : 2024-09-07 DOI: 10.1038/s41375-024-02398-1

Sian Faustini, Y. L. Tracey Chan, Lilli Evans, Emily Collman, Alec Rapson, Claire Backhouse, Annabelle Emery, John P. Campbell, Sally Moore, Alex Richter, Guy Pratt, Mark T. Drayson, Jennifer L. J. Heaney

引用次数: 0

JAK2V617F impairs lymphoid differentiation in myeloproliferative neoplasms JAK2V617F 会损害骨髓增殖性肿瘤中的淋巴分化

IF 11.4 1区医学

Leukemia Pub Date : 2024-09-07 DOI: 10.1038/s41375-024-02388-3

Daniel C. Choi, Nassima Messali, Narasimha Rao Uda, Ghaith Abu-Zeinah, Pouneh Kermani, Maria Mia Yabut, Heidi E. L. Lischer, Franco Castillo Tokumori, Katie Erdos, Thomas Lehmann, Marta Sobas, Tata Nageswara Rao, Joseph M. Scandura

{"title":"JAK2V617F impairs lymphoid differentiation in myeloproliferative neoplasms","authors":"Daniel C. Choi, Nassima Messali, Narasimha Rao Uda, Ghaith Abu-Zeinah, Pouneh Kermani, Maria Mia Yabut, Heidi E. L. Lischer, Franco Castillo Tokumori, Katie Erdos, Thomas Lehmann, Marta Sobas, Tata Nageswara Rao, Joseph M. Scandura","doi":"10.1038/s41375-024-02388-3","DOIUrl":"https://doi.org/10.1038/s41375-024-02388-3","url":null,"abstract":"Myeloproliferative neoplasms (MPNs) arise from a single hematopoietic stem cell (HSC) that acquires a driver mutation, often decades prior to clinical manifestations [1]. The most common driver mutation, JAK2V617F, activates aberrant JAK/STAT signaling via receptors critical for myelopoiesis [2]. Over time, this MPN HSC clone outcompetes its normal counterparts, leading to excessive myeloid cell production. However, lymphopenia is also seen in patients with MPNs [3, 4] and contributes to elevated neutrophil-to-lymphocyte ratio (NLR), which predicts disease-related complications including thrombosis and mortality [5, 6]. We conducted this study to learn how JAK2V617F hematopoiesis affects lymphoid differentiation in MPNs.To assess the effect of JAK2V617F on hematopoiesis in our MPN cohort, we measured JAK2V617F mutation allele frequency (MAF) by droplet digital PCR in hematopoietic subsets fractionated from peripheral blood (PB) by fluorescence activated cell sorting (FACS). MAF increased in HSCs and multipotent progenitors (HSC/MPPs, CD45dimCD34+CD38-CD45RA-) by 1.6% (±0.5%) per year of MPN duration (Fig. 1B). Despite this progressive dominance of JAK2V617F hematopoiesis, JAK2V617F was largely absent from lymphocytes (Fig. 1C and Supplementary Fig. 1) as previously reported [9]. Thus, inadequate lymphopoiesis may drive lymphopenia in JAK2V617F MPNs.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142144316","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Phase 3 study of gilteritinib versus salvage chemotherapy in predominantly Asian patients with relapsed/refractory FLT3-mutated acute myeloid leukemia 以亚洲人为主的FLT3突变急性髓性白血病复发/难治患者吉特替尼与挽救性化疗的3期研究

IF 11.4 1区医学

Leukemia Pub Date : 2024-09-05 DOI: 10.1038/s41375-024-02382-9

Jianxiang Wang, Bin Jiang, Jian Li, Ligen Liu, Xin Du, Hao Jiang, Jianda Hu, Menghe Yuan, Taishi Sakatani, Takeshi Kadokura, Masato Takeuchi, Masanori Kosako, Xiao Ma, Larisa Girshova, Jerome Tan, Sergey Bondarenko, Lily Wong Lee Lee, Archrob Khuhapinant, Elena Martynova, Nahla Hasabou

{"title":"Phase 3 study of gilteritinib versus salvage chemotherapy in predominantly Asian patients with relapsed/refractory FLT3-mutated acute myeloid leukemia","authors":"Jianxiang Wang, Bin Jiang, Jian Li, Ligen Liu, Xin Du, Hao Jiang, Jianda Hu, Menghe Yuan, Taishi Sakatani, Takeshi Kadokura, Masato Takeuchi, Masanori Kosako, Xiao Ma, Larisa Girshova, Jerome Tan, Sergey Bondarenko, Lily Wong Lee Lee, Archrob Khuhapinant, Elena Martynova, Nahla Hasabou","doi":"10.1038/s41375-024-02382-9","DOIUrl":"https://doi.org/10.1038/s41375-024-02382-9","url":null,"abstract":"The phase 3 COMMODORE trial evaluated gilteritinib versus salvage chemotherapy (SC) in a predominantly Asian relapsed/refractory (R/R) FLT3-mutated (FLT3mut+) acute myeloid leukemia (AML) patient population. The primary endpoint was overall survival (OS); secondary endpoints included event-free survival (EFS) and complete remission (CR) rate. As of June 30, 2020 (interim analysis: 32.2 months after study initiation), 234 patients were randomized (gilteritinib, n = 116; SC, n = 118). Median OS was significantly longer with gilteritinib versus SC (9.6 vs. 5.0 months; HR 0.566 [95% CI: 0.392, 0.818]; p = 0.00211) with a median follow-up of 10.3 months. Median EFS was also significantly longer with gilteritinib (2.8 vs. 0.6 months; HR 0.551 [95% CI: 0.395, 0.769]; p = 0.00004). CR rates with gilteritinib and SC were 16.4% and 10.2%, respectively; composite CR rates were 50.0% and 20.3%, respectively. Exposure-adjusted grade ≥3 adverse event (AE) rates were lower with gilteritinib (58.38 events/patient-year [E/PY]) versus SC (168.30 E/PY). Common AEs with gilteritinib were anemia (77.9%) and thrombocytopenia (45.1%). Gilteritinib plasma concentration peaked ~4 h postdose; ~3-fold accumulation occurred with multiple dosing. The COMMODORE trial demonstrated that gilteritinib significantly improved OS and EFS in predominantly Asian patients, validating the outcomes of gilteritinib from the ADMIRAL trial in R/R FLT3mut+ AML.<figure></figure>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142138026","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mutational mechanisms in multiply relapsed pediatric acute lymphoblastic leukemia. 多次复发的小儿急性淋巴细胞白血病的突变机制。

IF 12.8 1区医学

Leukemia Pub Date : 2024-09-04 DOI: 10.1038/s41375-024-02403-7

Cédric G van der Ham, Lianne C Suurenbroek, Michelle M Kleisman, Željko Antić, Stefan H Lelieveld, Marley Yeong, Liset Westera, Edwin Sonneveld, Peter M Hoogerbrugge, Vincent H J van der Velden, Frank N van Leeuwen, Roland P Kuiper

{"title":"Mutational mechanisms in multiply relapsed pediatric acute lymphoblastic leukemia.","authors":"Cédric G van der Ham, Lianne C Suurenbroek, Michelle M Kleisman, Željko Antić, Stefan H Lelieveld, Marley Yeong, Liset Westera, Edwin Sonneveld, Peter M Hoogerbrugge, Vincent H J van der Velden, Frank N van Leeuwen, Roland P Kuiper","doi":"10.1038/s41375-024-02403-7","DOIUrl":"https://doi.org/10.1038/s41375-024-02403-7","url":null,"abstract":"Pediatric acute lymphoblastic leukemia (ALL) is marked by low mutational load at initial diagnosis, which increases at relapse. To determine which processes are active in (relapsed) ALL and how they behave during disease progression before and after therapy, we performed whole genome sequencing on 97 tumor samples of 29 multiply relapsed ALL patients. Mutational load increased upon relapse in 28 patients and upon every subsequent relapse in 22 patients. In addition to two clock-like mutational processes, we identified UV-like damage, APOBEC activity, reactive oxygen species, thiopurine-associated damage and an unknown therapy component as drivers of mutagenesis. Mutational processes often affected patients over longer time periods, but could also occur in isolated events, suggesting the requirement of additional triggers. Thiopurine exposure was the most prominent source of new mutations in relapse, affecting over half of the studied patients in first and/or later relapse and causing potential relapse-driving mutations in multiple patients. Our data demonstrate that multiple mutational processes frequently act in parallel as prominent secondary drivers with dynamic activity during ALL development and progression.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142133167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Genome-wide CRISPR/Cas9 library screening identified OGDH as a regulator of disease progress and resistance to decitabine in myelodysplastic neoplasm by reprogramming glutamine metabolism 全基因组CRISPR/Cas9文库筛选发现OGDH是骨髓增生异常性肿瘤疾病进展和对地西他滨耐药性的调节因子，其作用是对谷氨酰胺代谢进行重编程

IF 11.4 1区医学

Leukemia Pub Date : 2024-09-03 DOI: 10.1038/s41375-024-02377-6

Xiaoyan Xu, Jiaqian Qi, Hong Wang, Ziyan Zhang, Tingting Pan, Xueqian Li, Jingyi Yang, Haohao Han, Mengting Guo, Meng Zhou, Chengsen Cai, Yaqiong Tang, Qixiu Hou, Suning Chen, Depei Wu, Yue Han

{"title":"Genome-wide CRISPR/Cas9 library screening identified OGDH as a regulator of disease progress and resistance to decitabine in myelodysplastic neoplasm by reprogramming glutamine metabolism","authors":"Xiaoyan Xu, Jiaqian Qi, Hong Wang, Ziyan Zhang, Tingting Pan, Xueqian Li, Jingyi Yang, Haohao Han, Mengting Guo, Meng Zhou, Chengsen Cai, Yaqiong Tang, Qixiu Hou, Suning Chen, Depei Wu, Yue Han","doi":"10.1038/s41375-024-02377-6","DOIUrl":"https://doi.org/10.1038/s41375-024-02377-6","url":null,"abstract":"Myelodysplastic neoplasms (MDS) are clonal disorders of hematopoietic stem cells, characterized by ineffective hematopoiesis, cytopenia, and dysplasia, which often progress to acute myeloid leukemia (AML) [1]. Decitabine (DAC), a hypomethylating agents (HMAs), plays a crucial role in the treatment of MDS [2]. However, the complete remission rate with HMAs remains low at 15–20%, and nearly half of the patients ultimately develop resistance during therapy [3, 4]. The molecular mechanisms underlying resistance to decitabine in MDS are still not fully understood [5]. With an increasing understanding of tumor pathogenesis, metabolic reprogramming, especially enhanced reductive carboxylation of glutamine or disrupted oxidative phosphorylation, is also reported to be closely associated with drug resistance in hematological malignancies [6, 7].Herein, a combination of genome-wide CRISPR/Cas9 library screening and whole exome sequencing (WES) was employed to identify candidate genes involved in decitabine sensitivity. OGDH, which encodes a key enzyme in the tricarboxylic acid (TCA) cycle, was identified as a regulator of resistance to decitabine in MDS. The biological functions of OGDH in regulating glutamine metabolism were explored both in vitro and in vivo. Overall, we first reported that low expression of OGDH enhances reductive glutamine metabolism in MDS. The results highlight the important role of OGDH in resistance to decitabine and provide insights into potential therapeutic strategies for MDS, including targeting glutaminase (GLS).","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142123489","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}

引用次数: 0

Mosaic chromosomal alterations in hematopoietic cells and clinical outcomes in patients with multiple myeloma. 多发性骨髓瘤患者造血细胞中的染色体镶嵌改变与临床预后。

IF 12.8 1区医学

Leukemia Pub Date : 2024-09-02 DOI: 10.1038/s41375-024-02396-3

Simon Husby, Morten Tulstrup, Mads Harsløf, Christian Nielsen, Eva Haastrup, Lene Hyldahl Ebbesen, Mette Klarskov Andersen, Maroulio Pertesi, Christian Brieghel, Carsten U Niemann, Björn Nilsson, Agoston Gyula Szabo, Niels Frost Andersen, Niels Abildgaard, Annette Vangsted, Kirsten Grønbæk

{"title":"Mosaic chromosomal alterations in hematopoietic cells and clinical outcomes in patients with multiple myeloma.","authors":"Simon Husby, Morten Tulstrup, Mads Harsløf, Christian Nielsen, Eva Haastrup, Lene Hyldahl Ebbesen, Mette Klarskov Andersen, Maroulio Pertesi, Christian Brieghel, Carsten U Niemann, Björn Nilsson, Agoston Gyula Szabo, Niels Frost Andersen, Niels Abildgaard, Annette Vangsted, Kirsten Grønbæk","doi":"10.1038/s41375-024-02396-3","DOIUrl":"https://doi.org/10.1038/s41375-024-02396-3","url":null,"abstract":"Mosaic chromosomal alterations (mCAs) in hematopoietic cells increase mortality and risk of hematological cancers and infections. We investigated the landscape of mCAs and their clinical consequences in 976 patients with multiple myeloma undergoing high-dose chemotherapy and autologous stem cell support (ASCT) with median 6.4 years of follow-up. mCAs were detected in the stem cell harvest product of 158 patients (16.2%). Autosomal aberrations were found in 60 patients (6.1%) and affected all chromosomes. Loss of chromosome X was found in 51 females (12.7%) and loss of chromosome Y in 55 males (9.6%). Overall survival and progression were similar between carriers of autosomal mCAs and non-carriers. In contrast, female patients with loss of the X chromosome had longer overall survival (age-adjusted[a.a.] HR 0.54, 95% CI 0.32-0.93, p = 0.02), lower risk of progression (a.a. HR 0.55, 95% CI 0.35-0.87; p = 0.01), and better post-transplant response (higher degree of complete response (CR) or very good partial response (VGPR)). The reason for this substantial effect is unknown. Additionally, myeloma clones in the stem cell product was confirmed by mCA analysis in the few patients with multiple mCAs (n = 12 patients). Multiple mCAs conferred inferior overall survival (a.a. HR 2.0, 95% CI 1.02-3.84; p = 0.04) and higher risk of myeloma progression (a.a. HR 3.36, 95% CI 1.67-6.81; p < 0.001), which is presumed to be driven by suspected myeloma contaminants.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142120206","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}

引用次数: 0

Correction: Dose modification dynamics of ponatinib in patients with chronic-phase chronic myeloid leukemia (CP-CML) from the PACE and OPTIC trials 更正：PACE和OPTIC试验中，慢性期慢性髓性白血病（CP-CML）患者服用泊纳替尼的剂量调整动态。

IF 12.8 1区医学

Leukemia Pub Date : 2024-09-02 DOI: 10.1038/s41375-024-02385-6

Elias Jabbour, Jane Apperley, Jorge Cortes, Delphine Rea, Michael Deininger, Elisabetta Abruzzese, Charles Chuah, Daniel J. DeAngelo, Andreas Hochhaus, Jeffrey H. Lipton, Michael Mauro, Franck Nicolini, Javier Pinilla-Ibarz, Gianantonio Rosti, Philippe Rousselot, Neil P. Shah, Moshe Talpaz, Alexander Vorog, Xiaowei Ren, Hagop Kantarjian

引用次数: 0

Star wars against leukemia: attacking the clones 抗击白血病的星球大战：攻击克隆人

IF 11.4 1区医学

Leukemia Pub Date : 2024-09-02 DOI: 10.1038/s41375-024-02369-6

Monika M. Toma, Tomasz Skorski

引用次数: 0