Leukemia最新文献

{"title":"Monitoring clonal burden as an alternative to blast count for myelodysplastic neoplasm treatment response","authors":"Meagan A. Jacoby, Eric D. Duncavage, Ajay Khanna, Gue Su Chang, Sridhar Nonavinkere Srivatsan, Christopher A. Miller, Feng Gao, Josh Robinson, Jin Shao, Robert S. Fulton, Catrina C. Fronick, Michelle O’Laughlin, Sharon E. Heath, Kimberly Brendel, Monique Chavez, John F. DiPersio, Camille N. Abboud, Keith Stockerl-Goldstein, Peter Westervelt, Amanda Cashen, Iskra Pusic, Stephen T. Oh, John S. Welch, Denise A. Wells, Michael R. Loken, Geoffrey L. Uy, Matthew J. Walter","doi":"10.1038/s41375-024-02426-0","DOIUrl":"10.1038/s41375-024-02426-0","url":null,"abstract":"Accurate assessment of therapy response in myelodysplastic neoplasm (MDS) has been challenging. Directly monitoring mutational disease burden may be useful, but is not currently included in MDS response criteria, and the correlation of mutational burden and traditional response endpoints is not completely understood. Here, we used genome-wide and targeted next-generation sequencing (NGS) to monitor clonal and subclonal molecular disease burden in 452 samples from 32 patients prospectively treated in a clinical trial. Molecular responses were compared with International Working Group (IWG) 2006-defined response assessments. We found that myeloblast percentage consistently underestimates MDS molecular disease burden and that mutational clearance patterns for marrow complete remission (mCR), which depends on myeloblast assessment, was not different than stable disease or bone marrow aplasia, underscoring a major limitation of using mCR. In contrast, achieving a complete remission (CR) was associated with the highest level of mutation clearance and lowest residual mutational burden in higher-risk MDS patients. A targeted gene panel approach was inferior to genome-wide sequencing in defining subclones and their molecular responses but may be adequate for monitoring molecular disease burden when a targeted gene is present in the founding clone. Our work supports incorporating serial NGS-based monitoring into prospective MDS clinical trials.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 1","pages":"166-177"},"PeriodicalIF":12.8,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142374245","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}

{"title":"Rapid increase of C/EBPα p42 induces growth arrest of acute myeloid leukemia (AML) cells by Cop1 deletion in Trib1-expressing AML","authors":"Yoshitaka Sunami, Seiko Yoshino, Yukari Yamazaki, Takashi Iwamoto, Takuro Nakamura","doi":"10.1038/s41375-024-02430-4","DOIUrl":"10.1038/s41375-024-02430-4","url":null,"abstract":"Cop1 encodes a ubiquitin E3 ligase that has been well preserved during evolution in both plants and metazoans. In metazoans, the C/EBP family transcription factors are targets for degradation by Cop1, and this process is regulated by the Tribbles pseudokinase family. Over-expression of Tribbles homolog 1 (Trib1) induces acute myeloid leukemia (AML) via Cop1-dependent degradation of the C/EBPα p42 isoform. Here, we induced rapid growth arrest and granulocytic differentiation of Trib1-expressing AML cells using a Cop1 conditional knockout (KO), which is associated with a transient increase in the C/EBPα p42 isoform. The growth-suppressive effect of Cop1 KO was canceled by silencing of Cebpa and reinforced by exogenous expression of the p42 isoform. Moreover, Cop1 KO improved the survival of recipients transplanted with Trib1-expressing AML cells. We further identified a marked increase in Trib1 protein expression in Cop1 KO, indicating that Trib1 is self-degraded by the Cop1 degradosome. COP1 downregulation also inhibits the proliferation of human AML cells in a TRIB1-dependent manner. Taken together, our results provide new insights into the role of Trib1/Cop1 machinery in the C/EBPα p42-dependent leukemogenic activity, and a novel idea to develop new therapeutics.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"38 12","pages":"2585-2597"},"PeriodicalIF":12.8,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142374244","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}

{"title":"Synergistic effect of concurrent high molecular risk mutations and lower JAK2 mutant variant allele frequencies on prognosis in patients with myelofibrosis—insights from a multicenter study","authors":"Yu-Hung Wang, Chao-Hung Wei, Chien-Chin Lin, Carmelo Gurnari, Hussein Awada, Lina Benajiba, Rafael Daltro de Oliveira, Juliette Soret-Dulphy, Bruno Cassinat, Andrius Zucenka, Adrián Mosquera Orgueira, Chang-Tsu Yuan, Sze-Hwei Lee, Chi-Yuan Yao, Kristian Gurashi, Hsin-An Hou, Kiran Batta, Manuel Mateo Pérez Encinas, Wen-Chien Chou, Jaroslaw P. Maciejewski, Daniel H. Wiseman, Jean-Jacques Kiladjian, Hwei-Fang Tien","doi":"10.1038/s41375-024-02422-4","DOIUrl":"10.1038/s41375-024-02422-4","url":null,"abstract":"In addition to high-molecular risk (HMR) mutations (ASXL1, EZH2, SRSF2, IDH, and U2AF1Q157), lower JAK2V617F variant allele frequencies (VAF) have been demonstrated to be associated with poor prognosis of myelofibrosis (MF) patients. Nevertheless, the relationship between JAK2V617F VAF and HMR mutations remains inconclusive. To address this, we analyzed the mutation status of 54 myeloid neoplasm-relevant genes using targeted next-generation sequencing in 124 MF patients. Three cohorts from multiple international centers were analyzed for external validation. Among JAK2-mutated patients, the presence of HMR mutations drove poor prognosis in patients with lower JAK2V617F VAF but not in those with higher JAK2V617F VAF. Survival analyses showed consistent results across validation cohorts. In multivariable analysis, concurrent HMR and a lower JAK2V617F VAF was identified as an independent adverse prognostic factor for survival, irrespective of age, MIPSS70, MIPSS70 + v2, and GIPSS risk groups. Mutation co-occurrence tests revealed no shared mutational pattern over different cohorts, excluding potential confounding effect from other concurrent mutations. Importantly, the integration of HMR/JAK2V617F VAF (≤50%) status significantly enhanced existing prognostic models, as evidenced by higher c-indexes and time-dependent ROC analyses. Single-cell studies with sequential follow-ups are warranted to decipher the clonal evolution of MF and how it relates to JAK2V617F VAF dynamics.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 1","pages":"144-154"},"PeriodicalIF":12.8,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142374243","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}

{"title":"Disparities in incidence and mortality of pediatric acute lymphoblastic leukemia across countries with different incomes","authors":"Nan Zhang, Diguang Wen, Teng Wang, Jianchuan Deng","doi":"10.1038/s41375-024-02433-1","DOIUrl":"10.1038/s41375-024-02433-1","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"38 12","pages":"2731-2734"},"PeriodicalIF":12.8,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142372239","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}

{"title":"Cellular taxonomy of the preleukemic bone marrow niche of acute myeloid leukemia","authors":"Chinmayee Goda, Rohan Kulkarni, Yaphet Bustos, Wenjun Li, Alexander Rudich, Ozlen Balcioglu, Sadie Chidester, Amog P. Urs, Malith Karunasiri, Yzen Al-Marrawi, Erin Korn, Sanjay Kanna, Elizabeth A. R. Garfinkle, Nisarg Shah, Ashley Wooten, Bethany Mundy-Bosse, Lalit Sehgal, Bin Zhang, Guido Marcucci, Elaine R. Mardis, Ramiro Garzon, Robert L. Bowman, Aaron D. Viny, Linde A. Miles, Katherine E. Miller, Adrienne M. Dorrance","doi":"10.1038/s41375-024-02415-3","DOIUrl":"10.1038/s41375-024-02415-3","url":null,"abstract":"Leukemias arise from recurrent clonal mutations in hematopoietic stem/progenitor cells (HSPCs) that cause profound changes in the bone marrow microenvironment (BMM) favoring leukemic stem cell (LSC) growth over normal HSPCs. Understanding the cross talk between preleukemic mutated HSPCs and the BMM is critical to develop novel therapeutic strategies to prevent leukemogenesis. We hypothesize that preleukemic-LSCs (pLSCs) induce BMM changes critical for leukemogenesis. Using our AML-murine model, we performed single-cell RNA-sequencing of preleukemic BMM (pBMM) cells. We found normal HSC (nHSC)-regulating LepR+ mesenchymal stem cells, and endothelial cells were decreased, along with increases in CD55+ fibroblasts and pericytes. Preleukemic CD55+ fibroblasts had higher proliferation rates and decreased collagen expression, suggesting extracellular matrix remodeling during leukemogenesis. Importantly, co-culture assays found preleukemic CD55+ fibroblasts expanded pLSCs significantly over nHSCs. In conclusion, we have identified a distinct pBMM and a novel CD55+ fibroblast population that is expanded in pBMM that promote fitness of pLSCs over nHSCs.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 1","pages":"51-63"},"PeriodicalIF":12.8,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02415-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142362895","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}

{"title":"The epigenetic state of the cell of origin defines mechanisms of leukemogenesis","authors":"Zhiheng Li, Sara Fierstein, Mayuri Tanaka-Yano, Katie Frenis, Chun-Chin Chen, Dahai Wang, Marcelo Falchetti, Parker Côté, Christina Curran, Kate Lu, Tianxin Liu, Stuart Orkin, Hojun Li, Edroaldo Lummertz da Rocha, Shaoyan Hu, Qian Zhu, R. Grant Rowe","doi":"10.1038/s41375-024-02428-y","DOIUrl":"10.1038/s41375-024-02428-y","url":null,"abstract":"Acute myeloid leukemia (AML) shows variable clinical outcome. The normal hematopoietic cell of origin impacts the clinical behavior of AML, with AML from hematopoietic stem cells (HSCs) prone to chemotherapy resistance in model systems. However, the mechanisms by which HSC programs are transmitted to AML are not known. Here, we introduce the leukemogenic MLL-AF9 translocation into defined human hematopoietic populations, finding that AML from HSCs is enriched for leukemic stem cells (LSCs) compared to AML from progenitors. By epigenetic profiling, we identify a putative inherited program from the normal HSC that collaborates with oncogene-driven programs to confer aggressive behavior in HSC-AML. We find that components of this program are required for HSC-AML growth and survival and identify RNA polymerase (RNAP) II-mediated transcription as a therapeutic vulnerability. Overall, we propose a mechanism as to how epigenetic programs from the leukemic cell of origin are inherited through transformation to impart the clinical heterogeneity of AML.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 1","pages":"87-97"},"PeriodicalIF":12.8,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02428-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142361746","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}

{"title":"Managing the unmanageable: evidence-driven approaches to real-world patient prototypes of TP53-mutant myelodysplastic neoplasms and acute myeloid leukemia","authors":"Shyam A. Patel","doi":"10.1038/s41375-024-02417-1","DOIUrl":"10.1038/s41375-024-02417-1","url":null,"abstract":"Patients with TP53 aberrations comprise the highest risk subset of all myeloid malignancies. The managerial conundrum of TP53-mutant myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML) stems from refractoriness to or relapse after conventional chemotherapy, as well as the limited translational success of investigational therapies targeting TP53-mutant cells. Thus far, no targeted therapies have been commercially approved for this mutational subset. As a result, management plans for patients with TP53-mutant MDS and AML are often driven by clinical judgment and/or physician preference rather than consensus guidelines backed by a rigorous evidence basis. This clinical case-based, evidence-driven review highlights the most salient data that guides the management of commonly encountered patient prototypes. This review discusses the therapeutic menu of first-line options that derive from multi-institutional experiences as well as from disease-centric consortia and discusses how these first-line options can be optimally tailored to heterogeneous groups of patients. The debate regarding whether allogeneic stem cell transplant should be offered to these patients is summarized. Finally, this review explores the recent unfortunate news of pauses in clinical trials for the leading investigational agents – eprenetapopt, magrolimab, sabatolimab, and idasanutlin – and offers solutions toward re-invigorating the pipeline of precision therapeutics in 2025.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"38 12","pages":"2544-2551"},"PeriodicalIF":12.8,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02417-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142329985","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}

{"title":"Characterization of myeloproliferative neoplasms based on genetics only and prognostication of transformation to blast phase","authors":"Wencke Walter, Niroshan Nadarajah, Stephan Hutter, Heiko Müller, Claudia Haferlach, Wolfgang Kern, Torsten Haferlach, Manja Meggendorfer","doi":"10.1038/s41375-024-02425-1","DOIUrl":"10.1038/s41375-024-02425-1","url":null,"abstract":"Myeloproliferative neoplasms (MPN) are a heterogeneous group of clonal disorders characterized by aberrant hematopoietic proliferation and an intrinsic risk of progression to blast phase. The WHO classification 2022 identifies chronic myeloid leukemia and the BCR::ABL1 negative MPNs polycythemia vera, primary myelofibrosis and essential thrombocythemia as individual entities. However, overlaps, borderline findings or transitions between MPN subtypes occur and incomplete clinical data often complicates diagnosis. By conducting a thorough genetic analysis, we’ve developed a model that relies on 12 genetic markers to accurately stratify MPN patients. The model can be simplified into a decision tree for routine use. Comparing samples at chronic and blast phase revealed, that one third of patients lost their MPN driver-gene mutation, while mutations in splicing and chromatin modifying genes were stable, indicating a shared founder clone of chronic and blast phase with different driver mutations and therefore different progressing capacities. This was further supported by gain of typical de novo AML gene mutations, accompanied by gain of complex karyotypes and RAS pathway gene mutations. Our data suggest to perform a broader genetic screening at diagnosis and also at clinical progression, as driver mutations may change and the MPN-driver mutations present at diagnosis may disappear.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"38 12","pages":"2644-2652"},"PeriodicalIF":12.8,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02425-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142328693","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}

{"title":"Essential role of Dhx16-mediated ribosome assembly in maintenance of hematopoietic stem cells","authors":"Zhigang Li, Jiankun Fan, Yalan Xiao, Wei Wang, Changlin Zhen, Junbing Pan, Weiru Wu, Yuanyuan Liu, Zhe Chen, Qinrong Yan, Hanqing Zeng, Shuyu Luo, Lun Liu, Zhanhan Tu, Xueya Zhao, Yu Hou","doi":"10.1038/s41375-024-02423-3","DOIUrl":"10.1038/s41375-024-02423-3","url":null,"abstract":"Hematopoietic stem cells (HSCs) are vital for the differentiation of all mature blood cells, with their homeostasis being tightly regulated by intrinsic and extrinsic factors. Alternative splicing, mediated by the spliceosome complex, plays a crucial role in regulating HSC homeostasis by increasing protein diversity. This study focuses on the ATP-dependent RNA helicase DHX16, a key spliceosome component, and its role in HSC regulation. Using conditional knockout mice, we demonstrate that loss of Dhx16 in the hematopoietic system results in significant depletion of hematopoietic stem and progenitor cells, bone marrow failure, and rapid mortality. Dhx16-deficient HSCs exhibit impaired quiescence, G2-M phase cell cycle arrest, reduced protein synthesis, abnormal ribosome assembly, increased apoptosis, and decreased self-renewal capacity. Multi-omics analysis identified intron 4 retention in Emg1 mRNA in Dhx16 knockout HSCs, leading to reduced EMG1 protein expression, disrupted ribosome assembly, and nucleolar stress, activating the p53 pathway. Overexpression of Emg1 in Dhx16-deficient HSCs partially restored ribosome assembly and HSC function, suggesting Emg1 as a potential therapeutic target for ribosomopathies. Our findings reveal the critical role of Dhx16 in HSC homeostasis through the regulation of alternative splicing and ribosome assembly, providing insights into the molecular mechanisms underlying hematopoietic diseases and potential therapeutic strategies.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"38 12","pages":"2699-2708"},"PeriodicalIF":12.8,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142325543","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}

{"title":"Prognostic value of response to first-line hydroxyurea according to IPSET stratification in essential thrombocythemia","authors":"Marta Santaliestra, Marta Garrote, María Soledad Noya, Manuel Pérez-Encinas, Alicia Senín, Raúl Pérez-López, Francisca Ferrer-Marín, Gonzalo Carreño-Tarragona, Gonzalo Caballero, Elena Magro, Patricia Vélez, Miguel Ángel Cortés Vázquez, Ana Moretó, Anna Angona, Irene Pastor-Galán, José María Guerra, Carmen García Hernández, María Isabel Mata, Ruth Stuckey, María Teresa Gómez-Casares, Laura Fox, Beatriz Cuevas, Valentín García-Gutiérrez, Ana Triguero, Eduardo Arellano-Rodrigo, Juan Carlos Hernández-Boluda, Alberto Alvarez-Larrán","doi":"10.1038/s41375-024-02416-2","DOIUrl":"10.1038/s41375-024-02416-2","url":null,"abstract":"Hydroxyurea (HU) constitutes the first-line treatment in most patients with essential thrombocythemia (ET), but criteria for changing therapy are not clearly established. The prognostic value of complete hematological response (CHR) and resistance/intolerance to HU was assessed in 1080 patients from the Spanish Registry of ET, classified according to revised IPSET-Thrombosis stratification (Very low- n = 61, Low- n = 83, Intermediate- n = 261, and High-risk n = 675). With a median therapy duration of 5 years, CHR was registered in 720 (67%) patients (1-year probability 51%) and resistance/intolerance in 219 (20%) patients (5-years probability 13%). After correction by other risk factors, High-risk patients achieving CHR showed a reduced risk of arterial thrombosis (HR: 0.35, 95%CI: 0.2–0.6, p = 0.001) and a trend towards lower risk of venous thrombosis (HR: 0.45, 95%CI: 0.2–1.02, p = 0.06) whereas no association was observed for intermediate- or low-risk patients. In comparison with non-responders, intermediate- and high-risk patients achieving CHR had longer survival and lower myelofibrosis incidence. Development of resistance/intolerance to HU, mainly cytopenia, was associated with higher probability of myelofibrosis but no effect on survival or thrombotic risk was demonstrated. In conclusion, CHR with HU is associated with better outcomes and might be an early indicator for selecting candidates to second-line clinical trials.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"38 12","pages":"2636-2643"},"PeriodicalIF":12.8,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02416-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142328771","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}