LeukemiaPub Date : 2024-10-02DOI: 10.1038/s41375-024-02415-3
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
{"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":"https://doi.org/10.1038/s41375-024-02415-3","url":null,"abstract":"<p>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.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
LeukemiaPub Date : 2024-10-01DOI: 10.1038/s41375-024-02428-y
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
{"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":"https://doi.org/10.1038/s41375-024-02428-y","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
LeukemiaPub Date : 2024-09-30DOI: 10.1038/s41375-024-02417-1
Shyam A. Patel
{"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":"https://doi.org/10.1038/s41375-024-02417-1","url":null,"abstract":"<p>Patients with <i>TP53</i> aberrations comprise the highest risk subset of all myeloid malignancies. The managerial conundrum of <i>TP53</i>-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 <i>TP53</i>-mutant cells. Thus far, no targeted therapies have been commercially approved for this mutational subset. As a result, management plans for patients with <i>TP53</i>-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.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
LeukemiaPub Date : 2024-09-28DOI: 10.1038/s41375-024-02425-1
Wencke Walter, Niroshan Nadarajah, Stephan Hutter, Heiko Müller, Claudia Haferlach, Wolfgang Kern, Torsten Haferlach, Manja Meggendorfer
{"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":"https://doi.org/10.1038/s41375-024-02425-1","url":null,"abstract":"<p>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 <i>BCR</i>::<i>ABL1</i> 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.</p><figure></figure>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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":"https://doi.org/10.1038/s41375-024-02423-3","url":null,"abstract":"<p>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 <i>Dhx16</i> in the hematopoietic system results in significant depletion of hematopoietic stem and progenitor cells, bone marrow failure, and rapid mortality. <i>Dhx16</i>-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 <i>Emg1</i> mRNA in <i>Dhx16</i> knockout HSCs, leading to reduced EMG1 protein expression, disrupted ribosome assembly, and nucleolar stress, activating the p53 pathway. Overexpression of <i>Emg1</i> in <i>Dhx16</i>-deficient HSCs partially restored ribosome assembly and HSC function, suggesting <i>Emg1</i> as a potential therapeutic target for ribosomopathies. Our findings reveal the critical role of <i>Dhx16</i> 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.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":11.4,"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}
LeukemiaPub Date : 2024-09-27DOI: 10.1038/s41375-024-02416-2
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
{"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":"https://doi.org/10.1038/s41375-024-02416-2","url":null,"abstract":"<p>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- <i>n</i> = 61, Low- <i>n</i> = 83, Intermediate- <i>n</i> = 261, and High-risk <i>n</i> = 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, <i>p</i> = 0.001) and a trend towards lower risk of venous thrombosis (HR: 0.45, 95%CI: 0.2–1.02, <i>p</i> = 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.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
LeukemiaPub Date : 2024-09-25DOI: 10.1038/s41375-024-02410-8
Catherine Thieblemont, Yasmin H. Karimi, Herve Ghesquieres, Chan Y. Cheah, Michael Roost Clausen, David Cunningham, Wojciech Jurczak, Young Rok Do, Robin Gasiorowski, David John Lewis, Tae Min Kim, Marjolein van der Poel, Michelle Limei Poon, Tatyana Feldman, Kim M. Linton, Anna Sureda, Martin Hutchings, Minh H. Dinh, Nurgul Kilavuz, David Soong, Thomas Mark, Mariana Sacchi, Tycel Phillips, Pieternella J. Lugtenburg
{"title":"Epcoritamab in relapsed/refractory large B-cell lymphoma: 2-year follow-up from the pivotal EPCORE NHL-1 trial","authors":"Catherine Thieblemont, Yasmin H. Karimi, Herve Ghesquieres, Chan Y. Cheah, Michael Roost Clausen, David Cunningham, Wojciech Jurczak, Young Rok Do, Robin Gasiorowski, David John Lewis, Tae Min Kim, Marjolein van der Poel, Michelle Limei Poon, Tatyana Feldman, Kim M. Linton, Anna Sureda, Martin Hutchings, Minh H. Dinh, Nurgul Kilavuz, David Soong, Thomas Mark, Mariana Sacchi, Tycel Phillips, Pieternella J. Lugtenburg","doi":"10.1038/s41375-024-02410-8","DOIUrl":"https://doi.org/10.1038/s41375-024-02410-8","url":null,"abstract":"<p>Primary results (median follow-up, 10.7 months) from the pivotal EPCORE<sup>®</sup> NHL-1 study in relapsed or refractory (R/R) large B-cell lymphoma (LBCL) demonstrated deep, durable responses with epcoritamab, a CD3xCD20 bispecific antibody, when used as monotherapy. We report long-term efficacy and safety results in patients with LBCL (<i>N</i> = 157; 25.1-month median follow-up). As of April 21, 2023, overall response rate was 63.1% and complete response (CR) rate was 40.1%. Estimated 24-month progression-free survival (PFS) and overall survival (OS) rates were 27.8% and 44.6%, respectively. An estimated 64.2% of complete responders remained in CR at 24 months. Estimated 24-month PFS and OS rates among complete responders were 65.1% and 78.2%, respectively. Of 119 minimal residual disease (MRD)-evaluable patients, 45.4% had MRD negativity, which correlated with longer PFS and OS. CR rates were generally consistent across predefined subgroups: 36% prior chimeric antigen receptor (CAR) T-cell therapy, 32% primary refractory disease, and 37% International Prognostic Index ≥3. The most common treatment-emergent adverse events were cytokine release syndrome (51.0%), pyrexia (24.8%), fatigue (24.2%), and neutropenia (23.6%). These results underscore the long-term benefit of epcoritamab for treating R/R LBCL with deep responses across subgroups, including patients with hard-to-treat disease and expected poor prognosis (ClinicalTrials.gov Registration: NCT03625037).</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142317198","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}
LeukemiaPub Date : 2024-09-25DOI: 10.1038/s41375-024-02420-6
Georg Lenz, Hervé Tilly, Marita Ziepert, Bettina Altmann, Charles Herbaux, Fabian Frontzek, Maike Nickelsen, Calvin Lee, Jamie Hirata, Deniz Sahin, Saibah Chohan, Connie Lee Batlevi, Mark Yan, Franck Morschhauser, Norbert Schmitz
{"title":"Pola-R-CHP or R-CHOEP for first-line therapy of younger patients with high-risk diffuse large B-cell lymphoma: a retrospective comparison of two randomized phase 3 trials","authors":"Georg Lenz, Hervé Tilly, Marita Ziepert, Bettina Altmann, Charles Herbaux, Fabian Frontzek, Maike Nickelsen, Calvin Lee, Jamie Hirata, Deniz Sahin, Saibah Chohan, Connie Lee Batlevi, Mark Yan, Franck Morschhauser, Norbert Schmitz","doi":"10.1038/s41375-024-02420-6","DOIUrl":"https://doi.org/10.1038/s41375-024-02420-6","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142321320","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}
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