Leukemia最新文献

{"title":"Post-transplant cyclophosphamide separates graft-versus host disease and graft versus leukemia effects after HLA-matched stem-cell transplantation for acute myeloid leukemia.","authors":"Avichai Shimoni, Christophe Peczynski, Myriam Labopin, Alexander Kulagin, Ellen Meijer, Jan Cornelissen, Goda Choi, Jaime Sanz, Montserrat Rovira, Gwendolyn Van Gorkom, Nicolaus Kröger, Yener Koc, Jan Vydra, J L Diez-Martin, Carlos Solano, Amit Patel, Patrizia Chiusolo, Fabio Ciceri, Arnon Nagler, Mohamad Mohty","doi":"10.1038/s41375-024-02445-x","DOIUrl":"https://doi.org/10.1038/s41375-024-02445-x","url":null,"abstract":"<p><p>The association of graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effects after allogeneic stem-cell transplantation (SCT) is well-established but was not confirmed in the modern era and following post-transplant cyclophosphamide (PTCy). We assessed GVHD/ GVL association in AML patients following HLA-matched SCT with standard calcineurin-based (n = 12,653, 57% with additional in-vivo T-cell depletion) or PTCy-based (n = 508) GVHD prophylaxis. Following standard prophylaxis, acute GVHD grade II-IV and III-IV, chronic GVHD, and extensive chronic GVHD rates were 23.8%, 7.5%, 37.0%, and 16.3%, respectively. Acute GVHD grade II and III-IV were associated with lower relapse [hazard-ratio (HR) 0.85, P = 0.002; HR 0.76, P = 0.003, respectively)], higher non-relapse mortality (NRM) (HR 1.5, P < 0.001; HR 6.21, P < 0.001) and lower overall survival (OS) (HR 1.49, P < 0.001; HR 6.1, P < 0.001). Extensive chronic GVHD predicted lower relapse (HR 0.69, P < 0.001), higher NRM (HR 2.83, P < 0.001), and lower OS (HR 2.74, P < 0.001). Following PTCy, GVHD rates were 22.8%, 6.2%, 35.5%, and 17.7%, respectively. Acute GVHD was not associated with relapse (HR 1.37, P = 0.15) but predicted higher NRM (HR 3.34, P < 0.001) and lower OS (HR 1.92, P = 0.001). Chronic GVHD was not prognostic for these outcomes. In conclusion, GVHD and GVL are strongly associated with contemporary SCT. However, following PTCy, GVHD is not associated with reduced relapse.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142558192","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":"The dynamic evolution of lineage switch under CD19 CAR-T treatment in non-KMT2A rearranged B-ALL patients","authors":"Shaowei Qiu, Yihan Mei, Runxia Gu, Yu Liu, Manling Chen, Haiyan Xing, Kejing Tang, Zheng Tian, Qing Rao, Donglin Yang, Aiming Pang, Shuning Wei, Yujiao Jia, Huijun Wang, Sizhou Feng, Hui Wei, Ping Zhu, Min Wang, Ying Wang, Wenbing Liu, Jianxiang Wang","doi":"10.1038/s41375-024-02449-7","DOIUrl":"https://doi.org/10.1038/s41375-024-02449-7","url":null,"abstract":"<p>Reconstructing the clonal evolution paradigm helps us understand the process of lineage switching [6]. Therefore, we depicted the clonal evolution pattern of patient 1 (P01) through single-cell targeted DNA sequencing (Supplementary Table 3). Through single-cell genomic sequencing and quality control, we obtained a total of 6566 high-quality cells with related gene mutations (<i>FLT3, BCORL1</i>, and <i>STAG2</i>) at the four time points for clone structure inference (Fig. 1B, Supplementary Table 4). The Tapestri insights analysis (Fig. 1B) revealed that the <i>FLT3-ITD</i> mutation consistently persisted at four different time points (83.3%, 69.4%, 98.8%, 9.0%). Pre-existing <i>BCORL1</i> mutation rapidly expanded after the initiation of myeloid relapse, while <i>STAG2</i> mutation occurred with the presence of <i>BCORL1</i> mutation (16.1%, 4.3%, 96.1%, 0.0%). Compared with the T1_Pre_CART time point, we found that the <i>BCORL1</i> mutation burden (Fig. 1C) increased at the T3_Relapse time point. Moreover, the single-cell membrane protein data (Supplementary Fig. 1A–D, Supplementary Table 5) showed that B-ALL blast cells expressed typical B-ALL-associated markers CD19 and CD10, along with co-expression of myeloid-associated markers CD33 and CD123 at the T1_Pre_CART time point and the blast cells lost the expression of lymphoid marker CD19 at relapse, confirming the phenomenon of lineage switch.</p><p>Moreover, the clonal evolution structure of patient 2 (P02) was reconstructed through whole exon sequencing and targeted sequencing (Fig. 1D, Supplementary Table 6). Throughout the treatment course of P02, the expression of fusion gene <i>EP300::ZNF384</i> persisted, the <i>IKZF2</i> mutated clone disappeared after CD19 CAR-T therapy, and the <i>BCOR</i> gene mutated clone emerged upon myeloid lineage relapse. Through BCR sequencing, we observed the presence of identical immunoglobulin sequences at the T2_Relapse time point as those in the T1_Pre_CART time point (Fig. 1E, Supplementary Table 7), and we could also observe that the clonal frequency of immunoglobulin sequences increased during relapse, suggesting their enrichment in the myeloid reprogramming process. This result suggested that the origin of myeloid progenitor cells was reprogrammed from B-ALL cells [7].</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142555985","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":"Comparative small molecule screening of primary human acute leukemias, engineered human leukemia and leukemia cell lines","authors":"Safia Safa-Tahar-Henni, Karla Páez Martinez, Verena Gress, Nayeli Esparza, Élodie Roques, Florence Bonnet-Magnaval, Mélanie Bilodeau, Valérie Gagné, Eva Bresson, Sophie Cardin, Nehme El-Hachem, Isabella Iasenza, Gabriel Alzial, Isabel Boivin, Naoto Nakamichi, Anne-Cécile Soufflet, Cristina Mirela Pascariu, Jean Duchaine, Simon Mathien, Éric Bonneil, Kolja Eppert, Anne Marinier, Guy Sauvageau, Geneviève Deblois, Pierre Thibault, Josée Hébert, Connie J. Eaves, Sonia Cellot, Frédéric Barabé, Brian T. Wilhelm","doi":"10.1038/s41375-024-02400-w","DOIUrl":"https://doi.org/10.1038/s41375-024-02400-w","url":null,"abstract":"<p>Targeted therapeutics for high-risk cancers remain an unmet medical need. Here we report the results of a large-scale screen of over 11,000 molecules for their ability to inhibit the survival and growth in vitro of human leukemic cells from multiple sources including patient samples, de novo generated human leukemia models, and established human leukemic cell lines. The responses of cells from de novo models were most similar to those of patient samples, both of which showed striking differences from the cell-line responses. Analysis of differences in subtype-specific therapeutic vulnerabilities made possible by the scale of this screen enabled the identification of new specific modulators of apoptosis, while also highlighting the complex polypharmacology of anti-leukemic small molecules such as shikonin. These findings introduce a new platform for uncovering new therapeutic options for high-risk human leukemia, in addition to reinforcing the importance of the test sample choice for effective drug discovery.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142536551","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":"Validation and refinement of the 2022 European LeukaemiaNet genetic risk classification of acute myeloid leukaemia patients receiving allogeneic haematopoietic cell transplantation","authors":"Weihao Chen, Lieguang Chen, Yang Cao, Chuanhe Jiang, Yi Luo, Guifang Ouyang, Jian Yu, Yamin Tan, Xiaoyu Lai, Lizhen Liu, Huarui Fu, Yishan Ye, Luxin Yang, Congxiao Zhang, Jimin Shi, Xiaoxia Hu, He Huang, Yanmin Zhao","doi":"10.1038/s41375-024-02440-2","DOIUrl":"https://doi.org/10.1038/s41375-024-02440-2","url":null,"abstract":"<p>A total of 757 de novo AML patients were eligible for training cohort, including 401 males and 356 females, with a median follow-up of 30 (range, 1–91) months after allo-HCT. The median age at allo-HCT was 40 (range, 14–69) years. According to the ELN2022 classification, 34% (<i>n</i> = 257) were favourable, 42% (<i>n</i> = 316) were intermediate, and 24% (n = 180) were adverse. Compared to the ELN2017 categories, 95% of favourable, 80% of intermediate, and 84% of adverse patients in the ELN2022 categories remained in their previous risk stratification. The redistribution of patients and major mutation types from the ELN2017 to ELN2022 is shown in Fig. 1B and Table S1, and the detailed baseline demographic is provided in Table S2.</p><p>According to the ELN2017, the 3-year cumulative incidence of relapse (CIR) for the favourable, intermediate, and adverse groups was 13%, 18 and 40%, respectively, with corresponding relapse-free survival (RFS) rates of 81%, 75 and 52%, and overall survival (OS) rates of 85%, 81%, and 59%, all showing statistically significant differences (P &lt; 0.001) (Fig. 1C, E, G). In the ELN2022, the 3-year CIR were 11%, 19%, and 40% (<i>P</i> &lt; 0.001); the 3-year RFS were 84%, 74%, and 52% (<i>P</i> &lt; 0.001); and the 3-year OS were 88%, 79%, and 59% (<i>P</i> &lt; 0.001) across the favourable, intermediate, and adverse groups, respectively (Fig. 1D, F, H). Similar results were observed when survival analysis was confined to patients who achieved complete remission (CR) at allo-HCT (Fig. S1). Furthermore, in multivariate model, the ELN2022 risk classification at diagnosis was an independent prognostic factor for CIR, RFS and OS (Table S3). Receiver operating characteristic (ROC) analysis was performed to compare the prognostic prediction power of the ELN2022 and ELN2017 risk systems in our training cohort. The C-statistics (area under the curves [AUC]) for predicting relapse (AUC_ELN2017 = 0.660 vs. AUC_ELN2022 = 0.668, <i>P</i> = 0.530), RFS (AUC_ELN2017 = 0.648 vs. AUC_ELN2022 = 0.658, <i>P</i> = 0.372), and OS (AUC_ELN2017 = 0.641 vs. AUC_ELN2022 = 0.653, <i>P</i> = 0.318) were not distinct between the ELN2022 and ELN2017 (Fig. 1I–K and Table S4).</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142519309","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":"Antibody blockade of the PSGL-1 immune checkpoint enhances T-cell responses to B-cell lymphoma","authors":"João L. Pereira, Liliana Arede, Francisca Ferreira, Andreia Matos, Dulcineia Pereira, Rita F. Santos, Alexandre M. Carmo, Maria J. Oliveira, José C. Machado, Delfim Duarte, Nuno R. dos Santos","doi":"10.1038/s41375-024-02446-w","DOIUrl":"https://doi.org/10.1038/s41375-024-02446-w","url":null,"abstract":"<p>Despite advancements in cancer immunotherapy, most lymphomas remain unresponsive to checkpoint inhibitors. P-selectin glycoprotein ligand-1 (PSGL-1), recently identified as a promoter of T-cell exhaustion in murine melanoma models, has emerged as a novel immune checkpoint protein and promising immunotherapeutic target. In this study, we investigated the potential of PSGL-1 antibody targeting in B-cell lymphoma. Using allogeneic co-culture systems, we demonstrated that targeted antibody interventions against human PSGL-1 enhanced T-cell activation and effector cytokine production in response to lymphoma cells. Moreover, in vitro treatment of primary lymphoma cell suspensions with PSGL-1 antibody resulted in increased activation of autologous lymphoma-infiltrating T cells. Using the A20 syngeneic B-cell lymphoma mouse model, we found that PSGL-1 antibody treatment significantly slowed tumor development and reduced the endpoint tumor burden. This antitumoral effect was accompanied by augmented tumor infiltration of CD4⁺ and CD8⁺ T cells and reduced infiltration of regulatory T cells. Finally, anti-PSGL-1 administration enhanced the expansion of CAR T cells previously transferred to mice bearing the aggressive Eμ-<i>Myc</i> lymphoma cells and improved disease control. These results demonstrate that PSGL-1 antibody blockade bolsters T-cell activity against B-cell lymphoma, suggesting a potential novel immunotherapeutic approach for treating these malignancies.</p><figure></figure>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142490304","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":"Leveraging CRISPR gene editing technology to optimize the efficacy, safety and accessibility of CAR T-cell therapy","authors":"Tao Lei, Yazhuo Wang, Yuchen Zhang, Yufei Yang, Jiaying Cao, Jiansong Huang, Jiali Chen, Huajing Chen, Jiayi Zhang, Luzheng Wang, Xinjie Xu, Robert Peter Gale, Liang Wang","doi":"10.1038/s41375-024-02444-y","DOIUrl":"https://doi.org/10.1038/s41375-024-02444-y","url":null,"abstract":"<p>Chimeric Antigen Receptor (CAR)-T-cell therapy has revolutionized cancer immune therapy. However, challenges remain including increasing efficacy, reducing adverse events and increasing accessibility. Use of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) technology can effectively perform various functions such as precise integration, multi-gene editing, and genome-wide functional regulation. Additionally, CRISPR screening using large-scale guide RNA (gRNA) genetic perturbation provides an unbiased approach to understanding mechanisms underlying anti-cancer efficacy of CAR T-cells. Several emerging CRISPR tools with high specificity, controllability and efficiency are useful to modify CAR T-cells and identify new targets. In this review we summarize potential uses of the CRISPR system to improve results of CAR T-cells therapy including optimizing efficacy and safety and, developing universal CAR T-cells. We discuss challenges facing CRISPR gene editing and propose solutions highlighting future research directions in CAR T-cell therapy.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142490306","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":"Aberrant BCAT1 expression augments MTOR activity and accelerates disease progression in chronic lymphocytic leukemia","authors":"Qiangqiang Shao, Jedrzej Wykretowicz, Nan Hu, Karan Bedi, Mohamed Rizk, Isabella A. Malek, Surinder Kumar, David B. Lombard, Kerby Shedden, David Scott, Sami N. Malek","doi":"10.1038/s41375-024-02448-8","DOIUrl":"https://doi.org/10.1038/s41375-024-02448-8","url":null,"abstract":"<p>We performed gene expression profiling of mRNA/cDNA isolated from <i>N</i> = 117 flow sorted CLL. We detected aberrant expression of the metabolic enzyme branched chain amino acid transferase (BCAT1) in CLL with del17p/<i>TP53</i>mut. Through extensive validation, we confirmed the highly preferential expression of BCAT1 in CLL with del17p/<i>TP53</i>mut (66%) or trisomy 12 (77%). BCAT1 was not expressed in B cells isolated from normal human lymph nodes. The products of the bidirectional BCAT1 reaction, including leucine, acetyl-CoA, and alpha-ketoglutarate are known activators of MTOR. We measured an ~two-fold higher MTOR activity via normalized p-S6K levels in primary CLL with BCAT1 high versus absent expression before and after sIgM crosslinking. Through steady state metabolomics and heavy isotope metabolic tracing in primary CLL cells, we demonstrate that CLL cells are avid consumers of branched chain amino acids (BCAAs) and that BCAT1 in CLL engages in bidirectional substrate reactions. Of additional interest, CLL with aberrant BCAT1 expression were less sensitive to Venetoclax-induced apoptosis. Biologically, three CLL-derived cell lines with disruption of <i>BCAT1</i> had substantially reduced growth ex vivo. Clinically, the expression of any detectable BCAT1 protein in CLL independently associated with shorter median survival (125 months versus 296 months; <i>p</i> &lt; 0.0001), even after exclusion of del17p/<i>TP53</i>mut cases.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142490301","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":"Apoliprotein E-mediated ferroptosis controls cellular proliferation in chronic lymphocytic leukemia","authors":"Federica Nardi, Rosita Del Prete, Roberta Drago, Anthea Di Rita, Francesco Edoardo Vallone, Sara Ciofini, Margherita Malchiodi, Laura Pezzella, Laura Tinti, Vittoria Cicaloni, Laura Salvini, Danilo Licastro, Aidan T. Pezacki, Christopher J. Chang, Giuseppe Marotta, Antonella Naldini, Silvia Deaglio, Tiziana Vaisitti, Alessandro Gozzetti, Monica Bocchia, Anna Kabanova","doi":"10.1038/s41375-024-02442-0","DOIUrl":"https://doi.org/10.1038/s41375-024-02442-0","url":null,"abstract":"<p>Unraveling vulnerabilities in chronic lymphocytic leukemia (CLL) represents a key approach to understand molecular basis for its indolence and a path toward developing tailored therapeutic approaches. In this study, we found that CLL cells are particularly sensitive to the inhibitory action of abundant serum protein, apolipoprotein E (ApoE). Physiological concentrations of ApoE affect CLL cell viability and inhibit CD40-driven proliferation. Transcriptomics of ApoE-treated CLL cells revealed a signature of redox and metal disbalance which prompted us to explore the underlying mechanism of cell death. We discover, on one hand, that ApoE treatment of CLL cells induces lipid peroxidation and ferroptosis. On the other hand, we find that ApoE is a copper-binding protein and that intracellular copper regulates ApoE toxicity. ApoE regulation tends to be lost in aggressive CLL. CLL cells from patients with high leukocyte counts are less sensitive to ApoE inhibition, while resistance to ApoE is possible in transformed CLL cells from patients with Richter syndrome (RS). Nevertheless, both aggressive CLL and RS cells maintain sensitivity to drug-induced ferroptosis. Our findings suggest a natural suppression axis that mediates ferroptotic disruption of CLL cell proliferation, building up the rationale for choosing ferroptosis as a therapeutic target in CLL and RS.</p><figure></figure>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142488327","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":"NPM1-fusion proteins promote myeloid leukemogenesis through XPO1-dependent HOX activation","authors":"Yuko Shimosato, Keita Yamamoto, Yuhan Jia, Wenyu Zhang, Norio Shiba, Yasuhide Hayashi, Shuichi Ito, Toshio Kitamura, Susumu Goyama","doi":"10.1038/s41375-024-02438-w","DOIUrl":"https://doi.org/10.1038/s41375-024-02438-w","url":null,"abstract":"<p>Nucleophosmin (<i>NPM1</i>) is a nucleolar protein and one of the most frequently mutated genes in acute myeloid leukemia (AML). In addition to the commonly detected frameshift mutations in exon12 (NPM1c), previous studies have identified <i>NPM1</i> gene rearrangements leading to the expression of NPM1-fusion proteins in pediatric AML. However, whether the NPM1-fusions are indeed oncogenic and how the NPM1-fusions cause AML have been largely unknown. In this study, we investigated the subcellular localization and leukemogenic potential of two rare NPM1-fusion proteins, NPM1::MLF1 and NPM1::CCDC28A. NPM1::MLF1 is present in both the nucleus and cytoplasm and occasionally induces AML in the mouse transplantation assay. NPM1::CCDC28A is more localized to the cytoplasm, immortalizes mouse bone marrow cells in vitro and efficiently induces AML in vivo. Mechanistically, both NPM1-fusions bind to the <i>HOX</i> gene cluster and, like NPM1c, cause aberrant upregulation of <i>HOX</i> genes in cooperation with XPO1. The XPO1 inhibitor selinexor suppressed <i>HOX</i> activation and colony formation driven by the NPM1-fusions. <i>NPM1::CCDC28A</i> cells were also sensitive to menin inhibition. Thus, our study provides experimental evidence that both <i>NPM1::MLF1</i> and <i>NPM1::CCDC28A</i> are oncogenes with functions similar to NPM1c. Inhibition of XPO1 and menin may be a promising strategy for the NPM1-rearranged AML.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142487525","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":"MSI2 mediates WNT/β-Catenin pathway function in hematopoietic stem cells","authors":"Huifang Zhang, Ruixue Guo, Zhenfen Li, Rui Ma, Shina Xu, Le Yin, Hongkai Zhu, Zineng Huang, Cheng Xing, Yunlong Yang, Yulin Pu, Zhao Cheng, Jing Liu, Hongling Peng, Yue Sheng","doi":"10.1038/s41375-024-02447-9","DOIUrl":"https://doi.org/10.1038/s41375-024-02447-9","url":null,"abstract":"&lt;p&gt;First, we sorted out hematopoietic stem cells (HSCs) and hematopoietic stem and progenitor cells (HSPCs) from wildtype (WT) and &lt;i&gt;Apc&lt;/i&gt; knockout (Apc KO, Apc&lt;sup&gt;−/−&lt;/sup&gt;) mice, which are Apc&lt;sup&gt;fl/fl&lt;/sup&gt; and Apc&lt;sup&gt;fl/fl&lt;/sup&gt;Mx1Cre respectively. The &lt;i&gt;Apc&lt;/i&gt; deletion was induced by Poly(I:C) injection. Quantitative PCR (qPCR) demonstrated a significant decrease of &lt;i&gt;Msi2&lt;/i&gt; expression in the HSCs (lin&lt;sup&gt;−&lt;/sup&gt;c-Kit&lt;sup&gt;+&lt;/sup&gt; Sca1&lt;sup&gt;+&lt;/sup&gt;CD150&lt;sup&gt;+&lt;/sup&gt;CD48&lt;sup&gt;−&lt;/sup&gt;) and HSPCs (lin&lt;sup&gt;−&lt;/sup&gt;c-Kit&lt;sup&gt;+&lt;/sup&gt;) of Apc KO mice (Fig. 1B, C). To investigate the role of MSI2 in the WNT signaling pathway, MSI2 was re-expressed in Apc&lt;sup&gt;−/−&lt;/sup&gt; HSPCs by retrovirus infection, and western blot (WB) confirmed Msi2 was successfully overexpressed (Supplementary Fig. 1). The colony-forming assay showed that restoring MSI2 expression could partially rescue the diminished colony-forming ability observed in Apc&lt;sup&gt;+/−&lt;/sup&gt; and Apc&lt;sup&gt;−/−&lt;/sup&gt; cells (Fig. 1D, E). Next, we collected colony cells from the above colony-forming assay, and found that restoration of MSI2 expression can significantly reduce the high apoptosis rate induced by &lt;i&gt;Apc&lt;/i&gt; KO (Fig. 1F and Supplementary Fig. 2).&lt;/p&gt;&lt;p&gt;To further investigate the relationship between MSI2 and WNT signaling pathway, we performed in vivo transplantation experiments following the restoration of MSI2 expression in &lt;i&gt;Apc&lt;/i&gt; KO cells. Five days after the 5-FU injection, HSPCs from WT (Apc&lt;sup&gt;fl/fl&lt;/sup&gt;) or Apc&lt;sup&gt;fl/fl&lt;/sup&gt; Mx1Cre mice were infected with MigR1 vector or MSI2, and then were transplanted into CD45.1 recipient mice irradiated lethally (10 Gray). One month later, pIpC was injected intra-peritoneally at bi-daily intervals to induce the expression of Mx1Cre to knock out &lt;i&gt;Apc&lt;/i&gt;. Seven days after the third pIpC injection, the mice were euthanized, and bone marrow cells were gathered for detection (Fig. 1G). The restoration of MSI2 expression considerably increased the populations of HSCs (Lin&lt;sup&gt;−&lt;/sup&gt;c-Kit&lt;sup&gt;+&lt;/sup&gt;Sca1&lt;sup&gt;+&lt;/sup&gt;CD48&lt;sup&gt;−&lt;/sup&gt;CD150&lt;sup&gt;+&lt;/sup&gt;), LSK (Lin&lt;sup&gt;−&lt;/sup&gt;c-Kit&lt;sup&gt;+&lt;/sup&gt;Sca1&lt;sup&gt;+&lt;/sup&gt;) and HPCs (Lin&lt;sup&gt;−&lt;/sup&gt;c-Kit&lt;sup&gt;+&lt;/sup&gt;Sca1&lt;sup&gt;−&lt;/sup&gt;) compared to cells from &lt;i&gt;Apc&lt;/i&gt; KO mice (Fig. 1H and Supplementary Fig. 3). Furthermore, the proportion of granulocyte-monocyte progenitors (GMP) and common myeloid progenitors (CMP) in the HPC population returned to normal. The megakaryocyte-erythroid progenitors (MEP) also changed, but not significantly (Fig. 1I and Supplementary Fig. 4). &lt;i&gt;Apc&lt;/i&gt; deletion can induce a significant increase in apoptosis, which is one of the main reasons for the decline of HSPCs [7]. We found that the restoration of MSI2 expression can significantly inhibit the increase of apoptosis caused by &lt;i&gt;Apc&lt;/i&gt; deletion (Fig. 1J and Supplementary Fig. 5A, B), suggesting that MSI2 can partially rescue the decline of HSPCs induced by &lt;i&gt;Apc&lt;/i&gt; loss through inhibiting apoptosis. In addition to HSPCs, w","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142487526","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}