LeukemiaPub Date : 2024-09-19DOI: 10.1038/s41375-024-02413-5
Joachim Alexandre, Jonaz Font, Da-Silva Angélique, Baptiste Delapierre, Ghandi Damaj, Anne-Flore Plane, Damien Legallois, Paul Milliez, Charles Dolladille, Basile Chrétien
{"title":"Is ibrutinib-related atrial fibrillation dose dependent? Insights from an individual case level analysis of the World Health Organization pharmacovigilance database","authors":"Joachim Alexandre, Jonaz Font, Da-Silva Angélique, Baptiste Delapierre, Ghandi Damaj, Anne-Flore Plane, Damien Legallois, Paul Milliez, Charles Dolladille, Basile Chrétien","doi":"10.1038/s41375-024-02413-5","DOIUrl":"10.1038/s41375-024-02413-5","url":null,"abstract":"Whether ibrutinib-related atrial fibrillation (IRAF) is a dose-dependent adverse drug reaction (ADR) and whether ibrutinib should be discontinued or dose-reduced in case of IRAF occurrence remains unknown. Using the World Health Organization individual case safety report pharmacovigilance database, VigiBase®, we aimed to determine the association between ibrutinib dosing regimens and IRAF reporting. Ibrutinib daily dose was extracted from IRAF cases from VigiBase® and was divided into 5 ibrutinib dosing regimen (140–280–420–560 and >560 mg/day). Disproportionality analysis was used to evaluate the association between IRAF reporting and ibrutinib daily dose, through logistic regression. Single term deletions produced the ibrutinib daily dose global p-value. Then, a multivariable adjusted reporting odds-ratio with its 95% confidence interval was calculated for each ibrutinib dosing regimen, against the lowest dosing regimen (140 mg/day) as reference. A total of 1162 IRAF cases were identified in VigiBase® (n = 62 for ibrutinib 140 mg/day, 114 for ibrutinib 280 mg/day, 811 for ibrutinib 420 mg/day, 164 for ibrutinib 560 mg/day and 11 for ibrutinib >560 mg/day). After adjustment on several variables of interest, IRAF reporting was not significantly associated with ibrutinib dosing regimen (p = 0.09). Our results from Vigibase® do not support IRAF as a dose-dependent ADR (ClinicalTrial registration number: NCT06224452).","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"38 12","pages":"2628-2635"},"PeriodicalIF":12.8,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02413-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142273465","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}
LeukemiaPub Date : 2024-09-18DOI: 10.1038/s41375-024-02409-1
Laura Volta, Renier Myburgh, Christian Pellegrino, Christian Koch, Monique Maurer, Francesco Manfredi, Mara Hofstetter, Anne Kaiser, Florin Schneiter, Jan Müller, Marco M. Buehler, Roberto De Luca, Nicholas Favalli, Chiara F. Magnani, Timm Schroeder, Dario Neri, Markus G. Manz
{"title":"Efficient combinatorial adaptor-mediated targeting of acute myeloid leukemia with CAR T-cells","authors":"Laura Volta, Renier Myburgh, Christian Pellegrino, Christian Koch, Monique Maurer, Francesco Manfredi, Mara Hofstetter, Anne Kaiser, Florin Schneiter, Jan Müller, Marco M. Buehler, Roberto De Luca, Nicholas Favalli, Chiara F. Magnani, Timm Schroeder, Dario Neri, Markus G. Manz","doi":"10.1038/s41375-024-02409-1","DOIUrl":"10.1038/s41375-024-02409-1","url":null,"abstract":"CAR T-cell products targeting lineage-specific cell-of-origin antigens, thereby eliminating both tumor and healthy counterpart cells, are currently clinically approved therapeutics in B- and plasma-cell malignancies. While they represent a major clinical improvement, they are still limited in terms of efficacy by e.g. single, sometimes low-expressed antigen targeting, and in terms of safety by e.g., lack of on-off activity. Successful cell-of-origin non-discriminative targeting of heterogeneous hematopoietic stem and progenitor cell malignancies, such as acute myeloid leukemia (AML), will require antigen-versatile targeting and off-switching of effectors in order to then allow rescue by hematopoietic stem cell transplantation (HSCT), preventing permanent myeloablation. To address this, we developed adaptor-CAR (AdFITC-CAR) T-cells targeting fluoresceinated AML antigen-binding diabody adaptors. This platform enables the use of adaptors matching the AML-antigen-expression profile and conditional activity modulation. Combining adaptors significantly improved lysis of AML cells in vitro. In therapeutic xenogeneic mouse models, AdFITC-CAR T-cells co-administered with single diabody adaptors were as efficient as direct CAR T-cells, and combinatorial use of adaptors further enhanced therapeutic efficacy against both, cell lines and primary AML. Collectively, this study provides proof-of-concept that AdFITC-CAR T-cells and combinations of adaptors can efficiently enhance immune-targeting of AML.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"38 12","pages":"2598-2613"},"PeriodicalIF":12.8,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02409-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142245874","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}
LeukemiaPub Date : 2024-09-17DOI: 10.1038/s41375-024-02412-6
Ekaterina Chelysheva, Jane Apperley, Anna Turkina, Mohamed A. Yassin, Delphine Rea, Franck E. Nicolini, Daniela Barraco, Khamida Kazakbaeva, Sukhrob Saliev, Adi Shacham Abulafia, Salam Al-Kindi, Jennifer Byrne, Harry F. Robertson, Marco Cerrano, Roman Shmakov, Evgenia Polushkina, Paolo de Fabritiis, Malgorzata Monika Trawinska, Elisabetta Abruzzese
{"title":"Correction: Chronic myeloid leukemia diagnosed in pregnancy: management and outcome of 87 patients reported to the European LeukemiaNet international registry","authors":"Ekaterina Chelysheva, Jane Apperley, Anna Turkina, Mohamed A. Yassin, Delphine Rea, Franck E. Nicolini, Daniela Barraco, Khamida Kazakbaeva, Sukhrob Saliev, Adi Shacham Abulafia, Salam Al-Kindi, Jennifer Byrne, Harry F. Robertson, Marco Cerrano, Roman Shmakov, Evgenia Polushkina, Paolo de Fabritiis, Malgorzata Monika Trawinska, Elisabetta Abruzzese","doi":"10.1038/s41375-024-02412-6","DOIUrl":"10.1038/s41375-024-02412-6","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"38 11","pages":"2514-2514"},"PeriodicalIF":12.8,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02412-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142290420","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}
LeukemiaPub Date : 2024-09-17DOI: 10.1038/s41375-024-02405-5
Melisa Halilovic, Mohamed Abdelsalam, Joanna Zabkiewicz, Michelle Lazenby, Caroline Alvares, Matthias Schmidt, Walburgis Brenner, Sara Najafi, Ina Oehme, Christoph Hieber, Yanira Zeyn, Matthias Bros, Wolfgang Sippl, Oliver H. Krämer
{"title":"Selective degradation of mutant FMS-like tyrosine kinase-3 requires BIM-dependent depletion of heat shock proteins","authors":"Melisa Halilovic, Mohamed Abdelsalam, Joanna Zabkiewicz, Michelle Lazenby, Caroline Alvares, Matthias Schmidt, Walburgis Brenner, Sara Najafi, Ina Oehme, Christoph Hieber, Yanira Zeyn, Matthias Bros, Wolfgang Sippl, Oliver H. Krämer","doi":"10.1038/s41375-024-02405-5","DOIUrl":"10.1038/s41375-024-02405-5","url":null,"abstract":"Internal tandem duplications in the FMS-like tyrosine kinase-3 (FLT3-ITD) are common mutations in acute myeloid leukemia (AML). Proteolysis-targeting chimeras (PROTACs) that induce proteasomal degradation of mutated FLT3 emerge as innovative pharmacological approach. Molecular mechanisms that control targeted proteolysis beyond the ubiquitin-proteasome-system are undefined and PROTACs are the only known type of FLT3 degraders. We report that the von-Hippel-Lindau ubiquitin-ligase based FLT3 PROTAC MA49 (melotinib-49) and the FLT3 hydrophobic tagging molecule MA50 (halotinib-50) reduce endoplasmic reticulum-associated, oncogenic FLT3-ITD but spare FLT3. Nanomolar doses of MA49 and MA50 induce apoptosis of human leukemic cell lines and primary AML blasts with FLT3-ITD (p < 0.05-0.0001), but not of primary hematopoietic stem cells and differentiated immune cells, FLT3 wild-type cells, retinal cells, and c-KIT-dependent cells. In vivo activity of MA49 against FLT3-ITD-positive leukemia cells is verified in a Danio rerio model. The degrader-induced loss of FLT3-ITD involves the pro-apoptotic BH3-only protein BIM and a previously unidentified degrader-induced depletion of protein-folding chaperones. The expression levels of HSP90 and HSP110 correlate with reduced AML patient survival (p < 0.1) and HSP90, HSP110, and BIM are linked to the expression of FLT3 in primary AML cells (p < 0.01). HSP90 suppresses degrader-induced FLT3-ITD elimination and thereby establishes a mechanistically defined feed-back circuit.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"38 12","pages":"2561-2572"},"PeriodicalIF":12.8,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02405-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142245596","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}
LeukemiaPub Date : 2024-09-17DOI: 10.1038/s41375-024-02411-7
Andrew J. Innes, Chloe Hayden, Victoria Orovboni, Simone Claudiani, Fiona Fernando, Afzal Khan, David Rees, Jennifer Byrne, Paolo Gallipoli, Sebastian Francis, Mhairi Copland, Gillian Horne, Manoj Raghavan, Claire Arnold, Angela Collins, Tanya Cranfield, Nicholas Cunningham, Akila Danga, Peter Forsyth, Rebecca Frewin, Paula Garland, Guy Hannah, Daniele Avenoso, Sandra Hassan, Brian J. P. Huntly, Jissan Husain, Sudhakaran Makkuni, Kate Rothwell, Jamshid Khorashad, Jane F. Apperley, Dragana Milojkovic
{"title":"Impact of BCR::ABL1 single nucleotide variants on asciminib efficacy","authors":"Andrew J. Innes, Chloe Hayden, Victoria Orovboni, Simone Claudiani, Fiona Fernando, Afzal Khan, David Rees, Jennifer Byrne, Paolo Gallipoli, Sebastian Francis, Mhairi Copland, Gillian Horne, Manoj Raghavan, Claire Arnold, Angela Collins, Tanya Cranfield, Nicholas Cunningham, Akila Danga, Peter Forsyth, Rebecca Frewin, Paula Garland, Guy Hannah, Daniele Avenoso, Sandra Hassan, Brian J. P. Huntly, Jissan Husain, Sudhakaran Makkuni, Kate Rothwell, Jamshid Khorashad, Jane F. Apperley, Dragana Milojkovic","doi":"10.1038/s41375-024-02411-7","DOIUrl":"10.1038/s41375-024-02411-7","url":null,"abstract":"Asciminib is a potent and selective inhibitor of BCR::ABL1, with potential to avoid toxicity resulting from off-target kinase inhibition. Forty-nine patients treated with asciminib under a managed access program in the UK were evaluated for toxicity and response. Intolerance, rather than resistance (65% vs. 35%), was the most common reason for cessation of the last-line of treatment but asciminib was well tolerated, with most patients (29, 59%) remaining on treatment at a median of 14 months follow-up, and only 6 (12%) stopping for intolerance. Of 44 patients assessable for response, 29 (66%) achieved a complete cytogenetic response (CCyR) or better, with poorer responses seen in those stopping their last-line of therapy for resistance. Fewer patients with a prior history of a non-T315I-BCR::ABL1 single nucleotide variant (BSNV), or a non-T315I-BSNV detectable at baseline achieved CCyR. Serial tracking of BSNV by next generation sequencing demonstrated clonal expansion of BSNV-harbouring populations, which in some settings was associated with resistance (E459K, F317L, F359I), while in others was seen in the context of ongoing response, often with intensified dosing (T315I, I502F). These data suggest that asciminib exerts selective pressure on some BSNV-harbouring populations in vivo, some of which may respond to intensified dosing.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"38 11","pages":"2443-2455"},"PeriodicalIF":12.8,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02411-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142245598","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}
LeukemiaPub Date : 2024-09-16DOI: 10.1038/s41375-024-02401-9
Brandon S. Willis, Kevin Mongeon, Hannah Dry, India L. Neveras, Nadezda Bryan, Meghana Pandya, Justine Roderick-Richardson, Wendan Xu, Li Yang, Alan Rosen, Corinne Reimer, Liliana Tuskova, Pavel Klener, Jerome T. Mettetal, Georg Lenz, Simon T. Barry
{"title":"Potent combination benefit of the AKT inhibitor capivasertib and the BCL-2 inhibitor venetoclax in diffuse large B cell lymphoma","authors":"Brandon S. Willis, Kevin Mongeon, Hannah Dry, India L. Neveras, Nadezda Bryan, Meghana Pandya, Justine Roderick-Richardson, Wendan Xu, Li Yang, Alan Rosen, Corinne Reimer, Liliana Tuskova, Pavel Klener, Jerome T. Mettetal, Georg Lenz, Simon T. Barry","doi":"10.1038/s41375-024-02401-9","DOIUrl":"10.1038/s41375-024-02401-9","url":null,"abstract":"The therapeutic potential of targeting PI3K/AKT/PTEN signalling in B-cell malignancies remains attractive. Whilst PI3K-α/δ inhibitors demonstrate clinical benefit in certain B-cell lymphomas, PI3K signalling inhibitors have been inadequate in relapsed/refractory diffuse large B-cell lymphoma (DLBCL) in part, due to treatment related toxicities. Clinically, AKT inhibitors exhibit a differentiated tolerability profile offering an alternative approach for treating patients with B-cell malignancies. To explore how AKT inhibition complements other potential therapeutics in the treatment of DLBCL patients, an in vitro combination screen was conducted across a panel of DLCBL cell lines. The AKT inhibitor, capivasertib, in combination with the BCL-2 inhibitor, venetoclax, produced notable therapeutic benefit in preclinical models of DLBCL. Capivasertib and venetoclax rapidly induced caspase and PARP cleavage in GCB-DLBCL PTEN wildtype cell lines and those harbouring PTEN mutations or reduced PTEN protein, driving prolonged tumour growth inhibition in DLBCL cell line and patient derived xenograft lymphoma models. The addition of the rituximab further deepened the durability of capivasertib and venetoclax responses in a RCHOP refractory DLBCL in vivo models. These findings provide preclinical evidence for the rational treatment combination of AKT and BCL-2 inhibitors using capivasertib and venetoclax respectively alongside anti-CD20 antibody supplementation for treatment of patients with DLBCL.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"38 12","pages":"2663-2674"},"PeriodicalIF":12.8,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02401-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142234434","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}
LeukemiaPub Date : 2024-09-16DOI: 10.1038/s41375-024-02375-8
Mouhamad Khouja, Linmiao Jiang, Karol Pal, Peter James Stewart, Binaya Regmi, Martin Schwarz, Wolfram Klapper, Stefan K. Alig, Nikos Darzentas, Hanneke C. Kluin-Nelemans, Olivier Hermine, Martin Dreyling, David Gonzalez de Castro, Eva Hoster, Christiane Pott, On behalf of the European Mantle Cell Lymphoma Network
{"title":"Comprehensive genetic analysis by targeted sequencing identifies risk factors and predicts patient outcome in Mantle Cell Lymphoma: results from the EU-MCL network trials","authors":"Mouhamad Khouja, Linmiao Jiang, Karol Pal, Peter James Stewart, Binaya Regmi, Martin Schwarz, Wolfram Klapper, Stefan K. Alig, Nikos Darzentas, Hanneke C. Kluin-Nelemans, Olivier Hermine, Martin Dreyling, David Gonzalez de Castro, Eva Hoster, Christiane Pott, On behalf of the European Mantle Cell Lymphoma Network","doi":"10.1038/s41375-024-02375-8","DOIUrl":"10.1038/s41375-024-02375-8","url":null,"abstract":"Recent studies highlighted genetic aberrations associated with prognosis in Mantle Cell lymphoma (MCL), yet comprehensive testing is not implemented in clinical routine. We conducted a comprehensive genomic characterization of 180 patients from the European MCL network trials by targeted sequencing of peripheral blood DNA using the EuroClonality(EC)-NDC assay. The IGH::CCND1 fusion was identified in 94% of patients, clonal IGH-V-(D)-J rearrangements in all, and 79% had ≥1 somatic gene mutation. The top mutated genes were ATM, TP53, KMT2D, SAMHD1, BIRC3 and NFKBIE. Copy number variations (CNVs) were detected in 83% of patients with RB1, ATM, CDKN2A/B and TP53 being the most frequently deleted and KLF2, CXCR4, CCND1, MAP2K1 and MYC the top amplified genes. CNVs and mutations were more frequently observed in older patients with adverse impact on prognosis. TP53mut, NOTCH1mut, FAT1mut TRAF2del, CDKN2A/Bdel and MAP2K1amp were linked to inferior failure-free (FFS) and overall survival (OS), while TRAF2mut, EGR2del and BCL2amp related to inferior OS only. Genetic complexity (≥3 CNVs) observed in 51% of analysed patients was significantly associated with impaired FFS and OS. We demonstrate that targeted sequencing from peripheral blood and bone marrow reliably detects diagnostically and prognostically important genetic factors in MCL patients, facilitating genetic characterization in clinical routine.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"38 12","pages":"2675-2684"},"PeriodicalIF":12.8,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02375-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142234502","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":"HDAC7 is a potential therapeutic target in acute erythroid leukemia","authors":"Wenyu Zhang, Keita Yamamoto, Yu-Hsuan Chang, Tomohiro Yabushita, Yangying Hao, Ruka Shimura, Jakushin Nakahara, Shiori Shikata, Kohei Iida, Qianyi Chen, Xichen Zhang, Toshio Kitamura, Susumu Goyama","doi":"10.1038/s41375-024-02394-5","DOIUrl":"10.1038/s41375-024-02394-5","url":null,"abstract":"Acute erythroleukemia (AEL) is a rare subtype of acute myeloid leukemia with a poor prognosis. In this study, we established a novel murine AEL model with Trp53 depletion and ERG overexpression. ERG overexpression in Trp53-deficient mouse bone marrow cells, but not in wild-type bone marrow cells, leads to AEL development within two months after transplantation with 100% penetrance. The established mouse AEL cells expressing Cas9 can be cultured in vitro, induce AEL in vivo even in unirradiated recipient mice, and enable efficient gene ablation using the CRISPR/Cas9 system. We also confirmed the cooperation between ERG overexpression and TP53 inactivation in promoting the growth of immature erythroid cells in human cord blood cells. Mechanistically, ERG antagonizes KLF1 and inhibits erythroid maturation, whereas TP53 deficiency promotes proliferation of erythroid progenitors. Furthermore, we identified HDAC7 as a specific susceptibility in AEL by the DepMap-based two-group comparison analysis. HDAC7 promotes the growth of human and mouse AEL cells both in vitro and in vivo through its non-enzymatic functions. Our study provides experimental evidence that TP53 deficiency and ERG overexpression are necessary and sufficient for the development of AEL and highlights HDAC7 as a promising therapeutic target for this disease.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"38 12","pages":"2614-2627"},"PeriodicalIF":12.8,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02394-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142233498","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}
LeukemiaPub Date : 2024-09-12DOI: 10.1038/s41375-024-02338-z
Bo Liu, Xianli Zhang, Yuanyuan Zhou, Haiping Liu, Zhenkun Wang, Yuting Fu, Qiongdan Gao, Xiang Cheng, Qingyuan Sun, Zhenyu Ju
{"title":"USP4 regulates ribosome biogenesis and protein synthesis for hematopoietic stem cell regeneration and leukemia progression","authors":"Bo Liu, Xianli Zhang, Yuanyuan Zhou, Haiping Liu, Zhenkun Wang, Yuting Fu, Qiongdan Gao, Xiang Cheng, Qingyuan Sun, Zhenyu Ju","doi":"10.1038/s41375-024-02338-z","DOIUrl":"10.1038/s41375-024-02338-z","url":null,"abstract":"Enhanced ribosome biogenesis and protein synthesis are required for cell proliferation. During hematopoietic regeneration, hematopoietic stem cells (HSCs) proliferate rapidly to replenish the hematopoietic system. How HSCs respond and regulate ribosome biogenesis and protein synthesis during regeneration remains unclear. Here, we analyzed the expression of a series of ubiquitin-specific-proteases (USPs) during HSC regeneration. We found USP4 expression is significantly increased in proliferating HSCs. Further functional and mechanistic investigations revealed a crucial regulatory function of USP4 in HSC regeneration and leukemia progression by modulating ribosome biogenesis and protein synthesis. USP4 deubiquitinates and stabilizes PES1 to facilitate ribosome biogenesis and protein synthesis in proliferative HSCs and leukemic cells. Usp4 deletion significantly decreases protein synthesis, proliferation and reconstitution capacity of HSCs. Usp4 inhibition suppresses ribosome biogenesis and proliferation of leukemic cells, and prolongs the survival of AML (Acute myeloid leukemia) mice. These findings provide a new insight into the response mechanism of ribosome biogenesis and protein synthesis in HSCs, and their contribution to leukemia progression.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"38 11","pages":"2466-2478"},"PeriodicalIF":12.8,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41375-024-02338-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142171066","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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