HaematologicaPub Date : 2024-11-07DOI: 10.3324/haematol.2024.285757
Alessandra Ferrajoli, George Follows, Yotvat Marmor, Jack Roos, Naghmana Bajwa, Venkata Madhira, Kenji Nozaki, Paulo Miranda, Dinci Pennap, Krish Patel
{"title":"Cumulative review of hypertension in patients with chronic lymphocytic leukemia treated with acalabrutinib.","authors":"Alessandra Ferrajoli, George Follows, Yotvat Marmor, Jack Roos, Naghmana Bajwa, Venkata Madhira, Kenji Nozaki, Paulo Miranda, Dinci Pennap, Krish Patel","doi":"10.3324/haematol.2024.285757","DOIUrl":"10.3324/haematol.2024.285757","url":null,"abstract":"<p><p>Not available.</p>","PeriodicalId":12964,"journal":{"name":"Haematologica","volume":null,"pages":null},"PeriodicalIF":8.2,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590016","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}
HaematologicaPub Date : 2024-11-07DOI: 10.3324/haematol.2024.285244
Christina Crossette-Thambiah, Anna M Randi, Michael Laffan
{"title":"Von Willebrand Disease and Angiodysplasia: a wider view of pathogenesis in pursuit of therapy.","authors":"Christina Crossette-Thambiah, Anna M Randi, Michael Laffan","doi":"10.3324/haematol.2024.285244","DOIUrl":"10.3324/haematol.2024.285244","url":null,"abstract":"<p><p>Bleeding in the GI tract continues to pose a therapeutic challenge for clinicians in patients with Von Willebrand Disease (VWD). It is associated with significant morbidity and mortality and represents the major unmet need in VWD. Defective angiogenesis in the gut is primarily responsible, resulting in angiodysplastic malformations making bleeding notoriously refractory to standard replacement therapy. A substantial body of evidence now shows that Von Willebrand Factor (VWF) has a role in the regulation of angiogenesis but the mechanisms responsible for the formation of vascular malformations remain incompletely understood. Data from the wider field of vascular malformations may lend insight and point to novel therapeutic approaches. Here we review evidence linking VWF to angiodysplasia, the associated molecular mechanisms and the implications for therapy.</p>","PeriodicalId":12964,"journal":{"name":"Haematologica","volume":null,"pages":null},"PeriodicalIF":8.2,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590151","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}
HaematologicaPub Date : 2024-11-07DOI: 10.3324/haematol.2024.285933
Jessie Zhao, Tiffany Khong, Malgorzata Gorniak, Abir Khaled, Zac McDonald, John Reynolds, Sridurga Mithraprabhu, Nicholas Bingham, Suehli Lim, Daniel Wong, Anna Johnston, Olga Motorna, Nicholas Murphy, Hang Quach, Liqiang Yang, Andrew Spencer
{"title":"Comparison of EasyM, a clonotypic mass spectrometry assay, and EuroFlow minimal residual disease assessment in multiple myeloma.","authors":"Jessie Zhao, Tiffany Khong, Malgorzata Gorniak, Abir Khaled, Zac McDonald, John Reynolds, Sridurga Mithraprabhu, Nicholas Bingham, Suehli Lim, Daniel Wong, Anna Johnston, Olga Motorna, Nicholas Murphy, Hang Quach, Liqiang Yang, Andrew Spencer","doi":"10.3324/haematol.2024.285933","DOIUrl":"10.3324/haematol.2024.285933","url":null,"abstract":"<p><p>Not available.</p>","PeriodicalId":12964,"journal":{"name":"Haematologica","volume":null,"pages":null},"PeriodicalIF":8.2,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142589910","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}
HaematologicaPub Date : 2024-11-07DOI: 10.3324/haematol.2024.286427
Ibrahim Aldoss, Jianying Zhang, Kathryn Shimamoto, Caner Saygin, Marjorie Robbins, Vaibhav Agrawal, Ahmed Aribi, Diren Arda Karaoglu, Hoda Pourhassan, Paul Koller, Haris Ali, Amanda Blackmon, Salman Otoukesh, Karamjeet Sandhu, Brian Ball, Andrew S Artz, Monzr M Al Malki, Amandeep Salhotra, Jose Tinajero, Zhaohui Gu, Ian Lagman, Michelle Velasquez, Jacqueline Dang, Pamela S Becker, Michelle Afkhami, Lucy Ghoda, Wendy Stock, Stephen J Forman, Anthony Stein, Guido Marcucci, Vinod Pullarkat
{"title":"Venetoclax in combination with a pediatric-inspired regimen for the treatment of newly diagnosed adults with Philadelphia chromosome-negative acute lymphoblastic leukemia.","authors":"Ibrahim Aldoss, Jianying Zhang, Kathryn Shimamoto, Caner Saygin, Marjorie Robbins, Vaibhav Agrawal, Ahmed Aribi, Diren Arda Karaoglu, Hoda Pourhassan, Paul Koller, Haris Ali, Amanda Blackmon, Salman Otoukesh, Karamjeet Sandhu, Brian Ball, Andrew S Artz, Monzr M Al Malki, Amandeep Salhotra, Jose Tinajero, Zhaohui Gu, Ian Lagman, Michelle Velasquez, Jacqueline Dang, Pamela S Becker, Michelle Afkhami, Lucy Ghoda, Wendy Stock, Stephen J Forman, Anthony Stein, Guido Marcucci, Vinod Pullarkat","doi":"10.3324/haematol.2024.286427","DOIUrl":"10.3324/haematol.2024.286427","url":null,"abstract":"<p><p>BCL-2 protein overexpression, common in B-cell acute lymphoblastic leukemia (B-ALL), including the Philadelphia (Ph)-like subtype, mediates leukemic cell survival. We treated 24 patients with 14 days of BCL-2 inhibitor, venetoclax, 400 mg daily (dose level 1) during induction and consolidation cycles combined with the CALGB 10403 regimen in newly diagnosed adults with Ph-negative B-ALL. Median age was 31 (range: 18-53) years, 92% were Hispanic, and 12 (50%) patients had Ph-like ALL. No dose limiting toxicity occurred in the phase 1 part. Median times to neutrophil and platelet count recovery were 20 and 21 days from start of induction, respectively. The most common grade ≥3 treatment-related adverse events were leukopenia (96%), neutropenia (83%), anemia (83%), thrombocytopenia (79%), lymphopenia (71%), hyperbilirubinemia (38%), and elevated ALT (33%). One patient with non-Ph-like ALL died from asparaginase-associated pancreatitis, and 23 (96%) patients achieved complete remission (CR) or CR with incomplete count recovery (CRi) following induction with or without extended induction phase. Of 22 patients who started consolidation, 20 (91%) achieved negative minimal residual disease status (MRD-) (.</p>","PeriodicalId":12964,"journal":{"name":"Haematologica","volume":null,"pages":null},"PeriodicalIF":8.2,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590211","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}
HaematologicaPub Date : 2024-11-07DOI: 10.3324/haematol.2024.285905
Shu Chen, Weiwei Qin, Xiaohong Lu, Li Liu, Yinsuo Zheng, Xinhua Lu, Xiaohui Wang, Xiaojuan Zhang, Sha Gong, Suhua Wei, Huiyun Zhang, Hanru Ding, Ranjbarha Seifollah, Jing Li, Haitao Zhang, Di Wu, Olubukola Abiona, Pengcheng He, Rong Zhang, David Wald, Huaiyu Wang
{"title":"Arsenic trioxide versus Realgar-Indigo naturalis formula in non-high-risk acute promyelocytic leukemia: a multicenter, randomized trial.","authors":"Shu Chen, Weiwei Qin, Xiaohong Lu, Li Liu, Yinsuo Zheng, Xinhua Lu, Xiaohui Wang, Xiaojuan Zhang, Sha Gong, Suhua Wei, Huiyun Zhang, Hanru Ding, Ranjbarha Seifollah, Jing Li, Haitao Zhang, Di Wu, Olubukola Abiona, Pengcheng He, Rong Zhang, David Wald, Huaiyu Wang","doi":"10.3324/haematol.2024.285905","DOIUrl":"10.3324/haematol.2024.285905","url":null,"abstract":"<p><p>Realgar-Indigo Naturalis Formula (RIF) is an oral form of arsenic that is effective against acute promyelocytic leukemia (APL). This multicenter, randomized, controlled trial compared the efficacy of all-trans retinoic acid (ATRA) plus RIF with ATRA plus arsenic trioxide (ATO) in a simplified regimen for non-high-risk APL. Following induction therapy with ATRA and ATO, participants were randomly assigned to receive either ATRA plus ATO or ATRA plus RIF both in a 2-week on 2-week off schedule for consolidation therapy. Once achieving molecular complete remission, the regimen was administered for a total of 6 cycles. All of 108 eligible patients achieved hematological complete remission after induction therapy. The median follow-up time was 29 months. The primary endpoint of two-year disease-free survival was 97% in the ATRA-RIF arm and 98% in the ATRA-ATO arm, respectively. (The ATRA-RIF arm was found to be non-inferior to the ATRA-ATO arm, (P < .01), with a percentage difference of -1% (95%CI, -4.8 to 6.9). No deaths have been observed. Most adverse events were moderate. This study confirms the noninferiority of RIF to ATO for non-high-risk APL, while also offering a more favorable regimen schedule for post-remission therapy. (ClinicalTrials gov. Identifier: as NCT02899169).</p>","PeriodicalId":12964,"journal":{"name":"Haematologica","volume":null,"pages":null},"PeriodicalIF":8.2,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142589818","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}
HaematologicaPub Date : 2024-11-07DOI: 10.3324/haematol.2024.285805
Marta Anna Sobas, Amin T Turki, Angela Villaverde Ramiro, Alberto Hernández Sánchez, Javier Martinez Elicegui, Teresa González, Raúl Azibeiro Melchor, María Abáigar, Laura Tur, Daniele Dall'Olio, Eric Sträng, Jesse M Tettero, Gastone Castellani, Axel Benner, Konstanze Döhner, Christian Thiede, Klaus H Metzeler, Torsten Haferlach, Frederik Damm, Rosa Ayala, Joaquín Martínez-López, Ken I Mills, Jorge Sierra, Sören Lehmann, Matteo G Della Porta, Jiri Mayer, Dirk Reinhardt, Rubén Villoria Medina, Renate Schulze-Rath, Martje Barbus, Jesús María Hernández-Rivas, Brian J P Huntly, Gert Ossenkoppele, Hartmut Döhner, Lars Bullinger
{"title":"Outcomes with intensive treatment for acute myeloid leukemia: an analysis of two decades of data from the HARMONY Alliance.","authors":"Marta Anna Sobas, Amin T Turki, Angela Villaverde Ramiro, Alberto Hernández Sánchez, Javier Martinez Elicegui, Teresa González, Raúl Azibeiro Melchor, María Abáigar, Laura Tur, Daniele Dall'Olio, Eric Sträng, Jesse M Tettero, Gastone Castellani, Axel Benner, Konstanze Döhner, Christian Thiede, Klaus H Metzeler, Torsten Haferlach, Frederik Damm, Rosa Ayala, Joaquín Martínez-López, Ken I Mills, Jorge Sierra, Sören Lehmann, Matteo G Della Porta, Jiri Mayer, Dirk Reinhardt, Rubén Villoria Medina, Renate Schulze-Rath, Martje Barbus, Jesús María Hernández-Rivas, Brian J P Huntly, Gert Ossenkoppele, Hartmut Döhner, Lars Bullinger","doi":"10.3324/haematol.2024.285805","DOIUrl":"10.3324/haematol.2024.285805","url":null,"abstract":"<p><p>Since 2017, targeted therapies combined with conventional intensive chemotherapy have started to improve outcome of patients with acute myeloid leukemia (AML). However, even before these innovations outcomes with intensive chemotherapy have improved, which has not yet been extensively studied. Thus, we used a large pan-European multicenter dataset of the HARMONY Alliance to evaluate treatment-time dependent outcomes over two decades. In 5359 AML patients, we compared the impact of intensive induction therapy on outcome over four consecutive 5-year calendar periods from 1997 to 2016. During that time, the 5- year survival of AML patients improved significantly, also across different genetic risk groups. In particular, the 60-day mortality rate has dropped from 13.0% to 4.7% over time. The independent effect of calendar periods on outcome was confirmed in multivariate models. Improvements were documented both for patients.</p>","PeriodicalId":12964,"journal":{"name":"Haematologica","volume":null,"pages":null},"PeriodicalIF":8.2,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590210","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}
HaematologicaPub Date : 2024-11-01DOI: 10.3324/haematol.2023.284332
Marine Baron, Karim Labreche, Marianne Veyri, Nathalie Désiré, Amira Bouzidi, Fatou Seck-Thiam, Frédéric Charlotte, Alice Rousseau, Véronique Morin, Cécilia Nakid-Cordero, Baptiste Abbar, Alberto Picca, Marie Le Cann, Noureddine Balegroune, Nicolas Gauthier, Ioannis Theodorou, Mehdi Touat, Véronique Morel, Franck Bielle, Assia Samri, Agusti Alentorn, Marc Sanson, Damien Roos-Weil, Corinne Haioun, Elsa Poullot, Anne Langlois De Septenville, Frédéric Davi, Amélie Guihot, Pierre-Yves Boelle, Véronique Leblond, Florence Coulet, Jean-Philippe Spano, Sylvain Choquet, Brigitte Autran
{"title":"Epstein-Barr virus and immune status imprint the immunogenomics of non-Hodgkin lymphomas occurring in immune-suppressed environments.","authors":"Marine Baron, Karim Labreche, Marianne Veyri, Nathalie Désiré, Amira Bouzidi, Fatou Seck-Thiam, Frédéric Charlotte, Alice Rousseau, Véronique Morin, Cécilia Nakid-Cordero, Baptiste Abbar, Alberto Picca, Marie Le Cann, Noureddine Balegroune, Nicolas Gauthier, Ioannis Theodorou, Mehdi Touat, Véronique Morel, Franck Bielle, Assia Samri, Agusti Alentorn, Marc Sanson, Damien Roos-Weil, Corinne Haioun, Elsa Poullot, Anne Langlois De Septenville, Frédéric Davi, Amélie Guihot, Pierre-Yves Boelle, Véronique Leblond, Florence Coulet, Jean-Philippe Spano, Sylvain Choquet, Brigitte Autran","doi":"10.3324/haematol.2023.284332","DOIUrl":"10.3324/haematol.2023.284332","url":null,"abstract":"<p><p>Non-Hodgkin lymphomas (NHL) commonly occur in immunodeficient patients, both those infected by human immunodeficiency virus (HIV) and those who have been transplanted, and are often driven by Epstein-Barr virus (EBV) with cerebral localization, raising the question of tumor immunogenicity, a critical issue for treatment responses. We investigated the immunogenomics of 68 lymphoproliferative disorders from 51 immunodeficient (34 post-transplant, 17 HIV+) and 17 immunocompetent patients. Overall, 72% were large B-cell lymphoma and 25% were primary central nervous system lymphoma, while 40% were EBV+. Tumor whole-exome and RNA sequencing, along with a bioinformatics pipeline allowed analysis of tumor mutational burden, tumor landscape and tumor microenvironment and prediction of tumor neoepitopes. Both tumor mutational burden (2.2 vs. 3.4/Mb, P=0.001) and numbers of neoepitopes (40 vs. 200, P=0.00019) were lower in EBV+ than in EBV- NHL, regardless of the immune status. In contrast both EBV and the immune status influenced the tumor mutational profile, with HNRNPF and STAT3 mutations observed exclusively in EBV+ and immunodeficient NHL, respectively. Peripheral blood T-cell responses against tumor neoepitopes were detected in all EBV- cases but in only half of the EBV+ ones, including responses against IgH-derived MHC-class-II restricted neoepitopes. The tumor microenvironment analysis showed higher CD8 T-cell infiltrates in EBV+ versus EBV- NHL, together with a more tolerogenic profile composed of regulatory T cells, type-M2 macrophages and an increased expression of negative immune-regulators. Our results highlight that the immunogenomics of NHL in patients with immunodeficiency primarily relies on the tumor EBV status, while T-cell recognition of tumor- and IgH-specific neoepitopes is conserved in EBV- patients, offering potential opportunities for future T-cell-based immune therapies.</p>","PeriodicalId":12964,"journal":{"name":"Haematologica","volume":null,"pages":null},"PeriodicalIF":8.2,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11532699/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141261250","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":"Decision analysis for transplant candidates with primary myelofibrosis in the ruxolitinib era.","authors":"Yosuke Okada, Hideki Nakasone, Shunto Kawamura, Kosuke Takano, Kazuki Yoshimura, Masaharu Tamaki, Akari Matsuoka, Takuto Ishikawa, Tomohiro Meno, Yuhei Nakamura, Masakatsu Kawamura, Junko Takeshita, Nozomu Yoshino, Yukiko Misaki, Machiko Kusuda, Aki Tanihara, Shun-Ichi Kimura, Shinichi Kako, Yoshinobu Kanda","doi":"10.3324/haematol.2024.285256","DOIUrl":"10.3324/haematol.2024.285256","url":null,"abstract":"<p><p>The recent progress with ruxolitinib treatment might improve quality of life as well as overall survival in patients with primary myelofibrosis. Therefore, the optimal timing of allogeneic hematopoietic cell transplantation (HCT) in the ruxolitinib era remains to be elucidated. We constructed a Markov model to simulate the 5-year clinical course of transplant candidates with primary myelofibrosis and compared outcomes between those who underwent immediate HCT and those whose HCT was delayed until after ruxolitinib failure. Since older age was associated with an increased risk of mortality, we analyzed patients aged <60 and ≥60 years separately in subgroup analyses. Life expectancy was consistently longer in the groups undergoing delayed HCT after ruxolitinib failure regardless of the patients' age. Regarding quality-adjusted life years, a baseline analysis showed that immediate HCT was inferior to delayed HCT after ruxolitinib failure (2.19 vs. 2.26). In patients aged <60 years, immediate HCT was equivalent to delayed HCT after ruxolitinib failure (2.31 vs. 2.31). On the other hand, in patients aged ≥60 years, immediate HCT was inferior to delayed HCT after ruxolitinib failure (1.98 vs. 2.21). A one-way sensitivity analysis showed that the utility of being alive without chronic graft-versus-host disease after immediate HCT was the most influential parameter for quality-adjusted life years, and that a value higher than 0.836 could reverse the superiority of delayed HCT after ruxolitinib failure. As a result, delayed HCT after ruxolitinib failure is expected to be superior to immediate HCT, especially in patients aged ≥60 years, and is also a promising strategy even in those aged <60 years.</p>","PeriodicalId":12964,"journal":{"name":"Haematologica","volume":null,"pages":null},"PeriodicalIF":8.2,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11532692/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141426734","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}
HaematologicaPub Date : 2024-11-01DOI: 10.3324/haematol.2024.285972
Robert Peter Gale, Giovanni Barosi
{"title":"The Gordian knot: ruxolitinib or transplants for high-risk myelofibrosis.","authors":"Robert Peter Gale, Giovanni Barosi","doi":"10.3324/haematol.2024.285972","DOIUrl":"10.3324/haematol.2024.285972","url":null,"abstract":"","PeriodicalId":12964,"journal":{"name":"Haematologica","volume":null,"pages":null},"PeriodicalIF":8.2,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11532677/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141579544","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":"A novel role of AURKA kinase in erythroblast enucleation.","authors":"Yuanlin Xu, Peijun Jia, Yating Li, Huan Zhang, Jingxin Zhang, Wanxin Li, Yazhe Zhen, Yan Li, Jiaming Cao, Tingting Zheng, Yihan Wang, Yanyan Liu, Xiuli An, Shijie Zhang","doi":"10.3324/haematol.2023.284873","DOIUrl":"10.3324/haematol.2023.284873","url":null,"abstract":"<p><p>Generation of mammalian red blood cells requires the expulsion of polarized nuclei late in terminal erythroid differentiation. However, the mechanisms by which spherical erythroblasts determine the direction of nuclear polarization and maintain asymmetry during nuclear expulsion are poorly understood. Given the analogy of erythroblast enucleation to asymmetric cell division and the key role of Aurora kinases in mitosis, we sought to investigate the function of Aurora kinases in erythroblast enucleation. We found that AURKA (Aurora kinase A) is abundantly expressed in orthochromatic erythroblasts. Intriguingly, high-resolution confocal microscopy analyses revealed that AURKA co-localized with the centrosome on the side of the nucleus opposite its membrane contact point during polarization and subsequently translocated to the anterior end of the protrusive nucleus upon nuclear exit. Mechanistically, AURKA regulated centrosome maturation and localization via interaction with γ-tubulin to provide polarization orientation for the nucleus. Furthermore, we identified ECT2 (epithelial cell transforming 2), a guanine nucleotide exchange factor, as a new interacting protein and ubiquitination substrate of AURKA. After forming the nuclear protrusion, AURKA translocated to the anterior end of the protrusive nucleus to directly degrade ECT2, which is partly dependent on kinase activity of AURKA. Moreover, knockdown of ECT2 rescued impaired enucleation caused by AURKA inhibition. Our findings have uncovered a previously unrecognized role of Aurora kinases in the establishment of nuclear polarization and eventual nuclear extrusion and provide new mechanistic insights into erythroblast enucleation.</p>","PeriodicalId":12964,"journal":{"name":"Haematologica","volume":null,"pages":null},"PeriodicalIF":8.2,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11532702/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141497895","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}