Article
Biochemistry & Molecular Biology
Matteo Zurlo, Cristina Zuccato, Lucia Carmela Cosenza, Jessica Gasparello, Maria Rita Gamberini, Alice Stievano, Monica Fortini, Marco Prosdocimi, Alessia Finotti, Roberto Gambari
Summary: This research demonstrates that sirolimus treatment can decrease autophagy-associated p62 protein, increase ULK-1 expression, and reduce excessive alpha-globin content in erythroid precursors. These findings suggest that autophagy, ULK-1 expression, and alpha-globin chain reduction should be considered important endpoints in sirolimus-based clinical trials for beta-thalassemias.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Chemistry, Medicinal
Rayan Bou-Fakhredin, Lucia De Franceschi, Irene Motta, Maria Domenica Cappellini, Ali T. Taher
Summary: Better understanding of gamma-globin regulation has led to advancements in pharmacologic agents for HbF induction and identification of novel HbF-inducing strategies.
Article
Medicine, General & Internal
Woratree Kaewsakulthong, Thunwarat Suriyun, Sukanya Chumchuen, Usanarat Anurathapan, Suradej Hongeng, Suthat Fucharoen, Orapan Sripichai
Summary: The pathophysiological properties of erythroid cells derived from different types of thalassemia were investigated. It was found that thalassemia cells exhibited accelerated expansion and limited differentiation. The severity of erythroid maturation arrest varied among different types of thalassemia. The induction of HSP70 transcripts was robust in thalassemia erythroid cells. Increased cell death was observed in homozygous beta(0)-thalassemia erythroblasts and associated with specific gene expression regulation.
JOURNAL OF CLINICAL MEDICINE
(2022)
Review
Medicine, General & Internal
Maria Sanchez-Villalobos, Miguel Blanquer, Jose M. Moraleda, Eduardo J. Salido, Ana B. Perez-Oliva
Summary: In this article, the main pathophysiological pathways involved in beta-thalassemia are reviewed, with a focus on the development of new therapies directed at new therapeutic targets.
FRONTIERS IN MEDICINE
(2022)
Review
Biology
Roberto Gambari, Cristina Zuccato, Lucia Carmela Cosenza, Matteo Zurlo, Jessica Gasparello, Alessia Finotti, Maria Rita Gamberini, Marco Prosdocimi
Summary: This review article presents the fascinating story of sirolimus (rapamycin), a drug known to induce fetal hemoglobin and of great interest for the treatment of beta-thalassemia. It discusses the discovery of rapamycin, its antimicrobial properties, its inhibition of tumor cell growth, and its potential immunosuppressive effects. The article also highlights recent findings regarding rapamycin's ability to induce fetal hemoglobin, paving the way for clinical trials on beta-thalassemia patients.
Review
Medicine, General & Internal
Fangfang Wang, Ling Ling, Duonan Yu
Summary: Beta-thalassemia is a lethal inherited disease that requires regular blood transfusions, but other interventions like iron chelation, stem cell transplantation, and gene therapy have improved quality of life. Certain microRNAs play important roles in regulating globin expression and can potentially serve as biomarkers for diagnosing and predicting outcomes of beta-thalassemia.
AMERICAN JOURNAL OF THE MEDICAL SCIENCES
(2021)
Article
Medicine, Research & Experimental
Hanan Kamel M. Saad, Wan Rohani Wan Taib, Imilia Ismail, Muhammad Farid Johan, Abdullah Saleh Al-Wajeeh, Hamid Ali Nagi Al-Jamal
Summary: The study revealed that HEPC levels were significantly decreased while FPN1 levels were markedly increased in HbE/beta-thalassemia patients and their parents, along with elevated serum ferritin levels. This suggests that decreased HEPC function as a negative regulator of FPN1 may result in iron overload in these patients. Assessing HEPC and FPN1 gene expression could be a useful tool to evaluate the risk of iron toxicity and may serve as a therapeutic target for managing iron burden in individuals with HbE/beta-thalassemia.
EXPERIMENTAL AND THERAPEUTIC MEDICINE
(2021)
Article
Multidisciplinary Sciences
M. N. Gnanapragasam, A. Planutis, J. A. Glassberg, J. J. Bieker
Summary: The onset of erythropoiesis is regulated by various factors, including the zinc finger transcription factor KLF1. A conserved enhancer element in KLF1 intron 1 is important for optimal KLF1 levels during erythropoiesis. This site exhibits cell-type specificity and binds multiple transcription factors. Editing this region reduces KLF1 expression, but downstream effects vary, suggesting a buffered state that maintains overall KLF1 activity.
SCIENTIFIC REPORTS
(2023)
Article
Genetics & Heredity
Shuang-Ping Ma, Xu-Xia Gao, Guo-Qiang Zhou, Hao-Kun Zhang, Jing-Min Yang, Wen-Juan Wang, Xian-Min Song, Hong-Yan Chen, Da-Ru Lu
Summary: Reactivation of fetal hemoglobin by editing the B-cell lymphoma/leukemia 11A (BCL11A) erythroid enhancer is an effective gene therapy for beta-thalassemia. In this study, it was found that the transfection efficiency of CD34(+) hematopoietic stem/progenitor cells (HSPCs) was negatively correlated with plasmid length and greatly affected by plasmid linearization. The use of minicircles (MC) DNA without plasmid backbone sequences was shown to be a better method for transgene expression both in vitro and in vivo. The developed MC DNA vector provided a safe and efficient approach for delivering the Cas9 cassette and reactivating gamma-globin expression to ameliorate symptoms of beta-thalassemia.
Article
Biochemistry & Molecular Biology
Gaijing Han, Cong Cao, Xi Yang, Guo-Wei Zhao, Xin-Jun Hu, Dong-Lin Yu, Rui-Feng Yang, Ke Yang, Ying-Ying Zhang, Wen-Tian Wang, Xiu-Zhen Liu, Peng Xu, Xue-Hui Liu, Ping Chen, Zheng Xue, De-Pei Liu, Xiang Lv
Summary: In beta-thalassemia, AHSP plays a crucial role in regulating redox balance by escorting free alpha-globin and inhibiting ROS production. Nrf2 and its agonist tBHQ can stimulate AHSP expression, and MafG facilitates AHSP gene activation through Nrf2. Excessive alpha-globin and ROS production can be partially alleviated by reducing AHSP level.
Article
Hematology
Durga Devi Sundaresan, Jasbir Kaur Hira, Sanjeev Chhabra, Amita Trehan, Alka Rani Khadwal, Pankaj Malhotra, Prashant Sharma, Reena Das
Summary: This study reports on the rare combination of beta-thalassemia with supernumerary alpha-globin genes. Patients with this combination showed clinical features such as anemia, jaundice, splenomegaly, and hepatomegaly. Symptomatic patients had significantly lower hemoglobin levels and higher fetal hemoglobin levels compared to asymptomatic ones.
EUROPEAN JOURNAL OF HAEMATOLOGY
(2023)
Letter
Oncology
Huiqiao Chen, Zixuan Wang, Shanhe Yu, Xiao Han, Yun Deng, Fuhui Wang, Yi Chen, Xiaohui Liu, Jun Zhou, Jun Zhu, Hao Yuan
Summary: The study identified TRIAC, a bioactive thyroid hormone metabolite, as a potent inducer of zeta-globin expression, which could potentially be a new therapeutic option for patients with severe alpha-thalassemia or sickle-cell disease. The researchers also found that THRA deficiency abolished the zeta-globin-inducing effect of TRIAC, suggesting a direct regulatory role of THRA in zeta-globin expression.
JOURNAL OF HEMATOLOGY & ONCOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Cristina Zuccato, Lucia Carmela Cosenza, Matteo Zurlo, Ilaria Lampronti, Monica Borgatti, Chiara Scapoli, Roberto Gambari, Alessia Finotti
Summary: This study analyzed Cinchona alkaloids as natural HbF-inducing agents in human erythroid cells, and found that cinchonidine and quinidine are potent inducers of gamma-globin mRNA and HbF in erythroid progenitor cells isolated from beta-thalassemia patients. These compounds may be considered for the development of pre-clinical approaches for therapeutic protocols of beta-thalassemia.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Multidisciplinary Sciences
Stacy Colaco, Roshan Colah, Anita Nadkarni
Summary: Increased HbA(2) levels are typical in beta-thalassemia carriers, but some carriers have borderline HbA(2) levels. This study identified the determinants of borderline HbA(2) levels in 205 individuals and found that genetic factors play a role in this condition.
SCIENTIFIC REPORTS
(2022)
Article
Biochemistry & Molecular Biology
Rossella Daidone, Antonella Carollo, Maria Patrizia Perricone, Renato Messina, Carmela Rita Balistreri
Summary: Thalassemia is a Mendelian inherited blood disease caused by gene mutations, and it is a major health problem in Mediterranean populations. This study investigated the distribution of gene defects in the Trapani province population and found high frequencies of certain mutations in the alpha and beta globin genes. The findings highlight the importance of carrier screening and prenatal diagnosis, as well as the need for public awareness campaigns and screening programs.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Hematology
Asiri Ediriwickrema, Andrew J. Gentles, Ravindra Majeti
Summary: The era of genomic medicine has advanced AML research, but AML remains a lethal cancer due to its complex and plastic cellular architecture. Single-cell genomics has the potential to address the challenges posed by cellular heterogeneity and provide unique opportunities in AML research.
Letter
Hematology
Maximilian Stahl, Omar Abdel-Wahab, Andrew H. Wei, Michael R. Savona, Mina L. Xu, Zhuoer Xie, Justin Taylor, Daniel Starczynowski, Guillermo F. Sanz, David A. Sallman, Valeria Santini, Gail J. Roboz, Mrinal M. Patnaik, Eric Padron, Olatoyosi Odenike, Aziz Nazha, Stephen D. Nimer, Ravindra Majeti, Richard F. Little, Steven Gore, Alan F. List, Vijay Kutchroo, Rami S. Komrokji, Tae Kon Kim, Nina Kim, Christopher S. Hourigan, Robert P. Hasserjian, Stephanie Halene, Elizabeth A. Griffiths, Peter L. Greenberg, Maria Figueroa, Pierre Fenaux, Fabio Efficace, Amy E. DeZern, Matteo G. Della Porta, Naval G. Daver, Jane E. Churpek, Hetty E. Carraway, Andrew M. Brunner, Uma Borate, John M. Bennett, Rafael Bejar, Jacqueline Boultwood, Sanam Loghavi, Jan Philipp Bewersdorf, Uwe Platzbecker, David P. Steensma, Mikkael A. Sekeres, Rena J. Buckstein, Amer M. Zeidan
Article
Virology
Frederik Holm Rothemejer, Nanna Pi Lauritsen, Anna Karina Juhl, Mariane Hogsbjerg Schleimann, Saskia Konig, Ole Schmeltz Sogaard, Rasmus O. Bak, Martin Tolstrup
Summary: This study demonstrates the development of HIV-resistant CAR T cells using CRISPR/Cas9 targeted integration of a CAR cassette into the CCR5 locus. The anti-HIV CAR T cells showed specific lysis of HIV-infected cells in vitro and transiently limited HIV infection in a PBMC humanized mouse model of HIV infection.
Letter
Hematology
Yannis Hara, Viktor T. Lemgart, Nis Halland, Kiana Mahdaviani, Jean-Antoine Ribeil, Samuel Lessard, Alexandra Hicks, David R. Light
Article
Oncology
Eileen Wedge, Ulvi Ahmadov, Thomas B. Hansen, Zongliang Gao, Morten Tulstrup, Christophe Come, Sridhar Nonavinkere Srivatsan, Tanzir Ahmed, Jakob S. Jespersen, Balthasar C. Schlotmann, Claudia Schollkopf, Klas Raaschou-Jensen, Niels Odum, Jorgen Kjems, Rasmus O. Bak, Matthew J. Walter, Kirsten Gronbaek, Lasse S. Kristensen
Summary: Mutations in the U2AF1 gene are associated with a higher occurrence of myelodysplastic neoplasms (MDS) and a worse prognosis, but the exact molecular mechanisms are not fully understood. This study found that U2AF1 mutations may impact circRNA production, leading to increased cancer development. Increased circRNA expression levels were observed in cells and patient samples with U2AF1 mutations, suggesting a potential role of circRNA as a biomarker and therapeutic target in MDS.
Article
Multidisciplinary Sciences
Mingyu He, Kate Roussak, Feiyang Ma, Nicholas Borcherding, Vince Garin, Mike White, Charles Schutt, Trine I. Jensen, Yun Zhao, Courtney A. Iberg, Kairav Shah, Himanshi Bhatia, Daniel Korenfeld, Sabrina Dinkel, Judah Gray, Alina Ulezko Antonova, Stephen Ferris, David Donermeyer, Cecilia Lindestam Arlehamn, Matthew M. Gubin, Jingqin Luo, Laurent Gorvel, Matteo Pellegrini, Alessandro Sette, Thomas Tung, Rasmus Bak, Robert L. Modlin, Ryan C. Fields, Robert D. Schreiber, Paul M. Allen, Eynav Klechevsky
Summary: The reduction of human CD1c+CD5+ dendritic cells (DCs) in melanoma-affected lymph nodes and the correlation between CD5 expression on DCs and patient survival have been observed. Activating CD5 on DCs enhances T cell priming and improves survival after immune checkpoint blockade (ICB) therapy. CD5+ DCs are essential for optimal ICB therapy.
Article
Oncology
Miles H. Linde, Amy C. Fan, Thomas Koehnke, Aaron C. Trotman-Grant, Sarah F. Gurev, Paul Phan, Feifei Zhao, Naomi L. Haddock, Kevin A. Nuno, Eric J. Gars, Melissa Stafford, Payton L. Marshall, Christopher G. Dove, Ian L. Linde, Niklas Landberg, Lindsay P. Miller, Robbie G. Majzner, Tian Yi Zhang, Ravindra Majeti
Summary: Therapeutic cancer vaccination aims to activate tumor-reactive T cells for recognizing tumor-associated antigens (TAA) and eliminating malignant cells. The study proposes a cancer vaccination approach using myeloid-lineage reprogramming to convert cancer cells into tumor-reprogrammed antigen-presenting cells (TR-APC). The results demonstrate the effectiveness of TR-APCs in inducing clonal expansion of cancer-specific T cells, establishing immune memory, and promoting leukemia eradication.
Article
Biology
Francisco X. Galdos, Carissa Lee, Soah Lee, Sharon Paige, William Goodyer, Sidra Xu, Tahmina Samad, Gabriela V. Escobar, Adrija Darsha, Aimee Beck, Rasmus O. Bak, Matthew H. Porteus, Sean M. Wu
Summary: The study provides a detailed characterization of human-induced pluripotent stem cells (hiPSCs) undergoing cardiac differentiation using genetic lineage tracing and single-cell transcriptomics. By comparing data from different model systems, they confirmed the predominance of left ventricular cardiomyocytes in hiPSC-derived progeny.
Article
Medicine, Research & Experimental
Nanna S. Mikkelsen, Sabina S. Hernandez, Trine I. Jensen, Jessica L. Schneller, Rasmus O. Bak
Summary: This article investigates a CRISPRa-induced enrichment strategy for transgenic cells, which can achieve higher editing efficiency in primary cells and promote the development of gene and cellular therapies. The strategy was successfully applied in human T cells and CD34+ hematopoietic stem and progenitor cells, resulting in a 2.5-fold enrichment of CAR T cells and improved cytotoxicity.
MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT
(2023)
Article
Oncology
Andriana G. Kotini, Saul Carcamo, Nataly Cruz-Rodriguez, Malgorzata Olszewska, Tiansu Wang, Deniz Demircioglu, Chan-Jung Chang, Elsa Bernard, Mark P. Chao, Ravindra Majeti, Hanzhi Luo, Michael G. Kharas, Dan Hasson, Eirini P. Papapetrou
Summary: A reprogramming method tailored to cancer cells was developed to generate iPSCs from AML patients, and the resulting iPSC-derived leukemias faithfully mimicked the primary patient-matched xenografts.
BLOOD CANCER DISCOVERY
(2023)
Article
Biochemistry & Molecular Biology
Fanghui Ren, Ryo Narita, Ahmad S. Rashidi, Stefanie Fruhwurth, Zongliang Gao, Rasmus O. Bak, Martin K. Thomsen, Georges M. G. M. Verjans, Line S. Reinert, Soren R. Paludan
Summary: Neurotropic viruses such as herpes simplex virus (HSV) can infect neurons and cause severe diseases. HSV-induced neuronal cell death is mediated by gasdermin E (GSDME) and involves endoplasmic reticulum stress, caspase activation, and mitochondria-dependent apoptosis. The necrotic neurons release alarmins, triggering inflammatory responses in microglia.
Article
Oncology
Signe Neldeborg, Johannes Frasez Soerensen, Charlotte Thornild Moller, Marie Bill, Zongliang Gao, Rasmus O. Bak, Kasper Holm, Boe Sorensen, Mette Nyegaard, Yonglun Luo, Peter Hokland, Magnus Stougaard, Maja Ludvigsen, Christian Kanstrup Holm
Summary: Oncogenic fusion drivers in hematological cancers can be targeted using a new dual intron-targeting CRISPR-Cas9 treatment strategy. This strategy can efficiently disrupt fusion genes without requiring precise knowledge of the breakpoints in t(8;21) AML. In vitro and in vivo experiments showed significant reduction in cell growth and tumor growth in response to disruption of RUNX1-RUNX1T1. These findings were confirmed in primary cells from an AML patient.
Review
Medicine, Research & Experimental
Sofie R. Dorset, Rasmus O. Bak
Summary: Ex vivo gene editing in hematopoietic stem and progenitor cells holds promise for treating monogenic blood disorders, but challenges remain regarding DNA damage response and p53 activation, which need further research for safe and efficient clinical implementation of gene editing.
MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT
(2023)
Review
Cell Biology
Nanna S. Mikkelsen, Rasmus O. Bak
Summary: Genome editing technologies have great potential for various applications, but they often suffer from low editing efficiencies. Enrichment strategies can help improve these technologies and their applications in research and therapy.
JOURNAL OF BIOMEDICAL SCIENCE
(2023)
Article
Medicine, Research & Experimental
Amy C. Fan, Yusuke Nakauchi, Lawrence Bai, Armon Azizi, Kevin A. Nuno, Feifei Zhao, Thomas Koehnke, Daiki Karigane, David Cruz-Hernandez, Andreas Reinisch, Purvesh Khatri, Ravindra Majeti
Summary: This study reveals the dependence of RUNX1-mutant leukemias on IL-3/JAK/STAT signaling, which can potentially be targeted using JAK inhibitors.
JOURNAL OF CLINICAL INVESTIGATION
(2023)
