Article
Physiology
Beren Karaosmanoglu, M. Alper Kursunel, Duygu Uckan Cetinkaya, Fatma Gumruk, Gunes Esendagli, Sule Unal, Ekim Z. Taskiran
Summary: Diamond Blackfan Anemia (DBA) is an inherited bone marrow failure syndrome caused mainly by mutations in ribosomal protein genes. Studies have shown that DBA patients have distinct transcriptomic profiles in certain bone marrow cells, particularly in proerythroblasts, indicating functional impairment in erythroid differentiation. Additionally, patients with mutations in RPS19 and CECR1 may share common transcriptomic signatures, suggesting a potential role of inflammatory bone marrow niche in DBA pathogenesis.
FRONTIERS IN PHYSIOLOGY
(2021)
Article
Hematology
Lei Yu, Philippe Lemay, Alexander Ludlow, Marie-Claude Guyot, Morgan Jones, Fatma F. Mohamed, Ghazi-Abdullah Saroya, Christopher Panaretos, Emily Schneider, Yu Wang, Greggory Myers, Rami Khoriaty, Qing Li, Renny Franceschi, James Douglas Engel, Vesa Kaartinen, Thomas L. Rothstein, Monica J. Justice, Zoha Kibar, Sharon A. Singh
Summary: Ribosome dysfunction is associated with various abnormal developmental and disease states in humans. The study identified a novel ENU mouse mutant with growth and skeletal defects, cardiac malformations, and increased mortality, caused by an intronic Rpl5 mutation leading to decreased ribosome generation and erythroid maturation delay. This mutant mouse model may be useful for studying the factors influencing variable penetrance observed in DBA.
Article
Genetics & Heredity
Ke An, Jing-Bo Zhou, Yao Xiong, Wei Han, Tao Wang, Zhi-Qiang Ye, Yun-Dong Wu
Summary: This study comprehensively investigated the structural basis of DBA mutations of RPS19 using computational methods, revealing how these mutations destabilize RPS19 or disrupt RPS19-RNA interaction to contribute to the pathogenesis of DBA. Additionally, a machine-learning model was trained to predict the pathogenicity of RPS19 mutations, laying a foundation for understanding the pathogenesis of DBA from a structural perspective.
FRONTIERS IN GENETICS
(2021)
Article
Genetics & Heredity
Noemy Piantanida, Marta La Vecchia, Marika Sculco, Maria Talmon, Gioele Palattella, Ryo Kurita, Yukio Nakamura, Antonella Ellena Ronchi, Irma Dianzani, Steven R. Ellis, Luigia Grazia Fresu, Anna Aspesi
Summary: In this study, we characterized the phenotype of RPS26-deficiency in a human erythroid progenitor cell line and demonstrated that these cells can be used as a model system to study aspects of Diamond Blackfan anemia pathophysiology.
FRONTIERS IN GENETICS
(2022)
Review
Biochemistry & Molecular Biology
Jeanne Rakotopare, Franck Toledo, Alfonso Baldi
Summary: Studies on both animal models and humans have revealed that mutations affecting p53 activity can lead to features of certain bone marrow failure syndromes, including dyskeratosis congenita, Diamond-Blackfan anemia, and Fanconi anemia. p53 regulates multiple genes related to these syndromes, forming a positive feedback loop.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Hematology
Pedro Gonzalez-Menendez, Ira Phadke, Meagan E. Olive, Axel Joly, Julien Papoin, Hongxia Yan, Jeremy Galtier, Jessica Platon, Sun Woo Sophie Kang, Kathy L. McGraw, Marie Daumur, Marie Pouzolles, Taisuke Kondo, Stephanie Boireau, Franciane Paul, David J. Young, Sylvain Lamure, Raghavendra G. Mirmira, Anupama Narla, Guillaume Cartron, Cynthia E. Dunbar, Myriam Boyer-Clavel, Natalie Porat-Shliom, Valerie Dardalhon, Valderie S. Zimmermann, Marc Sitbon, Thomas E. Dever, Narla Mohandas, Lydie Da Costa, Namrata D. Udeshi, Lionel Blanc, Sandrina Kinet, Naomi Taylor
Summary: This study demonstrates that metabolic programs play a role in the fate of hematopoietic stem and progenitor cells (HSPCs), and the metabolic regulation of protein synthesis controls HSPC differentiation. The researchers found that the uptake of arginine and its catabolism to spermidine control erythroid specification of HSPCs through the activation of eIF5A. The study also reveals the importance of mitochondrial translation and oxidative phosphorylation in eIF5A-regulated erythropoiesis. Rating: 8/10
Article
Hematology
Raymond T. Doty, Xiaowei Yan, Changting Meng, Christopher Lausted, Qiang Tian, Janis L. Abkowitz
Summary: This study fully characterized Rpl11 haploinsufficient mice as a model of DBA, showing similarities to the macrocytic anemia seen in DBA patients. The researchers found that heme excess and toxicity were the primary drivers of this anemia, and identified pathways associated with erythroid differentiation impairment. These findings suggest that Rpl11 haploinsufficient mice can be used as a valuable model to study DBA pathogenesis and test novel therapies.
EXPERIMENTAL HEMATOLOGY
(2021)
Article
Cell Biology
Husam Qanash, Yongqin Li, Richard H. Smith, Kaari Linask, Sara Young-Baird, Waleed Hakami, Keyvan Keyvanfar, John S. Choy, Jizhong Zou, Andre Larochelle
Summary: Diamond Blackfan Anemia (DBA) is a congenital macrocytic anemia associated with ribosomal protein haploinsufficiency. The FDA-approved drug eltrombopag shows promise in improving anemia in DBA patients by restricting the labile iron pool derived from excessive free heme.
Article
Biochemistry & Molecular Biology
Derek A. Franklin, Shijie Liu, Aiwen Jin, Pengfei Cui, Zengli Guo, Kyle C. Arend, Nathaniel J. Moorman, Shenghui He, Gang Greg Wang, Yisong Y. Wan, Yanping Zhang
Summary: Recent discovery of the RP-MDM2-p53 signaling pathway implicates the role of p53 in ribosomopathies. Conditional RPL11 deletion in mice results in embryonic lethality or acute anemia depending on the stage of deletion. Mechanistically, RPL11 haploinsufficiency activates p53, impeding erythroid precursor differentiation and causing insufficient red blood cell development. Reducing p53 dosage or blocking the RP-MDM2-p53 pathway rescues the anemia phenotype in mice. These findings highlight the critical role of the RP-MDM2-p53 pathway in maintaining RP homeostasis and the molecular basis for RP deficiency-associated anemia.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2023)
Article
Medicine, Research & Experimental
Senthil Velan Bhoopalan, Jonathan S. Yen, Thiyagaraj Mayuranathan, Kalin D. Mayberry, Yu Yao, Maria Angeles Lillo Osuna, Yoonjeong Jang, Janaka S. S. Liyanage, Lionel Blanc, Steven R. Ellis, Marcin W. Wlodarski, Mitchell J. Weiss
Summary: Diamond-Blackfan anemia (DBA) is a genetic blood disease caused by heterozygous loss-of-function mutations in ribosomal protein genes, resulting in hypoplastic anemia and later multilineage cytopenias. A tractable experimental model of DBA was created through genome editing of human HSPCs, revealing associated hematopoietic stem cell defects in the disease.
Article
Pathology
Yuko Fukui, Satoru Hayano, Noriaki Kawanabe, Ziyi Wang, Akira Shimada, Megumu K. Saito, Isao Asaka, Hiroshi Kamioka
Summary: Diamond-Blackfan anemia (DBA) is a genetic disorder characterized by erythroid aplasia and various physical abnormalities due to mutations in ribosomal protein genes. RPL5 haploinsufficiency specifically induces p53-mediated apoptosis in chondrocytes through MDM2 inhibition, leading to the physical abnormalities seen in DBA patients.
PATHOLOGY INTERNATIONAL
(2021)
Article
Oncology
Daria Fedorova, Galina Ovsyannikova, Maria Kurnikova, Anna Pavlova, Tatiana Konyukhova, Alexey Pshonkin, Nataliya Smetanina
Summary: This study reports two patients with a DBA-like phenotype who have germline de novo variants in the TP53 gene. Both patients became transfusion independent after L-leucine therapy. Therefore, the possible role of TP53 variants should be considered in patients with a DBA-like phenotype without mutations in RP genes.
PEDIATRIC BLOOD & CANCER
(2022)
Article
Biochemistry & Molecular Biology
Maria Sona Jerome, Dechamma Pandyanda Nanjappa, Anirban Chakraborty, Sanjiban Chakrabarty
Summary: Ribosomopathies are rare congenital disorders caused by genetic variations in ribosome-related proteins, resulting in defective ribosome biogenesis. This leads to nucleolar stress response, impaired protein synthesis, and tissue-specific phenotypes. In addition, defects in mitochondrial ribosome biogenesis affect multiple organs. Deregulated ribosomal function is also observed in certain human malignancies. This article highlights the clinical conditions, affected genes, implicated pathways, and current treatment strategies for these disorders.
Review
Oncology
Senthil Velan Bhoopalan, Shruthi Suryaprakash, Akshay Sharma, Marcin W. Wlodarski
Summary: Diamond-Blackfan anemia is a common genetic cause of bone marrow failure in children, characterized by anemia and bone marrow hypoplasia. It is associated with congenital anomalies, immunodeficiency, and increased risk of malignancies. Corticosteroids provide temporary relief for anemia, but most patients require lifelong blood transfusions. Allogeneic hematopoietic cell transplantation is a potential curative option, but with significant risks. Autologous genetic therapies are being developed to address the lack of suitable donors.
FRONTIERS IN ONCOLOGY
(2023)
Article
Pediatrics
Nicole Vogel, Markus Schmugge, Raffaele Renella, Nicolas Waespe, Heinz Hengartner
Summary: Diamond-Blackfan anemia (DBA) is a rare genetic disorder caused by mutations in ribosomal subunit genes, leading to macrocytic anemia and congenital malformations. A retrospective study of 17 pediatric DBA patients in Switzerland revealed a wide range of clinical presentations and treatment needs, with patients carrying RPL mutations showing more physical malformations and milder anemia compared to RPS mutation carriers.
EUROPEAN JOURNAL OF PEDIATRICS
(2021)
Article
Neurosciences
Kelly C. Bishop, Sehba Husain-Krautter, Jonathan D. Ketcham, Nicolai Kuminoff, Corbett Schimming
Summary: The study investigates the long-term effects of air pollution on dementia by analyzing individual-level secondary data using instrumental variable (IV) methods. It discusses the importance of overcoming biases from measurement errors and unmeasured variables through IV estimation. By linking air-quality data with Medicare claims data, the study illustrates the use of secondary data to document associations and presents findings suggesting that PM2.5's effects on dementia are larger than non-causal associations.
JOURNAL OF ALZHEIMERS DISEASE
(2021)
Article
Hematology
Yu Wang, Lei Yu, James Douglas Engel, Sharon A. Singh
Summary: Interest in the role of epigenetic mechanisms in human biology has grown significantly in recent decades, with a particular focus on chromatin-modifying enzymes and coregulator complexes in erythropoiesis. These studies have laid the groundwork for developing novel treatments, such as manipulating epigenetic enzymes to treat red cell diseases like sickle cell disease and beta-thalassemias. Other potential applications include redirecting hematopoietic commitment decisions for bone marrow failure syndromes.
SEMINARS IN HEMATOLOGY
(2021)
Article
Hematology
Lixiang Chen, Jie Wang, Jing Liu, Hua Wang, Christopher D. Hillyer, Lionel Blanc, Xiuli An, Narla Mohandas
Summary: The study on postnatal erythropoiesis in mice showed that the liver and spleen sustain active erythropoietic activity for a period after birth, before the bone marrow becomes the predominant site of erythropoiesis in adulthood. Changes in red cell parameters reflected these postnatal dynamic changes, with red cell numbers, hemoglobin concentration, and hematocrit increasing while reticulocyte counts decrease during the first few weeks of life. Our findings highlight the developmental changes in murine erythropoiesis postnatally and their significance for interpreting results from murine models of normal and disordered erythropoiesis.
Article
Health Care Sciences & Services
Madison Irwin, William Gunther, Patricia Keefer, D'Anna Saul, Sharon A. Singh, Jennifer Wright, Michael A. Smith
JOURNAL OF PAIN AND SYMPTOM MANAGEMENT
(2021)
Article
Hematology
Lei Yu, Greggory Myers, Chia-Jui Ku, Emily Schneider, Yu Wang, Sharon A. Singh, Natee Jearawiriyapaisarn, Andrew White, Takashi Moriguchi, Rami Khoriaty, Masayuki Yamamoto, Michael G. Rosenfeld, Julien Pedron, John H. Bushweller, Kim-Chew Lim, James Douglas Engel
Summary: Studies have shown that LSD1 promotes erythropoiesis by repressing myeloid cell fate in adult erythroid progenitors, and inhibiting the myeloid-differentiation pathway can reverse the lineage switch induced by LSD1 inactivation.
Letter
Oncology
Nour K. Kadouh, Stacy Lang, Mark Shamoun, Eric L. Scott, Sharon A. Singh, Michael A. Smith
PEDIATRIC BLOOD & CANCER
(2022)
Article
Behavioral Sciences
Sehba Husain-Krautter, Jihui Lee, Duncan Vos, Juan A. Gallego, Anil K. Malhotra, Thomas L. Rothstein
Summary: Autoantibodies play a role in the etiology of some neuropsychiatric disorders. This study examined B cells in cerebrospinal fluid (CSF) and peripheral blood (PB) of schizophrenic patients and healthy control volunteers. The results showed that CSF B cells represented a select subset and were different from B cells in PB. Additionally, there were significant differences in antibodies generated by CSF B cells between schizophrenic patients and healthy control group.
BEHAVIOURAL BRAIN RESEARCH
(2022)
Article
Hematology
Lei Yu, Greggory Myers, Emily Schneider, Yu Wang, Raven Mathews, Kim Chew Lim, David Siemieniak, Vi Tang, David Ginsburg, Ginette Balbin-Cuesta, Sharon A. Singh, Pongpon Phuwakanjana, Natee Jearawiriyapaisarn, Rami Khoriaty, James Douglas Engel
Summary: This study generated a CRISPR knockout library to target erythroid genes and identified novel gamma-globin repressors. Deletion of VHL and PTEN induces HbF synthesis, and small-molecule inhibitors of PTEN and EZH can also induce HbF production.
Editorial Material
Hematology
Lionel Blanc, Jeffrey M. Lipton
Meeting Abstract
Hematology
Kaiwen Deng, Lei Yu, Susan Hammoud, Alejandra Sanchez-Martinez, Xiaofang Liu, Ghazi-Abullah Saroya, Greggory Myers, Yu Wang, Ginette Balbin-Cuesta, Yuanfang Guan, Vesa Kaartinen, Rami Khoriaty, James Douglas Engel, Sharon A. Singh
Article
Medicine, Research & Experimental
Senthil Velan Bhoopalan, Jonathan S. Yen, Thiyagaraj Mayuranathan, Kalin D. Mayberry, Yu Yao, Maria Angeles Lillo Osuna, Yoonjeong Jang, Janaka S. S. Liyanage, Lionel Blanc, Steven R. Ellis, Marcin W. Wlodarski, Mitchell J. Weiss
Summary: Diamond-Blackfan anemia (DBA) is a genetic blood disease caused by heterozygous loss-of-function mutations in ribosomal protein genes, resulting in hypoplastic anemia and later multilineage cytopenias. A tractable experimental model of DBA was created through genome editing of human HSPCs, revealing associated hematopoietic stem cell defects in the disease.
Article
Immunology
Tengfei Song, Yonghong Yao, Julien Papoin, Barbara Sherry, Betty Diamond, Hua Gu, Lionel Blanc, Yong-Rui Zou
Summary: Infection can enhance myeloid output even after it is cleared, and TIMP1 plays a role in sustaining this effect by suppressing the activation of the Notch signaling pathway.
JOURNAL OF EXPERIMENTAL MEDICINE
(2023)
Article
Hematology
Greggory Myers, Yu Wang, Qing Wang, Ann Friedman, Alejandra Sanchez-Martinez, Xiaofang Liu, Singh A. Sharon, Kim-Chew Lim, Rami Khoriaty, James Douglas Engel, Lei Yu
Summary: This study investigated the kinetics of erythroid differentiation under steady-state conditions using a transgenic mouse model, revealing important time points and factors in the process.
Meeting Abstract
Oncology
Kaiwen Deng, Alejandra SanchezMartinez, Susan Hammoud, Xiaofang Liu, Yuanfang Guan, James Engel, Sharon Singh
PEDIATRIC BLOOD & CANCER
(2023)
Article
Oncology
Alexander Ludlow, Nicholas George, Megan Glassfora, Katie Udenberg, Mark C. Hannibal, Carla Schwalm, Katie Scott, Thomas L. Rothstein, Sharon A. Singh
Summary: Polysome profiling is a useful tool for validating large subunit RP variants in DBA patients, as seen in two children with novel missense RPL5 (uL18) and RPL26 (uL24) variants. This method can assist in identifying ribosomal subunit defects and requires further validation in patients with known DBA mutations.
JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY
(2021)