Review
Chemistry, Medicinal
Michael Stephan Bader, Sara Christina Meyer
Summary: The discovery of the activating V617F mutation in JAK2 has greatly contributed to our understanding of myeloproliferative neoplasms (MPN). JAK2 inhibitors have become a standard treatment option for certain forms of MPN and offer significant benefits for patients. However, there are still challenges to be addressed in the targeted therapy of MPN with JAK2 inhibitors, such as reducing the MPN clone and overcoming drug resistance.
Letter
Oncology
Antonella Zagaria, Francesco Tarantini, Paola Orsini, Luisa Anelli, Cosimo Cumbo, Nicoletta Coccaro, Giuseppina Tota, Crescenzio Francesco Minervini, Elisa Parciante, Maria Rosa Conserva, Immacolata Redavid, Alessandra Ricco, Immacolata Attolico, Giorgina Specchia, Pellegrino Musto, Francesco Albano
Summary: This study investigated the genomic and clinical features of 80 erythrocytosis patients and found that male patients with idiopathic erythrocytosis and normal EPO levels may be the best candidates for searching for the JAK2 GGCC_46/1 haplotype and CALR rs1049481_G allele.
EXPERIMENTAL HEMATOLOGY & ONCOLOGY
(2022)
Article
Medicine, Research & Experimental
Huan Ge, Caolin Wang, Chaoquan Tian, Yanyan Diao, Wanqi Wang, Xiangyu Ma, Jian Zhang, Honglin Li, Zhenjiang Zhao, Lili Zhu
Summary: WWQ-131, a highly selective JAK2 inhibitor, effectively inhibits cell proliferation, blocks aberrant activation of JAK2 signaling pathway, and shows therapeutic potential in mouse models for MPNs treatment.
BIOMEDICINE & PHARMACOTHERAPY
(2022)
Article
Cell Biology
Ana Guijarro-Hernandez, Laura Eder-Azanza, Cristina Hurtado, David Navarro-Herrera, Begona Ezcurra, Francisco Javier Novo, Juan Cabello, Jose Luis Vizmanos
Summary: There is increasing evidence that Ph-negative myeloproliferative neoplasms (MPNs) are characterized by disruption of multiple molecular mechanisms. In this study, patient-like calreticulin mutations were introduced into a C. elegans model lacking JAK2 and MPL orthologs. Transcriptomic analysis revealed genes and processes associated with MPN pathogenesis, some of which were validated through qPCR. This research provides a new experimental model for studying JAK2/MPL-independent mechanisms of mutant calreticulin.
Article
Pharmacology & Pharmacy
E. B. Yasin, R. Alserihi, H. Alkhatabi, H. M. H. Qutob, R. Qahwaji, S. W. Kattan, K. A. Gholam, E. Hussein, A. S. Barefah, M. E. Alghuthami, A. Abuzenadah
Summary: The activation of JAK/STAT signaling pathway with or without JAK2 mutations leads to SOCS1 hypermethylation, which could represent a potential therapeutic target.
EUROPEAN REVIEW FOR MEDICAL AND PHARMACOLOGICAL SCIENCES
(2022)
Review
Oncology
Ana Guijarro-Hernandez, Jose Luis Vizmanos
Summary: There is growing evidence that Ph-negative myeloproliferative neoplasms are disorders in which multiple signaling pathways are significantly disturbed. The discovery of somatic mutations in JAK2, MPL, and CALR has shed light on the aberrant functions of their mutant products, while additional somatic mutations in other genes have added complexity to the molecular pathogenesis of MPNs. This review highlights the involvement of a wide variety of cellular processes and pathways in the pathogenesis of MPNs, explaining their phenotypic heterogeneity.
Article
Chemistry, Medicinal
Pengfei Xu, Pei Shen, Hai Wang, Lian Qin, Jie Ren, Qiushuang Sun, Raoling Ge, Jinlei Bian, Yi Zhong, Zhiyu Li, JuBo Wang, Zhixia Qiu
Summary: In this study, a series of imidazopyrrolopyridines derivatives selectively inhibiting JAK2 were designed and synthesized. Compound 6k exhibited high potency and selectivity against JAK2, with promising pharmacokinetic properties. The results suggest that 6k could be a potential inhibitor for further development in the treatment of MPNs.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Cell Biology
Kengo Takeda, Kenji Tago, Megumi Funakoshi-Tago
Summary: The point mutation (V617F) in the JAK2 gene promotes the expression of DDX5, which contributes to the development of MPN through the activation of STAT5. Inhibition of DDX5 suppresses mTOR activation, cell proliferation, and tumor growth in a mouse model of MPN.
CELLULAR SIGNALLING
(2023)
Review
Oncology
Graeme Greenfield, Mary Frances McMullin
Summary: This review summarizes the mechanisms of epigenetic changes and nucleosomes in MPNs and discusses the alterations in methylation age and histone modification. The drivers and regulators of epigenetic changes in MPNs are outlined, and available therapeutic areas for altering the epigenome are discussed.
FRONTIERS IN ONCOLOGY
(2023)
Article
Hematology
Nabih Maslah, Odonchimeg Ravdan, Louis Drevon, Emmanuelle Verger, Celia Belkhodja, Christine Chomienne, Bruno Cassinat, Jean-Jacques Kiladjian, Stephane Giraudier, Marie-Helene Schlageter
Summary: This study evaluated the diagnostic performances of erythropoietin and JAK2 mutations in patients suspected of polycythemia, finding that low erythropoietin levels and JAK2 mutations have comparable positive predictive values for true polycythemia.
BRITISH JOURNAL OF HAEMATOLOGY
(2022)
Review
Oncology
Yingxin Sun, Yifeng Cai, Jia Chen, Jiannong Cen, Mingqing Zhu, Jinlan Pan, Depei Wu, Aining Sun, Suning Chen
Summary: For patients with MPN with PCM1-JAK2 fusion, the combination of ruxolitinib and Peg-IFN may be an effective treatment option, especially for those with poor efficacy of ruxolitinib monotherapy.
FRONTIERS IN ONCOLOGY
(2021)
Article
Hematology
Graciela Rabadan Moraes, Florence Pasquier, Christophe Marzac, Eric Deconinck, Carlotta Caterina Damanti, Gwendoline Leroy, Mira El-Khoury, Wassim El Nemer, Jean-Jacques Kiladjian, Hana Raslova, Albert Najman, William Vainchenker, Caroline Marty, Christine Bellanne-Chantelot, Isabelle Plo
Summary: This study identified an EPOR variant in a large family with JAK2-positive MPN, indicating the importance of inherited-risk alleles affecting the JAK2/STAT pathway in MPN. The findings suggest potential implications for risk assessment and treatment of MPN.
BRITISH JOURNAL OF HAEMATOLOGY
(2022)
Article
Oncology
Jie Zhou, Cheng Guo, Hao Wu, Bing Li, Li-Li Zhou, Ai-Bin Liang, Jian-Fei Fu
Summary: In Jak2(V617F) positive samples, Dnmt3a is downregulated due to the binding of Stat5a with the Dnmt3a promoter, affecting cell proliferation and cycle distribution. The specific site where Stat5a binds is the GAS motif at the Dnmt3a promoter. Dnmt3a induces G0/G1 arrest through regulating the miR-17-5p/Cdkn1a axis, providing a potential treatment target for cMPNs.
Article
Oncology
Evan M. Braunstein, Hang Chen, Felicia Juarez, Fanghan Yang, Lindsay Tao, Igor Makhlin, Donna M. Williams, Shruti Chaturvedi, Aparna Pallavajjala, Theodoros Karantanos, Renan Martin, Elizabeth Wohler, Nara Sobreira, Christopher D. Gocke, Alison R. Moliterno
Summary: Familial clustering of myeloproliferative neoplasms (MPN) is well known, with increased risk among first-degree relatives, and rare germline coding variants in the ERBB2 gene are associated with an increased risk for development of MPN. The ERBB2 gene is likely to contribute to cancer risk in combination with additional risk alleles.
Article
Biology
Hrvoje Holik, Ivan Krecak, Marko Lucijanic, Ivan Samardzic, Danijel Pilipac, Ivana Vucinic Ljubicic, Bozena Coha, Alma Kitter Pipic, Blazenka Miskic, Silva Zupancic-Salek
Summary: This study aimed to investigate the prevalence and associated risk factors of symptomatic osteoarthritis (sOA) in myeloproliferative neoplasms (MPN) patients. The prevalence of hip and/or knee sOA among MPN patients was significantly higher than that in the general population of similar age. Older age, higher body weight, and higher MPN-SAF score were recognized as independent risk factors for sOA, while cytoreductive treatment was identified as a protective factor.
Letter
Hematology
Ivan Sloma, Philip Beer, Christophe Desterke, Elizabeth Bulaeva, Misha Bilenky, Annaick Carles, Michelle Moksa, Kamini Raghuram, Cedric Brimacombe, Karen Lambie, Ali G. Turhan, Orianne Wagner-Ballon, Philippe Gaulard, Keith Humphries, Martin Hirst, Connie J. Eaves
Letter
Hematology
Hendrik F. P. Runge, Stuart Lacy, Sharon Barrans, Philip A. Beer, Daniel Painter, Alexandra Smith, Eve Roman, Cathy Burton, Simon Crouch, Reuben Tooze, Daniel J. Hodson
BRITISH JOURNAL OF HAEMATOLOGY
(2021)
Article
Gastroenterology & Hepatology
Stephan B. Dreyer, Rosie Upstill-Goddard, Viola Paulus-Hock, Clara Paris, Eirini-Maria Lampraki, Eloise Dray, Bryan Serrels, Giuseppina Caligiuri, Selma Rebus, Dennis Plenker, Zachary Galluzzo, Holly Brunton, Richard Cunningham, Mathias Tesson, Craig Nourse, Ulla-Maja Bailey, Marc Jones, Kim Moran-Jones, Derek W. Wright, Fraser Duthie, Karin Oien, Lisa Evers, Colin J. McKay, Grant A. McGregor, Aditi Gulati, Rachel Brough, Ilirjana Bajrami, Stephan Pettitt, Michele L. Dziubinski, Juliana Candido, Frances Balkwill, Simon T. Barry, Robert Grutzmann, Lola Rahib, Amber Johns, Marina Pajic, Fieke E. M. Froeling, Phillip Beer, Elizabeth A. Musgrove, Gloria M. Petersen, Alan Ashworth, Margaret C. Frame, Howard C. Crawford, Diane M. Simeone, Chris Lord, Debabrata Mukhopadhyay, Christian Pilarsky, David A. Tuveson, Susanna L. Cooke, Nigel B. Jamieson, Jennifer P. Morton, Owen J. Sansom, Peter J. Bailey, Andrew Biankin, David K. Chang
Summary: DDR deficiency and replication stress are independent of each other, offering opportunities for therapy in DDR-proficient PC and after platinum therapy. Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors, including previously described molecular subtypes, and serve as a valuable model for studying novel therapeutic strategies targeting DDR and replication stress in PC.
Editorial Material
Multidisciplinary Sciences
David Lara-Astiaso, Brian J. P. Huntly
Summary: UTX protein regulates chromatin by condensing into liquid-like droplets, thereby suppressing tumor growth.
Article
Genetics & Heredity
Haiyang Yun, Nisha Narayan, Shabana Vohra, George Giotopoulos, Annalisa Mupo, Pedro Madrigal, Daniel Sasca, David Lara-Astiaso, Sarah J. Horton, Shuchi Agrawal-Singh, Eshwar Meduri, Faisal Basheer, Ludovica Marando, Malgorzata Gozdecka, Oliver M. Dovey, Aracely Castillo-Venzor, Xiaonan Wang, Paolo Gallipoli, Carsten Muller-Tidow, Cameron S. Osborne, George S. Vassiliou, Brian J. P. Huntly
Summary: This study characterizes the cooperative effects of Flt3-ITD and Npm1c mutations, commonly found in acute myeloid leukemia, on the cellular epigenome and three-dimensional genome conformation during tumor development. The mutations alter the epigenetic landscape and genome organization, synergize to drive leukemia induction, and reveal long-range cis-regulatory circuits and gene-regulatory networks driven by transcription factors.
Correction
Immunology
Natalie Burrows, Rachael J. M. Bashford-Rogers, Vijesh J. Bhute, Ana Penalver, John R. Ferdinand, Benjamin J. Stewart, Joscelin E. G. Smith, Mukta Deobagkar-Lele, Girolamo Giudice, Thomas M. Connor, Akimichi Inaba, Laura Bergamaschi, Sam Smith, Maxine G. B. Tran, Evangelia Petsalaki, Paul A. Lyons, Marion Espeli, Brian J. P. Huntly, Kenneth G. C. Smith, Richard J. Cornall, Menna R. Clatworthy, Patrick H. Maxwell
Article
Hematology
Georgina S. F. Anderson, Jose Ballester-Beltran, George Giotopoulos, Jose A. Guerrero, Sylvanie Surget, James C. Williamson, Tsz So, David Bloxham, Anna Aubareda, Ryan Asby, Ieuan Walker, Lesley Jenkinson, Elizabeth J. Soilleux, James P. Roy, Ana Teodosio, Catherine Ficken, Leah Officer-Jones, Sara Nasser, Sheri Skerget, Jonathan J. Keats, Peter Greaves, Yu-Tzu Tai, Kenneth C. Anderson, Marion MacFarlane, James E. Thaventhiran, Brian J. P. Huntly, Paul J. Lehner, Michael A. Chapman
Summary: This study identifies cell surface proteins as potential targets for cancer immunotherapy and describes the discovery of a new target, SEMA4A, in primary human myeloma cells. It demonstrates the essential role of SEMA4A in myeloma cell growth and highlights the limitations of traditional CRISPR/Cas9 knockout screens in identifying this target. The study also shows the effective targeting of SEMA4A with a novel antibody-drug conjugate both in vitro and in vivo.
Article
Oncology
Bryann Pardieu, Justine Pasanisi, Frank Ling, Reinaldo Dal Bello, Justine Penneroux, Angela Su, Romane Joudinaud, Laureen Chat, Hsin Chieh Wu, Matthieu Duchmann, Gaetano Sodaro, Clementine Chauvel, Florence A. Castelli, Loic Vasseur, Kim Pacchiardi, Yannis Belloucif, Marie-Charlotte Laiguillon, Eshwar Meduri, Camille Vaganay, Gabriela Alexe, Jeannig Berrou, Chaima Benaksas, Antoine Forget, Thorsten Braun, Claude Gardin, Emmanuel Raffoux, Emmanuelle Clappier, Lionel Ades, Hugues de The, Francois Fenaille, Brian J. Huntly, Kimberly Stegmaier, Herve Dombret, Nina Fenouille, Camille Lobry, Alexandre Puissant, Raphael Itzykson
Summary: By analyzing multiple AML datasets, we identified SLC7A11 as a potential gene that is essential for AML cell survival. Inhibition of SLC7A11 using genetic and chemical methods reduced the viability and clonogenic capacity of AML cell lines. Sulfasalazine, a drug with xCT inhibitory activity, showed anti-leukemic effects against primary AML samples in vitro. Inhibition of xCT affected multiple metabolic pathways, leading to depletion of glutathione pools and oxidative stress-induced cell death in leukemic cells.
Article
Biochemistry & Molecular Biology
Nisha Narayan, Brian J. P. Huntly
Summary: This article investigates how mutations synergistically affect the cellular epigenetic and transcriptional state, disrupting key signaling pathways. The authors demonstrate that inhibition of epigenetic regulators can enhance sensitivity to kinase inhibitors, thereby regulating cellular differentiation in acute myeloid leukemia (AML).
Correction
Genetics & Heredity
Malgorzata Gozdecka, Eshwar Meduri, Milena Mazan, Konstantinos Tzelepis, Monika Dudek, Andrew J. Knights, Mercedes Pardo, Lu Yu, Jyoti S. Choudhary, Emmanouil Metzakopian, Vivek Iyer, Haiyang Yun, Naomi Park, Ignacio Varela, Ruben Bautista, Grace Collord, Oliver Dovey, Dimitrios A. Garyfallos, Etienne De Braekeleer, Saki Kondo, Jonathan Cooper, Berthold Gottgens, Lars Bullinger, Paul A. Northcott, David Adams, George S. Vassiliou, Brian J. P. Huntly
Article
Multidisciplinary Sciences
Shikha Gupta, Oliver M. Dovey, Ana Filipa Domingues, Oliwia W. Cyran, Caitlin M. Cash, George Giotopoulos, Justyna Rak, Jonathan Cooper, Malgorzata Gozdecka, Liza Dijkhuis, Ryan J. Asby, Noor Al-Jabery, Victor Hernandez-Hernandez, Sudhakaran Prabakaran, Brian J. Huntly, George S. Vassiliou, Cristina Pina
Summary: Transcriptional variability plays a crucial role in cell diversification and cancer progression. In this study, we disrupted the Kat2a gene to enhance transcriptional variability, leading to preleukemia and subsequent leukemia development. We found that the instability of ribosome biogenesis and protein synthesis contributes to this progression.
Article
Oncology
Mark A. Dawson, Gautam Borthakur, Brian J. P. Huntly, Anastasios Karadimitris, Adrian Alegre, Aristeidis Chaidos, Dan T. Vogl, Daniel A. Pollyea, Faith E. Davies, Gareth J. Morgan, Jacob L. Glass, Manali Kamdar, Maria -Victoria Mateos, Natalia Tovar, Paul Yeh, Regina Garcia Delgado, Faisal Basheer, Ludovica Marando, Paolo Gallipoli, Anastasia Wyce, Anu Shilpa Krishnatry, Olena Barbash, Evi Bakirtzi, Geraldine Ferron-Brady, Natalie O. Karpinich, Michael T. McCabe, Shawn W. Foley, Thierry Horner, Arindam Dhar, Brandon E. Kremer, Michael Dickinson
Summary: Molibresib, a selective inhibitor of BET proteins, was evaluated as a monotherapy for hematological malignancies. The study consisted of dose escalation to determine the recommended dose and dose expansion to assess safety and efficacy in relapsed/refractory MDS and CTCL patients. Results showed limited antitumor activity and significant toxicities, suggesting the need for combination regimens with molibresib.
CLINICAL CANCER RESEARCH
(2023)
Article
Multidisciplinary Sciences
Eshwar Meduri, Charles Breeze, Ludovica Marando, Simon E. Richardson, Brian J. P. Huntly
Summary: Several studies have shown that aberrant RNA editing patterns are present in various tumors, but limited research has been done on the role of RNA editing in acute myeloid leukemia (AML). Using data from the TCGA, we found that higher levels of RNA editing predicted poor outcomes in AML patients. We also observed differential editing patterns across different AML genotypes, and found a negative association between editing degree and mRNA abundance for certain transcripts, indicating the potential regulatory role of RNA editing in altering gene expression in AML.
Review
Oncology
Shuchi Agrawal-Singh, Jaana Bagri, Nathalie Sakakini, Brian J. P. Huntly
Summary: This article discusses the critical role of leukemia stem cells (LSCs) in the growth of hematological malignancies, emphasizing the importance of integrating epigenetic and genetic information to understand heterogeneity among patients. The article also explores efforts to identify mechanisms of resistance through longitudinal analysis of patient samples and highlights the potential of targeting aberrant epigenetic processes for better therapeutic outcomes and potentially eradicating LSCs.
MOLECULAR ONCOLOGY
(2023)
Article
Hematology
Liliana Arede, Elena Foerner, Selinde Wind, Rashmi Kulkarni, Ana Filipa Domingues, George Giotopoulos, Svenja Kleinwaechter, Maximilian Mollenhauer-Starkl, Holly Davison, Aditya Chandru, Ryan Asby, Ralph Samarista, Shikha Gupta, Dorian Forte, Antonio Curti, Elisabeth Scheer, Brian J. P. Huntly, Laszlo Tora, Cristina Pina
Summary: Epigenetic histone modifiers play key roles in regulating cell fate decisions in normal and malignant hematopoiesis. This study focuses on KAT2A, a lysine acetyltransferase, and explores its involvement in different macromolecular complexes and their distinct molecular and cellular consequences. The study identifies the contributions of ATAC and SAGA complexes in regulating biosynthetic activity and cell type-specific programs, providing insights into the requirements of KAT2A in leukemia and erythroid lineage specification and development.