Article
Oncology
Elisa Bianchi, Sebastiano Rontauroli, Lara Tavernari, Margherita Mirabile, Francesca Pedrazzi, Elena Genovese, Stefano Sartini, Massimiliano Dall'Ora, Giulia Grisendi, Luca Fabbiani, Monica Maccaferri, Chiara Carretta, Sandra Parenti, Sebastian Fantini, Niccolo Bartalucci, Laura Calabresi, Manjola Balliu, Paola Guglielmelli, Leonardo Potenza, Enrico Tagliafico, Lorena Losi, Massimo Dominici, Mario Luppi, Alessandro Maria Vannucchi, Rossella Manfredini
Summary: BM fibrosis is a major pathology in myelofibrosis and is associated with overexpression of OPN protein. ERK1/2 is a key regulator of OPN production, and inhibiting ERK1/2 activity can reduce OPN production and hinder the development of BM fibrosis. Targeting OPN and ERK1/2 could be potential therapeutic strategies for myelofibrosis.
Article
Multidisciplinary Sciences
Mattheus H. E. Wildschut, Julien Mena, Cyril Dordelmann, Marc van Oostrum, Benjamin D. Hale, Jens Settelmeier, Yasmin Festl, Veronika Lysenko, Patrick M. Schurch, Alexander Ring, Yannik Severin, Michael S. Bader, Patrick G. A. Pedrioli, Sandra Goetze, Audrey van Drogen, Stefan Balabanov, Radek C. Skoda, Massimo Lopes, Bernd Wollscheid, Alexandre P. A. Theocharides, Berend Snijder
Summary: In this study, we integrated ex vivo drug response and proteotype analyses to discover targetable vulnerabilities and associated therapeutic strategies for myelofibrosis patients. We identified three targetable vulnerabilities, including the sensitivity to BET and HDAC inhibitors driven by CALR mutations, the sensitivity to drugs targeting pro-survival signaling and DNA replication associated with an MCM complex-high proliferative signature, and the ER stress response in homozygous CALR mutations. Our findings provide a molecularly motivated roadmap for individualized treatment of myelofibrosis patients.
NATURE COMMUNICATIONS
(2023)
Article
Chemistry, Medicinal
Anniina T. Virtanen, Teemu Haikarainen, Parthasarathy Sampathkumar, Maaria Palmroth, Sanna Liukkonen, Jianping Liu, Natalia Nekhotiaeva, Stevan R. Hubbard, Olli Silvennoinen
Summary: This study identified novel small molecules targeting the JH2 domain of JAK2 V617F and characterized their binding properties. Screening of a large number of small molecules resulted in the identification of 55 binders to the ATP-binding pocket of JAK2 JH2 V617F protein. These findings reveal the unique structural characteristics of the JAK2 JH2 ATP-binding pocket.
Article
Multidisciplinary Sciences
Shivam Rai, Elodie Grockowiak, Nils Hansen, Damien Luque Paz, Cedric B. Stoll, Hui Hao-Shen, Gabriele Mild-Schneider, Stefan Dirnhofer, Christopher J. Farady, Simon Mendez-Ferrer, Radek C. Skoda
Summary: In this study, the authors demonstrate that the JAK2-V617F mutation is associated with increased expression of IL-1 in MPN patients. They also show that loss of IL-1 beta in JAK2-V617F mutant hematopoietic cells reduces MPN symptoms and myelofibrosis in a mouse model.
NATURE COMMUNICATIONS
(2022)
Article
Hematology
Nicole Naumann, Johannes Lubke, William Shomali, Lukas Reiter, Hans-Peter Horny, Mohamad Jawhar, Vito Dangelo, Alice Fabarius, Georgia Metzgeroth, Sebastian Kreil, Karl Sotlar, Claire Oni, Claire Harrison, Wolf-Karsten Hofmann, Nicholas C. P. Cross, Peter Valent, Deepti Radia, Jason Gotlib, Andreas Reiter, Juliana Schwaab
Summary: 45 patients with myeloid neoplasms and concurrent JAK2 V617F and KIT D816V mutations were studied, showing overlapping clinical features and discordant development of variant allele frequency for both mutations. The overall survival of patients without additional high-risk mutations was 77% at 5 years, indicating a fundamentally different prognosis compared to the impact of additional mutations in the individual disorders.
BRITISH JOURNAL OF HAEMATOLOGY
(2021)
Article
Oncology
Christophe Willekens, Lucie Laplane, Tracy Dagher, Camelia Benlabiod, Nicolas Papadopoulos, Catherine Lacout, Philippe Rameau, Cyril Catelain, Alexia Alfaro, Valerie Edmond, Nicolas Signolle, Valentine Marchand, Nathalie Droin, Remco Hoogenboezem, Rebekka. K. K. Schneider, Alex Penson, Omar Abdel-Wahab, Stephane Giraudier, Florence Pasquier, Caroline Marty, Isabelle Plo, Jean-Luc Villeval, Stefan. N. N. Constantinescu, Francoise Porteu, William Vainchenker, Eric Solary
Summary: Heterozygous mutation in SRSF2(P95H) and JAK2(V617F) is associated with some myeloproliferative neoplasms, especially primary myelofibrosis. In this study, it was found that Srsf2(P95H) mutation can delay myelofibrosis induced by Jak2(V617F) and decrease TGF beta 1 serum level. Furthermore, Srsf2(P95H) mutation reduces the competitiveness of transplanted Jak2(V617F) hematopoietic stem cells while preventing their exhaustion. These findings highlight the role of JAK2 exon 14 skipping promotion in reducing JAK/STAT signaling in pathological conditions.
Article
Hematology
Wenjuan Fan, Weijie Cao, Jianxiang Shi, Fengcai Gao, Meng Wang, Linping Xu, Fang Wang, Yingmei Li, Rong Guo, Zhilei Bian, Wei Li, Zhongxing Jiang, Wang Ma
Summary: The classic BCR-ABL1-negative myeloproliferative neoplasm (MPN) is a highly heterogeneous hematologic tumor that includes three subtypes. This study aimed to clarify the role of bone marrow (BM) monocytes/macrophages in MPN patients with the JAK2(V617F) mutation. The findings provide important resources for future studies and targets for the treatment of MPN patients.
ANNALS OF HEMATOLOGY
(2023)
Review
Rheumatology
Qin Xu, Xuexiao Jin, Yu Jiang, Xin Dang, Yongmei Han
Summary: The study presented a case of clinically amyopathic dermatomyositis and essential thrombocytosis with a somatic constitutive active mutation of JAK2(V617F). The research investigated the relationship between these two rare diseases and concluded that they are independent disorders, with JAK2(V617F) mutation burden being irrelevant to the severity of dermatomyositis.
CLINICAL RHEUMATOLOGY
(2021)
Review
Biochemistry & Molecular Biology
Mariarita Spampinato, Cesarina Giallongo, Alessandra Romano, Lucia Longhitano, Enrico La Spina, Roberto Avola, Grazia Scandura, Ilaria Dulcamare, Vincenzo Bramanti, Michelino Di Rosa, Nunzio Vicario, Rosalba Parenti, Giovanni Li Volti, Daniele Tibullo, Giuseppe A. Palumbo
Summary: Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by clonal proliferation of hematopoietic stem cells leading to bone marrow fibrosis. The main consequences of PMF include neoangiogenesis, megakaryocytes hyperplasia, extensive bone marrow fibrosis, osteosclerosis, and bone damage. The involvement of cytokines, growth factors, and resident cells in the bone marrow microenvironment are linked to disease progression in PMF.
Review
Pharmacology & Pharmacy
Erika Morsia, Naseema Gangat
Summary: Myelofibrosis is a disease characterized by anemia, splenomegaly, and bone marrow fibrosis. Treatment options include targeted therapies such as JAK inhibitors, but there is a need for long-term remissions and disease modifying abilities. Research is ongoing to develop agents targeting various pathways for potential use in managing MF patients who do not respond well to current treatments.
EXPERT OPINION ON THERAPEUTIC TARGETS
(2021)
Article
Hematology
Justin Anthony Chen, Yanli Hou, Krishna M. Roskin, Daniel A. Arber, Charles D. Bangs, Linda B. Baughn, Athena M. Cherry, Mark D. Ewalt, Andrew Z. Fire, Laure Fresard, Hutton M. Kearney, Stephen B. Montgomery, Robert S. Ohgami, Kathryn E. Pearce, Beth A. Pitel, Jason D. Merker, Jason Gotlib
Summary: The resistance mechanisms to ruxolitinib in a patient with JAK2-driven hematologic malignancies may involve IKZF1 deletion and an activated B-cell receptor-like signaling phenotype.
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)
Article
Oncology
Kaihong Xu, Qunfang Ge, Yanli Zhang, Guifang Ouyang, Xiao Yan
Summary: This study investigated the expression properties, structural features, and function of CALR E381A in MPN patients. The CALR variants p.L367fs*46, p.K385fs*47, and p.E381A were identified as the predominant types. CALR E381A coexisted with other genetic variants, with JAK2 V617F being more common. Bioinformatics analysis showed that CALR E381A did not change the physicochemical properties of the protein but affected the electrical charge and steric hindrance of amino acids. Functional analysis indicated that CALR E381A does not alter cell growth. CALR E381A may be a risk SNP suggesting an inherited predisposition for MPN disease in East Asian populations.
AMERICAN JOURNAL OF TRANSLATIONAL RESEARCH
(2023)
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)
Review
Oncology
Srdan Verstovsek, Ruben A. Mesa, Robert A. Livingston, Wilson Hu, John Mascarenhas
Summary: Myelofibrosis is a chronic myeloproliferative neoplasm characterized by bone marrow fibrosis, anemia, extramedullary hematopoiesis, and splenomegaly. Ruxolitinib, an oral JAK1/JAK2 inhibitor, has been approved for the treatment of intermediate or high-risk MF patients. It remains the standard of care for higher-risk MF, and dose optimization and management are crucial for maximizing its benefits.
JOURNAL OF HEMATOLOGY & ONCOLOGY
(2023)