Article
Oncology
Ting Song, Yafei Guo, Zuguang Xue, Zongwei Guo, Ziqian Wang, Donghai Lin, Hong Zhang, Hao Pan, Xiaodong Zhang, Fangkui Yin, Hang Wang, Laura Bonnette Uwituze, Zhichao Zhang
Summary: S1g-2, a novel inhibitor targeting Hsp70-Bim PPI, exhibits higher apoptosis-inducing activity in CML and disrupts BCR-ABL-driven interaction, showing potential therapeutic value in both TKI-sensitive and resistant CML patients.
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
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
Biochemistry & Molecular Biology
Raquel Alves, Diogo Santos, Joana Jorge, Ana Cristina Goncalves, Steve Catarino, Henrique Girao, Joana Barbosa Melo, Ana Bela Sarmento-Ribeiro
Summary: Heat shock protein 90 (HSP90) plays a crucial role in stabilizing and protecting client proteins. Alvespimycin, an HSP90 inhibitor, has shown potential in overcoming imatinib resistance in chronic myeloid leukemia (CML) cell lines. This study found that Alvespimycin effectively reduced metabolic activity and induced cell death, apoptosis, and cell cycle arrest in imatinib-sensitive and imatinib-resistant CML cells. It also increased HSP70 expression as a marker of HSP90 inhibition. These findings suggest that Alvespimycin could be a promising therapeutic approach for CML treatment, even in cases of imatinib resistance.
Article
Medicine, Research & Experimental
Ho Jin Lee, Hye-Young Min, Young-Sik Yong, Jihyae Ann, Cong Truong Nguyen, Minh Thanh La, Seung Yeob Hyun, Huong Thuy Le, Hyewon Kim, Hyukjin Kwon, Gibeom Nam, Hyun-Ju Park, Jeewoo Lee, Ho-Young Lee
Summary: This study revealed that Hsp90 inhibitors that block the N-terminal ATP-binding pocket activate STAT3, leading to the transcriptional upregulation of Wnt ligands and promoting cell survival in NSCLC. NCT-80 effectively reduced NSCLC cell viability, migration, and CSC-like phenotypes, and inhibited the growth of patient-derived xenograft tumors.
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
Biochemistry & Molecular Biology
Qiang Wang, Peng Liu, Yingfei Wen, Kuan Li, Bo Bi, Bin-bin Li, Miaojuan Qiu, Shiqiang Zhang, You Li, Jia Li, Hengxing Chen, Yuan Yin, Leli Zeng, Changhua Zhang, Yulong He, Jing Zhao
Summary: Clinical hyperthermic intraperitoneal chemotherapy (HIPEC) is a potential treatment for peritoneal metastases. However, heat resistant tumor cells are a challenge. Researchers developed a carrier-free nanoinhibitor that directly inhibited HSP90, induced oxidative stress, and triggered pyroptosis and immune response in tumor cells. This strategy effectively converted cold tumors to hot ones and provided a new treatment for colorectal peritoneal metastases.
Article
Hematology
Snjezana Janjetovic, Lennart Beckmann, Katharina Holstein, Christina Rolling, Benjamin Thiele, Philippe Schafhausen, Gerhard Schoen, Carsten Bokemeyer, Florian Langer, Minna Voigtlaender
Summary: The study identified a significant association between JAK2V617F-positive MPN and definite APS, with patients with APS potentially experiencing earlier onset of thrombotic events, necessitating more aggressive antithrombotic treatment strategies.
THROMBOSIS RESEARCH
(2021)
Review
Biochemistry & Molecular Biology
Ruchi Yadav, Narek Hakobyan, Jen-Chin Wang
Summary: The Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) are enduring and well-known conditions characterized by abnormal growth of hematopoietic cell lineages, chronic inflammation, and dysregulated immune system. Immune checkpoint inhibitor therapy (ICIT) has shown impressive clinical success but faces challenges of tumor resistance. Next-generation ICIT targeting new immune checkpoints in the tumor microenvironment (TME) may enhance MPN treatment. Monoclonal antibodies and vaccines targeting specific MPN epitopes show potential in augmenting tumor-related immune responses. Further research is needed to explore the application of next-generation ICIT in MPN treatment.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Genetics & Heredity
Mathilde Regimbeau, Romain Mary, Francois Hermetet, Francois Girodon
Summary: Polycythemia vera is a myeloproliferative neoplasm characterized by alterations in the JAK2 gene and other genetic mutations. Understanding the complex genomic landscape of PV has led to the identification of potential therapeutic strategies for patients.
Article
Genetics & Heredity
Jin Zhang, Kefeng Shen, Min Xiao, Jinjin Huang, Jin Wang, Yaqin Wang, Zhenya Hong
Summary: Novel pathogenic mutations were discovered by targeted NGS in 4 patients diagnosed with JAK2 unmutated PV or TN MPN. NGS is required to detect non-canonical driver variants and avoid misdiagnosis of TN MPN.
FRONTIERS IN GENETICS
(2023)
Review
Hematology
Franziska C. Zeeh, Sara C. Meyer
Summary: Philadelphia chromosome-negative myeloproliferative neoplasms are hematopoietic stem cell disorders characterized by dysregulated proliferation of mature myeloid blood cells. Recent advancements in understanding the pathogenesis and treatment options of MPN, including oncogenic driver mutations in JAK2, CALR, or MPL, have been made. Novel concepts for therapy, such as JAK2 inhibitors, combination therapy approaches, and targeting new molecular targets, are in development to address the need for more effective treatments in MF.
Review
Biochemistry & Molecular Biology
Xin Xie, Nan Zhang, Xiang Li, He Huang, Cheng Peng, Wei Huang, Leonard J. Foster, Gu He, Bo Han
Summary: Hsp90 is a crucial molecular chaperone that plays a critical role in biological pathways and cellular operations. It is closely linked to cancer and has been studied as a potential drug target. Combining Hsp90 inhibitors with other tumor inhibitors has shown synergistic antitumor effects, making the development of Hsp90 dual-target inhibitors a promising strategy in cancer treatment.
BIOORGANIC CHEMISTRY
(2023)
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
Paul Chauvet, Olivier Nibourel, Celine Berthon, Laure Goursaud, Benjamin Carpentier, Pauline Lionne-Huyghe, Mathieu Wemeau, Bruno Quesnel
Summary: Subsequent blast or accelerated phase is a severe complication of Philadelphia-negative myeloproliferative neoplasms. Hypomethylating agents may induce a long-lasting response in some patients. In this study, six patients with BP/AP-MPN who experienced MPN relapse after azacytidine treatment were analyzed. Most patients achieved complete remission, but relapses occurred within a few months. Thrombo-embolic events were also observed.
Article
Hematology
Srdan Verstovsek, Naveen Pemmaraju, Nancy L. Reaven, Susan E. Funk, Tracy Woody, Frank Valone, Suneel Gupta
Summary: Polycythemia vera (PV), a type of myeloproliferative neoplasm, has an increased risk of thrombotic events (TE) and mortality. Treatment interventions, such as phlebotomy and cytoreductive medications, aim to maintain hematocrit levels below 45% for better outcomes. A retrospective observational study including 28,306 PV patients found that a majority of both high- and low-risk patients initiated treatment with phlebotomy monotherapy, but hematocrit control was suboptimal in both risk groups. Around 16% of individuals experienced at least 1 TE after treatment initiation, suggesting that current PV treatments may not be fully utilized.
ANNALS OF HEMATOLOGY
(2023)
Review
Oncology
Helen T. Chifotides, Lucia Masarova, Srdan Verstovsek
Summary: The development of MF therapeutics has achieved remarkable progress, with JAK2 inhibitors playing a transformative role in MPN treatment. In addition to these inhibitors, there are numerous novel monotherapies and rational combinations being developed to address different aspects of the disease. These advancements have the potential to improve patient outcomes and lead to a golden era in MF treatment.
CLINICAL LYMPHOMA MYELOMA & LEUKEMIA
(2023)
Article
Pathology
Yahya A. Al-Ghamdi, Jonathan Lake, Adam Bagg, Beenu Thakral, Sa A. Wang, Carlos Bueso-Ramos, Lucia Masarova, Srdan Verstovsek, Heesun J. Rogers, Eric D. Hsi, Jonathon H. Gralewski, Devon Chabot-Richards, Tracy I. George, Anton Rets, Robert P. Hasserjian, Olga K. Weinberg, Megan Parilla, Daniel A. Arber, Osvaldo Padilla, Attilio Orazi, Wayne Tam
Summary: This study compared the pathological and genetic characteristics between triple-negative primary myelofibrosis (TN-PMF) and PMF with canonical driver mutations (DM-PMF). The results showed that TN-PMF patients were more likely to have thrombocytopenia and less likely to have organomegaly. The bone marrow of TN-PMF patients showed fewer granulocytic elements and more frequent dyserythropoiesis. Cytogenetic analysis revealed a higher incidence of trisomy 8, and targeted next-generation sequencing identified a lower frequency of ASXL1 mutations but enrichment of ASXL1/SRSF2 comutations. These findings suggest that TN-PMF may be pathogenetically different from DM-PMF, with potential prognostic implications.
Review
Oncology
Naveen Pemmaraju, Prithviraj Bose, Raajit Rampal, Aaron T. Gerds, Angela Fleischman, Srdan Verstovsek
Summary: Myelofibrosis (MF) is a chronic myeloproliferative neoplasm characterized by splenomegaly, abnormal cytokine expression, cytopenias, and progressive bone marrow fibrosis. Ruxolitinib, an oral Janus kinase (JAK) 1 and JAK2 inhibitor, was the first approved agent for MF and has revolutionized the treatment approach. The understanding of MF has improved significantly due to targeted JAK1/JAK2 inhibition and extensive literature on ruxolitinib, leading to better management strategies and discussion on future treatment options.
LEUKEMIA & LYMPHOMA
(2023)
Article
Hematology
Ivan Krecak, Marko Skelin, Srdan Verstovsek
Summary: Interferons (IFNs) have been used for decades to treat polycythemia vera (PV). Single-arm clinical trials have shown high hematological and molecular response rates with IFNs, indicating potential disease-modifying activity. However, discontinuation rates of IFNs have been rather high due to frequent treatment-related side-effects.
EXPERT REVIEW OF HEMATOLOGY
(2023)
Review
Hematology
Rodrick Babakhanlou, Srdan Verstovsek, Naveen Pemmaraju, Cristhiam M. M. Rojas-Hernandez
Summary: Erythrocytosis is characterized by elevated hemoglobin and hematocrit levels. It can be classified as primary or secondary, with primary erythrocytosis resulting from a clonal disorder in the bone marrow and secondary erythrocytosis being caused by external stimuli. This review focuses on secondary erythrocytosis, discussing its causes, clinical presentation, and diagnostic and therapeutic approaches.
EXPERT REVIEW OF HEMATOLOGY
(2023)
Article
Oncology
Ruben A. Mesa, Stacie Hudgens, Lysbeth Floden, Claire N. Harrison, Jeanne Palmer, Vikas Gupta, Donal P. McLornan, Mary F. McMullin, Jean-Jaques Kiladjian, Lynda Foltz, Uwe Platzbecker, M. Laura Fox, Adam J. Mead, David M. Ross, Stephen T. Oh, Andrew Perkins, Michael F. Leahy, Samineh Deheshi, Rafe Donahue, Barbara J. Klencke, Srdan Verstovsek
Summary: This study evaluated the longitudinal change in total symptom score (TSS) and individual symptom scores in MF patients receiving therapy, and found that momelotinib provided clinically relevant symptom benefits compared to control group.
Article
Hematology
Lucia Masarova, Prithviraj Bose, Naveen Pemmaraju, Lingsha Zhou, Sherry Pierce, Zeev Estrov, Hagop Kantarjian, Srdan Verstovsek
Summary: This retrospective study evaluates clinical features, predictive factors, and outcomes in patients with MF who remain on RUX therapy for 5 years or longer. The study finds that the absence of advanced clinical features at the start of therapy and age significantly affect the outcome of patients on long-term RUX therapy.
ACTA HAEMATOLOGICA
(2023)
Review
Hematology
Ivan Krecak, Srdan Verstovsek, Marko Lucijanic
Summary: The exact prognostic role of cardiovascular risk factors in BCR-ABL1 negative MPN patients is unknown. Current treatment of CV risk factors in MPNs is not guided by the presence of these risk factors. Target levels for different metabolic deflections in MPNs have not been defined. This review discusses the important aspects of individual CV risk factors in MPNs, summarizes recent advances, and proposes future directions and research areas.
ANNALS OF HEMATOLOGY
(2023)
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)
Article
Hematology
Aaron T. Gerds, Srdan Verstovsek, Alessandro M. Vannucchi, Haifa Kathrin Al-Ali, David Lavie, Andrew Kuykendall, Sebastian Grosicki, Alessandra Iurlo, Yeow Tee Goh, Mihaela C. Lazaroiu, Miklos Egyed, Maria Laura Fox, Donal McLornan, Andrew Perkins, Sung-Soo Yoon, Vikas Gupta, Jean-Jacques Kiladjian, Nikki Granacher, Sung-Eun Lee, Luminita Ocroteala, Francesco Passamonti, Claire N. Harrison, Stephen Oh, Barbara J. Klencke, Jing Yu, Rafe Donahue, Jun Kawashima, Ruben Mesa
Summary: The MOMENTUM study demonstrates the durable benefits of momelotinib in patients with myelofibrosis, including symptom, spleen, and anaemia improvements. The study also shows late responses after 24 weeks of treatment and favorable safety profile up to 48 weeks. These findings highlight the potential of momelotinib as a treatment option for myelofibrosis patients.
LANCET HAEMATOLOGY
(2023)
Review
Oncology
Helen T. Chifotides, Srdan Verstovsek, Prithviraj Bose
Summary: Myelofibrosis (MF) is a bone marrow cancer with diverse clinical manifestations and molecular profiles. The two distinct phenotypes, myeloproliferative and myelodepletive, are located at opposite ends of the disease spectrum and are defined by different degrees of cytopenias, splenomegaly, and molecular profiles. Treatment strategies can be tailored based on these phenotypes, with ruxolitinib, fedratinib, pacritinib, and momelotinib being potential options for specific phenotypes.
Article
Biochemistry & Molecular Biology
Srdan Verstovsek, Ivan Krecak, Florian H. Heidel, Valerio De Stefano, Kenneth Bryan, Mike W. Zuurman, Michael Zaiac, Mara Morelli, Aoife Smyth, Santiago Redondo, Erwan Bigan, Michael Ruhl, Christoph Meier, Magali Beffy, Jean-Jacques Kiladjian
Summary: The PV-AIM study used machine learning to identify markers of thromboembolic events (TE) in patients with polycythemia vera (PV). The study found that lymphocyte percentage (LYP), neutrophil percentage (NEP), and red cell distribution width (RDW) are closely associated with TE risk, and can be used to identify high-risk patients.
Article
Medicine, General & Internal
Srdan Verstovsek, Aaron T. Gerds, Alessandro M. Vannucchi, Haifa Kathrin Al-Ali, David Lavie, Andrew T. Kuykendall, Sebastian Grosicki, Alessandra Iurlo, Yeow Tee Goh, Mihaela C. Lazaroiu, Miklos Egyed, Maria Laura Fox, Donal McLornan, Andrew Perkins, Sung -Soo Yoon, Vikas Gupta, Jean -Jacques Kiladjian, Nikki Granacher, Sung-Eun Lee, Luminita Ocroteala, Francesco Passamonti, Claire N. Harrison, Barbara J. Klencke, Sunhee Ro, Rafe Donahue, Jun Kawashima, Ruben Mesa
Summary: This study aimed to compare the clinical effects of momelotinib and danazol in patients with intermediate or high-risk myelofibrosis. The results showed that momelotinib can significantly improve myelofibrosis-associated symptoms, anemia measures, and spleen response compared to danazol, with favorable safety.
Review
Oncology
Rodrick Babakhanlou, Lucia Masarova, Srdan Verstovsek
Summary: Essential thrombocythemia (ET) is a chronic myeloproliferative neoplasm characterized by increased platelet count and excessive megakaryopoiesis. While one-third of cases are benign, the remaining cases can lead to complications such as thromboembolism, hemorrhage, and transformation into aggressive myeloid neoplasms. Limited data exist regarding the management of complications and emergencies associated with ET, despite extensive research on its pathogenesis and etiology. This article focuses on discussing the complications, emergencies, treatment options, and controversies related to the management of ET.
CLINICAL ADVANCES IN HEMATOLOGY & ONCOLOGY
(2023)
