Article
Pharmacology & Pharmacy
Tingting Lu, Jiangyan Cao, Fengming Zou, Xixiang Li, Aoli Wang, Wenliang Wang, Huamin Liang, Qingwang Liu, Chen Hu, Cheng Chen, Zhenquan Hu, Wenchao Wang, Lili Li, Jian Ge, Yang Shen, Tao Ren, Jing Liu, Ruixiang Xia, Qingsong Liu
Summary: CHMFL-48 is a novel type II kinase inhibitor that potently inhibits the wild-type BCR-ABL kinase and a panel of imatinib-resistant mutants. This drug shows strong inhibitory activity in a cellular context, blocking autophosphorylation of BCR-ABL kinase, affecting downstream signaling mediators, and inducing cell cycle progression blockade and apoptosis.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2021)
Article
Oncology
Daisuke Koyama, Jiro Kikuchi, Yoshiaki Kuroda, Masatsugu Ohta, Yusuke Furukawa
Summary: This study reveals the critical role of metabolic homeostasis in the survival of CML cells, particularly in advanced stages of the disease. The BCR-ABL protein activates AMP-activated protein kinase and the mTOR pathway to regulate ATP production and autophagy, with nuclear BCR-ABL detected in advanced-stage CML cells. Activation of AMPK triggers autophagy under energy-deprived conditions, leading to cytoplasmic translocation of BCR-ABL and eventual apoptotic cell death when intracellular ATP is exhausted. This pathway represents a novel therapeutic vulnerability for treating TKI-resistant CML.
Article
Oncology
Angela McLigeyo, Jamilla Rajab, Peter Oyiro, Mohammed Ezzi, Yatich Bett, Matilda Ong'ondi, Andrew Odhiambo, Sitna Mwanzi, Nicholas Othieno-Abinya
Summary: This study analyzed the baseline characteristics and factors associated with cytopenia in Chronic Myeloid Leukemia patients treated with imatinib. The results showed no significant differences in gender, age, marital status, occupation, and education level between patients with and without cytopenia. Multivariable analysis revealed that baseline anemia, neutropenia, thrombocytopenia, and thrombocytosis increased the odds of developing cytopenia.
Article
Pharmacology & Pharmacy
Gang Xie, Wenjie Liu, Zhen Lian, Dantao Xie, Guixin Yuan, Jiajie Ye, Zihong Lin, Weidong Wang, Jican Zeng, Huaxing Shen, Xinjia Wang, Haotian Feng, Wei Cong, Guanfeng Yao
Summary: The study demonstrated the inhibitory effects of the SYK inhibitor PRT on osteoclast and breast cancer functionalities in vitro and in vivo. PRT showed inhibition on osteoclastogenesis, bone resorption, and breast cancer cell growth, migration, and invasion, as well as prevention of bone loss post-OVX and cancer-induced bone destruction.
BIOCHEMICAL PHARMACOLOGY
(2021)
Article
Cell Biology
Chang Liu, Waiyi Zou, Danian Nie, Shuyi Li, Chen Duan, Min Zhou, Peilong Lai, Shengyong Yang, Sen Ji, Yangqiu Li, Mei Mei, Shilai Bao, Yanli Jin, Jingxuan Pan
Summary: This study investigates the role of PRMT family member PRMT7 in the maintenance of leukemia stem cells (LSCs) in chronic myeloid leukemia (CML). The research shows that targeting PRMT7 delays leukemia development and impairs self-renewal of LSCs without affecting normal hematopoiesis. Mechanistically, loss of PRMT7 leads to reprogramming of glycine metabolism, generating methylglyoxal which is detrimental to LSCs. These findings suggest PRMT7 as a potential therapeutic target for eradicating LSCs in CML.
Article
Medicine, Research & Experimental
Mansi Shah, Harish Kumar, Shaowei Qiu, Hui Li, Mason Harris, Jianbo He, Ajay Abraham, David K. Crossman, Andrew Paterson, Robert S. Welner, Ravi Bhatia
Summary: In chronic myeloid leukemia (CML), LT-HSCs expressing low c-KIT levels are primitive, quiescent, and drug-resistant leukemia-initiating cells, representing a critical target for eliminating disease persistence.
Article
Biochemistry & Molecular Biology
Patrick Ehm, Bettina Bettin, Manfred Juecker
Summary: Among various subtypes of ALL, the worst survival probabilities are observed in patients with BCR-ABL-positive background and those with a genetic change in the KMT2A gene, both characterized by highly activated tyrosine kinases. This study investigates the expression of SHIP1 protein in these subtypes and reveals that constitutively activated Src kinases downstream of BCR-ABL and receptor tyrosine kinases reduce the SHIP1 expression through phosphorylation of SHIP1-Y1021 and subsequent ubiquitin marked proteasomal degradation. Inhibition of BCR-ABL, Flt3, or SrcKinase-Family leads to reconstitution of SHIP1 protein expression, suggesting a potential targeted therapy approach.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
(2023)
Article
Biochemistry & Molecular Biology
Myun Soo Kim, Dongmin Park, Sora Lee, Sunyoung Park, Kyung Eun Kim, Tae Sung Kim, Hyun Jeong Park, Daeho Cho
Summary: The erythroid differentiation regulator 1 (Erdr1) enhances TCR signaling strength in CD4 T cells by promoting the activation and proliferation of T cells, amplifying Ca2+ influx and phosphorylation of PLC gamma 1, and promoting NFAT1 translocation into nuclei in the presence of TCR stimulation.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Immunology
Vanessa de Carvalho Oliveira, Olga Tatsiy, Patrick. P. P. McDonald
Summary: Neutrophil extracellular traps (NETs) can immobilize and kill pathogens, but also contribute to inflammatory and autoimmune diseases as well as cancer. The PI3K signaling pathway is crucial for NET formation, but the specific components involved are not well understood. This study identified the PI3K isoforms and signaling partners activated in response to different physiological NET inducers. The data revealed complexity and redundancy in the PI3K pathway controlling NET formation and suggest therapeutic targets for diseases involving NETs.
FRONTIERS IN IMMUNOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Elena Vuelta, Jose L. Ordonez, David J. Sanz, Sandra Ballesteros, Jesus M. Hernandez-Rivas, Lucia Mendez-Sanchez, Manuel Sanchez-Martin, Ignacio Garcia-Tunon
Summary: This study demonstrates the therapeutic potential of a CRISPR-Trap system as a novel strategy for gene elimination in haematological neoplasms. The CRISPR-Trap efficiently interrupts the coding sequence of the oncogene and allows for the selection of edited cells. In vitro and in vivo experiments show the therapeutic benefit of this system.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Elena V. Koroleva, Yuri V. Kornoushenko, Anna D. Karpenko, Ivan P. Bosko, Julia V. Siniutsich, Zhanna V. Ignatovich, Alexander M. Andrianov
Summary: An integrated computational approach was used to identify potential inhibitors of Bcr-Abl tyrosine kinase, an enzyme involved in chronic myeloid leukemia. Five compounds were found to effectively block the enzyme activity and exhibit high binding affinity comparable to FDA-approved kinase inhibitors. These compounds may serve as good scaffolds for the design of novel anticancer agents.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2023)
Article
Multidisciplinary Sciences
R. C. Nayak, K. H. Chang, A. K. Singh, M. Kotliar, M. Desai, A. M. Wellendorf, M. Wunderlich, J. Bartram, B. Mizukawa, M. Cuadrado, P. Dexheimer, A. Barski, X. R. Bustelo, N. N. Nassar, J. A. Cancelas
Summary: This study investigates the function of leukemic VAV3 in Ph+ and Ph-like B-ALL and reveals that nuclear VAV3 controls repressive transcriptional activity through the AKT/PHLPP2-BMI1 pathway. The findings highlight the importance of non-canonical nuclear Rho GTPase signaling in leukemogenesis.
NATURE COMMUNICATIONS
(2022)
Article
Medicine, General & Internal
Jeannig Berrou, Melanie Dupont, Hanane Djamai, Emilie Adiceam, Veronique Parietti, Anna Kaci, Emmanuelle Clappier, Jean-Michel Cayuela, Andre Baruchel, Fabrice Paublant, Renaud Prudent, Jacques Ghysdael, Claude Gardin, Herve Dombret, Thorsten Braun
Summary: This study demonstrates that LIMKi CEL_Amide has anti-leukemic effects in Ph+ ALL models when combined with BCR::ABL-targeting TKIs, showing promising synergy that warrants further investigation.
JOURNAL OF CLINICAL MEDICINE
(2022)
Article
Chemistry, Medicinal
You-lu Pan, Shen-xin Zeng, Rong-rong Hao, Mei-hao Liang, Zheng-rong Shen, Wen-hai Huang
Summary: This review summarizes the current research progress of inhibitors and degraders targeting BCR-ABL for the treatment of CML, including first, second, and third-generation tyrosine kinase inhibitors targeting different mutations, as well as allosteric inhibitors and proteolysis-targeting chimeras (PROTAC) based on different E3 ligands.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Multidisciplinary Sciences
Pelin Ayaz, Agatha Lyczek, YiTing Paung, Victoria R. Mingione, Roxana E. Iacob, Parker W. de Waal, John R. Engen, Markus A. Seeliger, Yibing Shan, David E. Shaw
Summary: The authors used molecular dynamics simulations to study the binding process of Abl kinase with the cancer drug imatinib. The simulations revealed that imatinib induces a large conformational change of the protein and identified a region in Abl kinase that is structurally unstable during binding. Mutations in this region confer imatinib resistance by exacerbating structural instability.
NATURE COMMUNICATIONS
(2023)
Article
Multidisciplinary Sciences
Kyung Mok Kim, Anna Mura-Meszaros, Marie Tollot, Murali Shyam Krishnan, Marco Grundl, Laura Neubert, Marco Groth, Alejo Rodriguez-Fraticelli, Arthur Flohr Svendsen, Stefano Campaner, Nico Andreas, Thomas Kamradt, Steve Hoffmann, Fernando D. Camargo, Florian H. Heidel, Leonid Bystrykh, Gerald de Haan, Bjorn von Eyss
Summary: As individuals age, the immune system's function declines due to defects in hematopoietic stem cells (HSCs). Researchers have discovered that the Hippo pathway coactivator TAZ plays a crucial role in protecting aging HSCs from functional decline by buffering the loss of PU.1 activity, and have identified Clca3a1 as a marker for young-like HSCs even in old mice.
NATURE COMMUNICATIONS
(2022)
Article
Hematology
Steffen Koschmieder, Susanne Isfort, Dominik Wolf, Florian H. Heidel, Andreas Hochhaus, Philippe Schafhausen, Martin Griesshammer, Denise Wolleschak, Uwe Platzbecker, Konstanze Doehner, Philipp J. Jost, Stefani Parmentier, Markus Schaich, Nikolas von Bubnoff, Frank Stegelmann, Angela Maurer, Martina Crysandt, Deniz Gezer, Maike Kortmann, Jeremy Franklin, Julia Frank, Martin Hellmich, Tim H. Bruemmendorf
Summary: This study found that treatment with ruxolitinib is effective, well-tolerated, and efficient for previously untreated patients with polycythemia vera, with significant reduction in symptoms and improvement in hematological parameters.
ANNALS OF HEMATOLOGY
(2023)
Meeting Abstract
Hematology
Jean-Jacques Kiladjian, David M. Ross, Laura Maria Fogliatto, Lynda Foltz, Lambert Busque, Zhijian Xiao, Florian H. Heidel, Michael Koehler, Giuseppe A. Palumbo, Massimo Breccia, Norio Komatsu, Keita Kirito, Blanca Xicoy Cirici, Joaquin Martinez-Lopez, Alicia Rovo, Cheryl Petruk, Mike Zuurman, Laura Mirams, Abigail McMillan, Gavin Harper, Claire Harrison
Meeting Abstract
Hematology
Srdan Verstovsek, Florian H. Heidel, Valerio De Stefano, Mike Zuurman, Kenneth Bryan, Armita Afsharinejad, Jean-Jacques Kiladjian
Article
Hematology
Maximilian Schoenung, Mark Hartmann, Stephen Kraemer, Sina Staeble, Mariam Hakobyan, Emely Kleinert, Theo Aurich, Defne Cobanoglu, Florian H. Heidel, Stefan Froehling, Michael D. Milsom, Matthias Schlesner, Pavlo Lutsik, Daniel B. Lipka
Summary: The study reveals significant changes in DNA methylation during the differentiation of hematopoietic cells, which is associated with the differentiation of immune cells. By using the Infinium Mouse Methylation BeadChip technology, researchers successfully obtained a detailed DNA methylation map of mouse hematopoiesis. They found that dynamically regulated DNA methylation is closely associated with cell type-specificity and the expression of hematopoietic genes, and identified a large number of novel putative cis-regulatory elements. This study provides an important platform for studying the epigenetic regulation of normal and malignant hematopoiesis.
EXPERIMENTAL HEMATOLOGY
(2023)
Article
Oncology
Jasmin Straube, Theresa Eifert, Therese Vu, Yashaswini Janardhanan, Rohit Haldar, Bjoern von Eyss, Leanne Cooper, Claudia Bruedigam, Victoria Y. Ling, Emily Cooper, Ann-Marie Patch, Lars Bullinger, Tina M. Schnoeder, Megan Bywater, Florian H. Heidel, Steven W. Lane
Summary: Murine models are useful for studying AML subtypes and compound mutations. The Cre recombinase expression in a transgenic murine model can lead to aggressive leukemia phenotype, polyclonal expansion of FLT3(ITD/ITD) progenitor cells, differentiation block and activation of Myc-dependent gene expression programs. Our report highlights the potential risks and unexpected effects of Cre expression in investigating oncogenic mutations in murine cancer models.
Review
Oncology
Andreas Schmidt, Christiane Bernhardt, Dieter Buerkle, Stefan Fries, Carla V. Hannig, Kathleen Jentsch-Ullrich, Andreas Josting, Stephan Kreher, Marcel Reiser, Hans Tilman Steinmetz, Hans Tesch, Stephanie Terner, Alexander Schulte, Carl C. Crodel, Francesca Palandri, Florian H. Heidel
Summary: This study evaluated the real-life approach to clinical characteristics, diagnostic assessment, risk stratification, and treatment decisions for MPN patients classified as ET or MF after the implementation of the WHO 2016 classification. It was found that some patients diagnosed with ET did not undergo bone marrow testing, and some patients diagnosed with MF did not receive early prognostic risk assessment. Improved histopathologic diagnostics and dynamic risk stratification are recommended for precise risk assessment and therapeutic stratification.
JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY
(2023)
Article
Oncology
Annamaria Brioli, Laura Gengenbach, Katia Mancuso, Mascha Binder, Thomas Ernst, Florian H. Heidel, Thomas Stauch, Elena Zamagni, Inken Hilgendorf, Andreas Hochhaus, Monika Engelhardt, Marie von Lilienfeld-Toal
Summary: This study investigates the role of pomalidomide combinations in daratumumab-refractory multiple myeloma (MM) patients. The results show that pomalidomide-based combinations can be effective and safe for daratumumab-refractory patients.
JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY
(2023)
Letter
Oncology
Frank Stegelmann, Lino L. Teichmann, Florian H. Heidel, Carl C. Crodel, Thomas Ernst, Sebastian Kreil, Andreas Reiter, Sara Otten, Stefanie Schauer, Ruth-Miriam Korber, Kim Kricheldorf, Susanne Isfort, Hartmut Doehner, Tim H. H. Bruemmendorf, Martin Griesshammer, Konstanze Doehner, Steffen Koschmieder
Article
Oncology
Florian H. Heidel, Carl C. Crodel, Hans H. Kreipe
Summary: This review focuses on primary myelofibrosis (PMF) and provides an overview of diagnostic criteria, clinical presentation, and therapeutic options. Diagnostic criteria include histopathologic characteristics, molecular evidence, and exclusion of other myeloid neoplasms. Treatment strategies are based on risk of progression and symptom burden, including allogeneic stem cell transplantation and JAK inhibitors.
Meeting Abstract
Hematology
Francesca Palandri, Elena Maria Elli, Alessandra Iurlo, Giuseppe Auteri, Malgorzata Monika Trawinska, Massimiliano Bonifacio, Francesco Mendicino, Roberto Latagliata, Camilla Mazzoni, Mattia Biondo, Valentina Sangiorgio, Daniele Cattaneo, Edoardo Tamellini, Elisabetta Abruzzese, Mauro Krampera, Stefana Impera, Bruno Garibaldi, Simona Paglia, Daniela Bartoletti, Nicola Vianelli, Michele Cavo, Florian H. Heidel, Massimo Breccia, Giovanni Caocci, Giuseppe A. Palumbo
Meeting Abstract
Hematology
Andreas Schmidt, Christiane Bernhardt, Anette Fries, Kathleen Jentsch-Ulrich, Andreas Josting, Stephan Kreher, Marcel Reiser, H. Tilman Steinmetz, Hans Tesch, Bernhard Kaufmann, Uta Rager, Carl C. Crodel, Francesca Palandri, Florian H. Heidel