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
Multidisciplinary Sciences
Benjamin C. S. Leow, Chung H. Kok, David T. Yeung, Timothy P. Hughes, Deborah L. White, Laura N. Eadie
Summary: Exploratory sequencing of gene transcripts was used to determine the mechanisms of drug resistance in a dasatinib resistant cell line model. The study identified BCR::ABL1 overexpression, BCR::ABL1 kinase domain mutation, and ABCG2 overexpression as mechanisms of dasatinib resistance. The acquisition of mutations followed an order corresponding with the increase in selective fitness associated with each resistance mechanism.
SCIENTIFIC REPORTS
(2023)
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
Oncology
Dachuan Zeng, Miao Gao, Renren Zheng, Run Qin, Wei He, Suotian Liu, Wei Wei, Zhenglan Huang
Summary: The study revealed that KW-2478 has anti-cancer properties in both imatinib-sensitive and imatinib-resistant CML cells by inhibiting the chaperone function of HSP90α, weakening the BCR/ABL and MAPK signaling pathways. In mouse models, KW-2478 effectively prolonged lifespan and alleviated disease symptoms.
EXPERIMENTAL HEMATOLOGY & ONCOLOGY
(2022)
Article
Chemistry, Medicinal
Mingxing Teng, Marlise R. Luskin, Sandra W. Cowan-Jacob, Qiang Ding, Doriano Fabbro, Nathanael S. Gray
Summary: This review discusses the recent progress in the treatment of chronic myeloid leukemia (CML) and highlights the discovery and mechanism of action of allosteric inhibitors. The therapeutic potential of these inhibitors in delaying the development of acquired resistance is also explored. The article emphasizes the importance of understanding the fundamental regulatory mechanisms of kinases and presents key lessons learned from this program.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Oncology
Yun Xu, Ziting Wang, Lei Zhang, Congying Gao, Fahui Li, Xueming Li, Yu Ke, Hong-Min Liu, Zhenbo Hu, Liuya Wei, Zhe-Sheng Chen
Summary: The compound JOA can inhibit the proliferation of chronic myeloid leukemia cells, including those with the BCR-ABL-T315I mutation, and induce cell differentiation. This effect may be mediated by the inhibition of the BCR-ABL/c-MYC signaling pathway. JOA shows potential as a lead compound for overcoming imatinib resistance in CML therapy.
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
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
Ashraf K. El-Damasy, Heewon Jin, Jung Woo Park, Hyun Ji Kim, Hanan Khojah, Seon Hee Seo, Ju-Hyeon Lee, Eun-Kyoung Bang, Gyochang Keum
Summary: This study identifies AK-HW-90 (2b) as a potent inhibitor against imatinib-resistant BCR-ABL mutants, especially T315I. AK-HW-90 exhibits superior anticancer activity compared to imatinib and shows strong cytotoxicity against multiple cancer cells, including leukemia cells.
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
(2023)
Article
Oncology
Zhen Liu, Wenlong Zheng, Yuan Liu, Binghe Zhou, Yuqing Zhang, Fan Wang
Summary: The study showed that HSPA8 is overexpressed in imatinib-resistant CML cells and its ablation can inhibit cell proliferation, induce autophagy, and enhance the anti-tumor activity of imatinib. These findings reveal the role of HSPA8 in IR-CML and suggest its potential as a target for treatment.
EXPERIMENTAL CELL RESEARCH
(2021)
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
Oncology
Charlotte E. J. Downes, Barbara J. McClure, John B. Bruning, Elyse Page, James Breen, Jacqueline Rehn, David T. Yeung, Deborah L. White
Summary: The study demonstrates that the JAK2 p.G993A mutation can confer resistance to multiple JAK inhibitors by modulating the mobility of the JAK2 activation loop, providing insights for future drug design and therapeutic strategies in high-risk patients with JAK2-rearranged B-cell acute lymphoblastic leukemia.
NPJ PRECISION ONCOLOGY
(2021)
Article
Hematology
Hjalmar Flygt, Fredrik Sandin, Torsten Dahlen, Arta Dremaine, Anna Lubking, Berit Markevarn, Kristina Myhr-Eriksson, Karin Olsson, Ulla Olsson-Stromberg, Anders Sjalander, Stina Soderlund, Lovisa Wennstrom, Hans Wadenvik, Leif Stenke, Martin Hoglund, Johan Richter
Summary: Clinical trials have shown that discontinuing TKI treatment in selected patients with CML is feasible, and this practice is common in clinical settings. The main reasons for stopping TKI treatment are achieving deep molecular response or other specific causes.
BRITISH JOURNAL OF HAEMATOLOGY
(2021)
Article
Oncology
Nilgun Karasu, Hilal Akalin, Nuriye Gokce, Abdulbaki Yildirim, Mikail Demir, Hande Kulak, Serhat Celik, Muzaffer Keklik, Munis Dundar
Summary: Pyrosequencing detected a certain proportion of BCR/ABL mutations in patients with chronic myeloid leukemia, with a higher positive rate in patients who had no response to imatinib treatment. Performing NGS analysis on patients resistant to imatinib helps identify more mutations.
Article
Chemistry, Multidisciplinary
Bohan Ma, Hui Feng, Chao Feng, Yi Liu, Hailing Zhang, Jincheng Wang, Wenjuan Wang, Pengcheng He, Fan Niu
Summary: The study designed a dual-targeting proteolysis-targeting chimera (PROTAC) type drug that can induce Bcr/Abl degradation and activate the p53 pathway simultaneously, potentially overcoming drug resistance in Ph+ leukemias.
Correction
Oncology
Frank Kroschinsky, Jan Moritz Middeke, Martin Janz, Georg Lenz, Mathias Witzens-Harig, Reda Bouabdallah, Paul La Rosee, Andreas Viardot, Gilles Salles, Seok Jin Kim, Tae Min Kim, Oliver Ottmann, Joerg Chromik, Anne-Marie Quinson, Ute von Wangenheim, Ute Burkard, Andreas Berk, Norbert Schmitz
INVESTIGATIONAL NEW DRUGS
(2021)
Article
Hematology
Elisabeth Oppliger Leibundgut, Monika Haubitz, Bart Burington, Oliver G. Ottmann, Gary Spitzer, Olatoyosi Odenike, Michael A. McDevitt, Alexander Roeth, David S. Snyder, Gabriela M. Baerlocher
Summary: The telomerase inhibitor imetelstat showed rapid hematologic responses in the majority of patients within 3-6 months of treatment. Patients with additional somatic mutations might develop new mutations during treatment, but most still responded positively to imetelstat.
Article
Oncology
Afsar Ali Mian, Usva Zafar, Syed Muhammad Areeb Ahmed, Oliver Gerhard Ottmann, El-Nasir M. A. Lalani
Summary: This study investigated nonmutational resistance mechanisms in Ph+ ALL patients and found that the AKT/mTOR pathway plays a role in this resistance. This research suggests potential novel targeted therapy for Ph+ ALL patients with BCR-ABL1 independent nonmutational resistance.
Meeting Abstract
Hematology
Afsar Ali Mian, Hadiqa Raees, Sujjawal Ahmad, Oliver Ottmann, El-Nasir M. A. Lalani
Meeting Abstract
Hematology
Andrew M. Brunner, Jordi Esteve, Kimmo Porkka, Steve Knapper, Elie Traer, Sebasttian Scholl, Guillermo Garcia-Manero, Norbert Vey, Martin Wermke, Jeroen Janssen, Rupa Narayan, Sun Loo, Mika Kontro, Oliver Ottmann, Purushotham Naidu, Marc Pelletier, May Han, Andrew Lewandowski, Na Zhang, Anisha Mohammed, Mikael L. Rinne, Uma Borate, Andrew H. Wei, Natalia Tovar
Meeting Abstract
Hematology
Anna G. Turkina, Olga Vinogradova, Elza Lomaia, Evgeniya Shatokhina, Oleg A. Shukhov, Andrey Zaritskey, Ekaterina Yu. Chelysheva, Dzhariyat Shikhbabaeva, Irina Nemchenko, Anna Petrova, Anastasiya Bykova, Vasily Shuvaev, Nadia Siordia, Jorge E. Cortes, Robert Peter Gale, Michele Baccarani, Oliver Ottmann, Ilya Mikhailov, Fedor Novikov, Veronika Shulgina, Ghermes Chilov
Article
Hematology
Marina Y. Konopleva, Christoph Roellig, Jamie Cavenagh, Dries Deeren, Larisa Girshova, Juergen Krauter, Giovanni Martinelli, Pau Montesinos, Jonas A. Schaefer, Oliver Ottmann, Mario Petrini, Arnaud Pigneux, Alessandro Rambaldi, Christian Recher, Rebeca Rodriguez-Veiga, David Taussig, Norbert Vey, Sung-Soo Yoon, Marion Ott, Susanne Muehlbauer, Benjamin M. Beckermann, Olivier Catalani, Magali Genevray, Kirsten Mundt, Candice Jamois, Pierre Fenaux, Andrew H. Wei
Summary: A study evaluating the efficacy and safety of the MDM2 antagonist idasanutlin plus cytarabine in patients with relapsed/refractory acute myeloid leukemia found that this combination did not improve overall survival or complete remission rates, despite an increased overall response rate.
Article
Hematology
Claudia Chiriches, Dilawar Khan, Maria Wieske, Nathalie Guillen, Michal Rokicki, Carol Guy, Marieangela Wilson, Kate J. Heesom, Oliver Gerhard Ottmann, Martin Ruthardt
Summary: Patients with t(6;9)-positive acute myeloid leukemia (AML) have younger age and poor prognosis. FKH1 cell line represents a model for t(6;9)-AML and can also serve as a model for ETV6-ABL1-positive AML. The activation of ABL1 kinase and other signaling pathways in FKH1 is influenced by DEK-CAN and ETV6-ABL1.
ANNALS OF HEMATOLOGY
(2022)
Article
Multidisciplinary Sciences
Yanis Tazi, Juan Arango Ossa, Yangyu Zhou, Elsa Bernard, Ian Thomas, Amanda Gilkes, Sylvie Freeman, Yoann Pradat, Sean Johnson, Robert Hills, Richard Dillon, Max Levine, Dan Leongamornlert, Adam Butler, Arnold Ganser, Lars Bullinger, Konstanze Doehner, Oliver Ottmann, Richard Adams, Hartmut Doehner, Peter Campbell, Alan Burnett, Michael Dennis, Nigel Russell, Sean Devlin, Brian Huntly, Elli Papaemmanuil
Summary: This study characterizes the genomic landscape of AML and identifies 16 molecular subgroups that have clinical relevance in disease classification and risk prognostication. The findings provide a unified framework for AML classification and risk stratification, and also offer a patient-tailored clinical decision support tool.
NATURE COMMUNICATIONS
(2022)
Article
Genetics & Heredity
Claudia Chiriches, Nathalie Nicolaisen, Maria Wieske, Heba Elhaddad, Ecmel Mehmetbeyoglu, Caroline Alvares, Doerte Becher, Paul Hole, Oliver Gerhard Ottmann, Martin Ruthardt
Summary: This study examines the impact of aberrant localization of t(6;9)-DEK/NUP214 on the biology of AML and reveals new therapeutic targets through analysis of the interactome. The study finds that DEK/NUP214 strongly influences RNA-regulation, programmed cell death, and leukocyte activation, highlighting their significant role in the phenotype of t(6;9)-AML.
Article
Oncology
Michael J. Mauro, Timothy P. Hughes, Dong-Wook Kim, Delphine Rea, Jorge E. Cortes, Andreas Hochhaus, Koji Sasaki, Massimo Breccia, Moshe Talpaz, Oliver Ottmann, Hironobu Minami, Yeow Tee Goh, Daniel J. DeAngelo, Michael C. Heinrich, Valle Gomez-Garcia de Soria, Philipp le Coutre, Francois-Xavier Mahon, Jeroen J. W. M. Janssen, Michael Deininger, Naranie Shanmuganathan, Mark B. Geyer, Silvia Cacciatore, Fotis Polydoros, Nithya Agrawal, Matthias Hoch, Fabian Lang
Summary: Asciminib has been approved for patients with Philadelphia chromosome-positive chronic-phase chronic myeloid leukemia (CML-CP) who have received >= 2 prior tyrosine kinase inhibitors or have the T315I mutation. A phase 1 trial evaluated the safety and efficacy of asciminib monotherapy in 115 CML-CP patients without T315I. After a median exposure of approximately 4 years, most patients remained on asciminib and achieved significant molecular responses.
Meeting Abstract
Oncology
Guillermo Garcia-Manero, Andrew H. Wei, Kimmo Porkka, Steve Knapper, Elie Traer, Sebastian Scholl, Norbert Vey, Martin Wermke, Jeroen Janssen, Rupa Narayan, Sun Loo, Natalia Tovar, Mika Kontro, Oliver Ottmann, Purushotham Naidu, Elena Orlando, Nidhi Patel, Jessica Makofske, Fei Ma, Na Zhang, Anisa Mohammed, Mikael L. Rinne, Uma Borate, Andrew M. Brunner
CLINICAL LYMPHOMA MYELOMA & LEUKEMIA
(2021)
Article
Hematology
Hartmut Dohner, Argiris Symeonidis, Dries Deeren, Judit Demeter, Miguel A. Sanz, Achilles Anagnostopoulos, Jordi Esteve, Walter Fiedler, Kimmo Porkka, Hee-Je Kim, Je-Hwan Lee, Kensuke Usuki, Stefano D'Ardia, Chul Won Jung, Olga Salamero, Heinz-August Horst, Christian Recher, Philippe Rousselot, Irwindeep Sandhu, Koen Theunissen, Felicitas Thol, Konstanze Dohner, Veronica Teleanu, Daniel J. DeAngelo, Tomoki Naoe, Mikkael A. Sekeres, Valerie Belsack, Miaomiao Ge, Tillmann Taube, Oliver G. Ottmann
Summary: This phase 3 trial did not demonstrate a survival benefit with the polo-like kinase inhibitor volasertib combined with low-dose cytarabine in older patients with acute myeloid leukemia who were ineligible for intensive chemotherapy, potentially due to increased early mortality in the volasertib group from myelosuppression and infections.
Review
Immunology
Yasmin Jenkins, Joanna Zabkiewicz, Oliver Ottmann, Nicholas Jones
Summary: CAR-T cells show high success rates in treating hematological B-cell malignancies but are less effective in solid tumor treatment. Competing for nutrients in the tumor microenvironment and immunosuppression lead to mitochondrial dysfunction and depletion of CAR-T cells. Research focuses on enhancing metabolic pathways of CAR-T cells to overcome immunosuppressive microenvironment.
Letter
Oncology
Oliver G. Ottmann, Frank Stegelmann, Massimo Breccia, Juan Luis Steegmann, Eduardo Olavarria, Paola Aimone, Jeffrey H. Lipton
LEUKEMIA & LYMPHOMA
(2021)