Review
Cell & Tissue Engineering
Hanieh Mojtahedi, Niloufar Yazdanpanah, Nima Rezaei
Summary: CML is driven by the BCR-ABL1 oncoprotein, and TKI therapy has been successful. However, mechanisms leading to resistance and disease progression in CML LSCs call for targeted therapies to eradicate them.
STEM CELL RESEARCH & THERAPY
(2021)
Article
Multidisciplinary Sciences
Yosuke Tanaka, Reina Takeda, Tsuyoshi Fukushima, Keiko Mikami, Shun Tsuchiya, Moe Tamura, Keito Adachi, Terumasa Umemoto, Shuhei Asada, Naoki Watanabe, Soji Morishita, Misa Imai, Masayoshi Nagata, Marito Araki, Hitoshi Takizawa, Tomofusa Fukuyama, Chrystelle Lamagna, Esteban S. Masuda, Ryoji Ito, Susumu Goyama, Norio Komatsu, Tomoiku Takaku, Toshio Kitamura
Summary: Leukemia stem cells in chronic myeloid leukemia are resistant to imatinib, but can be eliminated by combining imatinib with IRAK1/4 inhibitors that inhibit the IRAK1/4-NF-kappa B-PD-L1 signaling pathway.
NATURE COMMUNICATIONS
(2022)
Article
Oncology
Florian Ramdohr, Alice Fabarius, Bettina Maier, Daniela Bretschneider, Anna Jauch, Astrid Monecke, Klaus H. Metzeler, Johannes W. G. Janssen, Richard F. Schlenk, Sabine Kayser
Summary: The presence of the BCR::ABL1 fusion transcript is the hallmark of chronic myeloid leukemia (CML). However, some patients have rare BCR::ABL1 fusion transcripts, such as e6a2, which are associated with aggressive disease. There is limited evidence on the efficacy of front-line second-generation tyrosine kinase inhibitors for this genotype.
FRONTIERS IN ONCOLOGY
(2022)
Review
Pharmacology & Pharmacy
Gustavo P. Amarante-Mendes, Aamir Rana, Tarcila Santos Datoguia, Nelson Hamerschlak, Gabriela Brumatti
Summary: The constitutively active BCR-ABL1 tyrosine kinase plays a role in leukemia and initiates a complex signaling transduction cascade. Tyrosine kinase inhibitors have revolutionized the treatment of CML, but complete cure is not achieved. Other mechanisms exist in the later stages of the disease.
Review
Medicine, General & Internal
Jorge Cortes, Carolina Pavlovsky, Susanne Saussele
Summary: Tyrosine-kinase inhibitors have significantly altered the natural course of chronic myeloid leukaemia, allowing some patients to approach a near-normal life expectancy. Successful treatment requires understanding the patient's treatment goals, monitoring optimal response hallmarks, timely interventions, recognition of adverse events, and management of comorbidities.
Review
Biochemistry & Molecular Biology
Simona Soverini, Sara De Santis, Cecilia Monaldi, Samantha Bruno, Manuela Mancini
Summary: Chronic myeloid leukemia (CML) originates from the transformation of multipotent hematopoietic stem cells, with the resulting BCR-ABL1 fusion gene encoding a deregulated tyrosine kinase. Treatment with tyrosine kinase inhibitors (TKIs) can eliminate progenitor cells but not quiescent LSCs. Researchers have been working on identifying druggable targets for LSC eradication in CML.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Oncology
Emanuela Andretta, Caterina Costa, Consiglia Longobardi, Sara Damiano, Antonio Giordano, Francesco Pagnini, Serena Montagnaro, Massimiliano Quintiliani, Chiara Lauritano, Roberto Ciarcia
Summary: TKIs have significantly changed the treatment of CML, but their continued use can lead to increased clinical resistance and persistence of resistant LSCs. Therefore, additional targeted therapies are urgently needed to eradicate quiescent LSCs. Emerging BCR-ABL targeted and non-BCR-ABL targeted drugs, as well as alternative treatments, offer potential new therapeutic approaches for CML patients.
FRONTIERS IN ONCOLOGY
(2021)
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
Biochemistry & Molecular Biology
Rachid Lahlil, Anne Aries, Maurice Scrofani, Celine Zanetti, Desline Hennequin, Bernard Drenou
Summary: Chronic myeloid leukemia (CML) is a clonal myeloproliferative disease characterized by the presence of the BCR-ABL fusion gene. Treatment with tyrosine kinase inhibitors (TKIs) such as imatinib mesylate (IM) has significantly improved clinical outcomes for CML patients, but IM resistance remains a major challenge. The cause of IM resistance in CML cells is unclear, but additional genetic alterations in leukemic stem cells (LSCs) are a common cause of relapse. A study found that a rare subpopulation of stem cells called very small embryonic-like stem cells (VSELs) in adult CML patients is resistant to IM and less sensitive to apoptosis compared to leukemic hematopoietic stem cells (HSCs). The expression levels of certain miRNAs are also affected in these IM-resistant VSELs, including miR-126 and miR-21, which are involved in LSC leukemia-initiating capacity and growth.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Oncology
Yilin Chen, Jing Zou, Fanjun Cheng, Weiming Li
Summary: The therapeutic landscape for chronic myeloid leukemia has improved significantly with the approval of tyrosine kinase inhibitors. Most patients experience normal life expectancy with optimal responses to TKIs, but relapse after discontinuation hinders attempts at treatment-free remission. New monitoring methods and strategies targeting leukemic stem cells are being explored to address this challenge.
FRONTIERS IN ONCOLOGY
(2021)
Article
Oncology
Christian Boni, Massimiliano Bonifacio, Marzia Vezzalini, Luigi Scaffidi, Luisa Tomasello, Laurie L. Parker, Diego Boscarino, Dino Paladin, Mauro Krampera, Claudio Sorio
Summary: Chronic myeloid leukemia (CML) is caused by the fusion tyrosine kinase BCR::ABL1 produced by t(9;22). However, the direct measurement of BCR::ABL1 kinase activity in chronic phase (CP) CML has never been achieved due to degradation in mature leukocytes. In this study, a method was developed to preserve BCR::ABL1 protein in primary CP-CML samples, allowing for the detection of specific kinase activity using a selective substrate. The results showed that BCR::ABL1 kinase activity was barely detectable in CP-CML compared to Ph+ acute lymphoblastic leukemia samples.
FRONTIERS IN ONCOLOGY
(2022)
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
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
Pharmacology & Pharmacy
Francois Pierre Combes, Ying Fei Li, Matthias Hoch, Sebastien Lorenzo, Yu-Yun Ho, Sherwin K. B. Sy
Summary: Asciminib has potent activity against the T315I mutation in chronic myeloid leukemia patients. A longitudinal pharmacokinetic/pharmacodynamic model was developed to characterize the exposure-efficacy relationship of Asciminib. The model demonstrated the appropriateness of different doses for patients with or without the T315I mutation.
CLINICAL PHARMACOLOGY & THERAPEUTICS
(2022)
Article
Oncology
Ryan Yen, Sarah Grasedieck, Andrew Wu, Hanyang Lin, Jiechuang Su, Katharina Rothe, Helen Nakamoto, Donna L. Forrest, Connie J. Eaves, Xiaoyan Jiang
Summary: This study analyzed differentially expressed miRNAs in CML patients, showing that the combination of miR-145 and miR-708 effectively predicts response to NL in treatment-naive patients, while miR-150 and miR-185 are significant classifiers at 1 month and 3 months post-NL therapy.