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)
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
Pharmacology & Pharmacy
Congying Gao, Lei Zhang, Yun Xu, Xiangyu Ma, Peilei Chen, Zhe-Sheng Chen, Liuya Wei
Summary: In this study, the potent histone deacetylase inhibitor I13 was assessed for its effect on chronic myeloid leukemia (CML) cells harboring T315I-mutated and wild-type BCR-ABL. I13 showed strong activity against both types of cells, inducing cell differentiation and suppressing proliferation by causing cell cycle G0/G1-phase accumulation. It was found that I13 blocked the CML signaling pathway by depleting BCR-ABL, resulting in cell differentiation. These findings highlight I13 as a BCR-ABL modulator for overcoming drug resistance caused by T315I-mutated BCR-ABL and have implications for CML therapy development.
FRONTIERS IN PHARMACOLOGY
(2023)
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
Hematology
Huimin Feng, Yue Fu, Zelong Cui, Minran Zhou, Lu Zhang, Zhenxing Gao, Sai Ma, Chunyan Chen
Summary: This study shows that PHF8 is significantly increased in CML patients and inhibits cell differentiation while promoting cell proliferation. Targeting PHF8, which directly regulates BCR::ABL1 expression, may be a useful therapeutic approach for CML.
BRITISH JOURNAL OF HAEMATOLOGY
(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
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
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
Cell Biology
Narissa Parry, Caroline Busch, Victoria Assmann, Jennifer Cassels, Alan Hair, G. Vignir Helgason, Helen Wheadon, Mhairi Copland
Summary: Dysregulation of the BCL-2 family is implicated in protecting CML cells, making it a viable therapeutic target. BH3 mimetics show clinical promise in the treatment of CML and can be used in combination with standard therapies. Combination of TKIs and BH3 mimetics significantly reduces cell viability and induces apoptosis in BP-CML cells. BH3 mimetics are more effective in myeloid BP-CML compared to single treatment.
CELL DEATH DISCOVERY
(2022)
Article
Medicine, General & Internal
Lu Gao, Ming-qiang Ren, Zu-guo Tian, Zhi-yuan Peng, Genghui Shi, Zhong Yuan
Summary: Chronic myelogenous leukemia patients with thrombocytosis and complex chromosomal translocation are extremely rare, and treatment with imatinib may be the preferred option. Performing BCR/ABL fusion gene examination can be an effective strategy to avoid misdiagnosis in patients with thrombocytosis.
Article
Oncology
Lioba Schoenfeld, Jenny Rinke, Anna Hinze, Saskia N. Nagel, Vivien Schaefer, Thomas Schenk, Christian Fabisch, Tim H. Bruemmendorf, Andreas Burchert, Philipp le Coutre, Stefan W. Krause, Susanne Saussele, Fatemeh Safizadeh, Markus Pfirrmann, Andreas Hochhaus, Thomas Ernst
Summary: Gene mutations independent of BCR::ABL1, especially in epigenetic modifier genes, are common in newly diagnosed patients with chronic myeloid leukemia in chronic phase. Specifically, ASXL1 mutations have been found to be the most commonly affected. These mutations are associated with less favorable molecular response to nilotinib treatment, and patients carrying ASXL1 mutations are typically younger and more frequently classified as high risk, suggesting a central role of clonal evolution associated with ASXL1 mutations in CML pathogenesis.
Article
Biochemistry & Molecular Biology
Dan Wang, Huan Yang, Yun Zhang, Rong Hu, Dongjie Hu, Qunxian Wang, Yannan Liu, Mingjing Liu, Zijun Meng, Weihui Zhou, Weihong Song
Summary: Increased levels of CBS and H2S have been found in pediatric CML patients and cells, inhibition of CBS can reduce cell proliferation, induce apoptosis, and inhibit cell migration.
SIGNAL TRANSDUCTION AND TARGETED THERAPY
(2021)
Article
Pharmacology & Pharmacy
Lihong Ding, Qinwei Chen, Kai Chen, Yuelong Jiang, Genhong Li, Qiuling Chen, Dongyu Bai, Dehong Gao, Manman Deng, Haiping Zhang, Bing Xu
Summary: Constitutively activated BCR-ABL kinase is the driver event in chronic myeloid leukemia (CML) development. Imatinib, the first BCR-ABL inhibitor, has improved clinical outcomes, but resistance occurs in 25-30% of patients. Simvastatin, a HMG-CoA reductase inhibitor, shows antitumor effects and acts as a sensitizer to kill imatinib-resistant and T315I mutated CML cells.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2021)
Article
Medicine, Research & Experimental
Kinjal D. Patel, Maitri De, Disha D. Jethva, Bharati S. Rathod, Prabhudas S. Patel
Summary: This study investigated the predictive value of sialylation changes in assessing imatinib mesylate (IM) resistance in chronic myeloid leukemia (CML) cases. The results showed that alterations in TSA, ST3GAL1, and ST3GAL2 levels were associated with IM resistance, providing clinical relevance in treatment monitoring and IM resistance treatment.
ARCHIVES OF MEDICAL RESEARCH
(2022)
Article
Hematology
Ahlam Nasser, Ally Hussein, Clara Chamba, Mbonea Yonazi, Rosemary Mushi, Anna Schuh, Lucio Luzzatto
Summary: Imatinib is the main treatment for chronic myeloid leukemia in Tanzania, but the majority of patients do not achieve deep molecular response, likely due to late diagnosis, cytopenias requiring drug interruptions, and poor treatment adherence.
Article
Biochemical Research Methods
Amna Jabbar Siddiqui, Caroline Le Senechal, Sebastien Vilain, Corinne Bure
JOURNAL OF MASS SPECTROMETRY
(2020)
Article
Oncology
Matthieu Lewis, Valerie Prouzet-Mauleon, Florence Lichou, Elodie Richard, Richard Iggo, Beatrice Turcq, Francois-Xavier Mahon
Article
Medicine, Research & Experimental
Marie-Julie Nokin, Elodie Darbo, Camille Travert, Benjamin Drogat, Aurelie Lacouture, Sonia San Jose, Nuria Cabrera, Beatrice Turcq, Valerie Prouzet-Mauleon, Mattia Falcone, Alberto Villanueva, Haiyun Wang, Michael Herfs, Miguel Mosteiro, Pasi A. Janne, Jean-Louis Pujol, Antonio Maraver, Mariano Barbacid, Ernest Nadal, David Santamaria, Chiara Ambrogio
Editorial Material
Oncology
Veronique Trezeguet, Sarah Lesjean, Philippe Veschambre, Patrick Auguste, Beatrice Turcq, Stephane Ducassou, Aksam Merched, Christophe F. Grosset
BULLETIN DU CANCER
(2020)
Article
Oncology
Gabriel Etienne, Stephanie Dulucq, Frederic Bauduer, Didier Adiko, Francois Lifermann, Corinne Dagada, Caroline Lenoir, Anna Schmitt, Emilie Klein, Samia Madene, Marie-Pierre Fort, Fontanet Bijou, Marius Moldovan, Beatrice Turcq, Fanny Robbesyn, Francoise Durrieu, Laura Versmee, Sandrine Katsahian, Carole Faberes, Axelle Lascaux, Francois-Xavier Mahon
Article
Oncology
Tra Ly Nguyen, Marie-Julie Nokin, Silvia Teres, Mercedes Tome, Clement Bodineau, Oriane Galmar, Jean-Max Pasquet, Benoit Rousseau, Sebastian van Liempd, Juan Manuel Falcon-Perez, Elodie Richard, Elodie Muzotte, Hamid-Reza Rezvani, Muriel Priault, Marion Bouchecareilh, Isabelle Redonnet-Vernhet, Julien Calvo, Benjamin Uzan, Francoise Pflumio, Patricia Fuentes, Maria L. Toribio, Abdel-Majid Khatib, Pierre Soubeyran, Piedad Del Socorro Murdoch, Raul Duran
Summary: Upregulation of Notch1 in T-ALL induces metabolic changes in glutamine, leading to increased glutamine addiction. Notch1 also activates the mTORC1 pathway through increased glutaminolysis, promoting cell growth. Combined treatment targeting mTORC1 and limiting glutamine availability has a synergistic effect in inducing apoptosis and preventing Notch1-driven leukemia progression.
MOLECULAR ONCOLOGY
(2021)
Article
Chemistry, Analytical
Corinne Bure, Caroline Le Senechal, Luis Macias, Caroline Tokarski, Sebastien Vilain, Jennifer S. Brodbelt
Summary: Lipopolysaccharides (LPS) form the outermost layer of Gram-negative bacteria, playing a crucial role in bacterial infections. Understanding the structure of lipid A, which anchors LPS to the bacterial outer membrane, is important in elucidating LPS virulence and toxicity. Various successful strategies utilizing tandem mass spectrometry have been employed for the structural analysis of lipid A, revealing new acyl chain positional isomers in the lipid A profile of Pseudomonas aeruginosa PAO1.
ANALYTICAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Caroline Le Senechal, Mathilde Puges, Christophe Barthe, Patricia Costaglioli, Caroline Tokarski, Corinne Bure, Sebastien Vilain
Summary: Bacteria form multicellular and resistant structures known as biofilms. Phospholipids, particularly PE 18:1-18:1, play a critical role in the attachment phase of biofilm formation. Different strains of Pseudomonas aeruginosa have distinct phospholipid profiles, with potential implications for developing strategies to combat biofilms.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Oncology
Gabriel Etienne, Carole Faberes, Frederic Bauduer, Didier Adiko, Francois Lifermann, Corinne Dagada, Caroline Lenoir, Anna Schmitt, Emilie Klein, Marie-Pierre Fort, Fontanet Bijou, Beatrice Turcq, Fanny Robbesyn, Francoise Durrieu, Laura Versmee, Samia Madene, Marius Moldovan, Sandrine Katsahian, Anais Charles-Nelson, Axelle Lascaux, Francois-Xavier Mahon, Stephanie Dulucq
Summary: Over a 10-year period, more than half of CP-CML patients were eligible for TKI discontinuation according to recommendations, and patients treated with second-generation TKI as frontline therapy had the lowest probability of molecular relapse after stopping TKI.
Article
Biochemistry & Molecular Biology
Laura Rodriguez, Pascale Duchez, Nicolas Touya, Christelle Debeissat, Amelie V. Guitart, Jean-Max Pasquet, Marija Vlaski-Lafarge, Philippe Brunet de la Grange, Zoran Ivanovic
Summary: Alpha tocopherol acetate affects the metabolic energy profile and functional properties of hematopoietic stem cells by attenuating oxidative phosphorylation and inhibiting the expression of Hypoxia-Inducible Factor-2 alpha. Experiments in ex vivo show that alpha TOA helps maintain stem cell activity, but its role in vivo remains unclear.
Article
Oncology
Pierre-Yves Dumas, Arnaud Villacreces, Amelie V. Guitart, Ali El-habhab, Layal Massara, Olivier Mansier, Audrey Bidet, Delphine Martineau, Solene Fernandez, Thibaut Leguay, Arnaud Pigneux, Isabelle Vigon, Jean-Max Pasquet, Vanessa Desplat
Summary: The study revealed that gilteritinib exhibited a stronger proapoptotic effect on FLT3-ITD AML cells in a simulated bone marrow microenvironment compared to quizartinib, and was more effective at targeting leukemia cells. Additionally, gilteritinib showed a toxicity profile on normal murine hematopoiesis similar to quizartinib.
CLINICAL CANCER RESEARCH
(2021)
Editorial Material
Oncology
Paulo De Sepulveda, Jean-Max Pasquet
Article
Endocrinology & Metabolism
Anne Trinh, Raeeka Khamari, Quentin Fovez, Francois-Xavier Mahon, Beatrice Turcq, Didier Bouscary, Patrice Maboudou, Marie Joncquel, Valerie Coiteux, Nicolas Germain, William Laine, Salim Dekiouk, Sandrine Jean-Pierre, Veronique Maguer-Satta, Bart Ghesquiere, Thierry Idziorek, Bruno Quesnel, Jerome Kluza, Philippe Marchetti
Summary: The study revealed that despite the suppression of glycolysis by TKI, glutamine-dependent mitochondrial oxidation supported the survival of CML cells. Inhibiting glutamine metabolism with L-Asparaginases made CML cells more susceptible to TKI and induced apoptosis, improving efficacy. Targeting glutamine metabolism with Kidrolase in combination with glycolysis-suppressing TKI is an effective therapeutic strategy for eradicating stem-like CML cells.
MOLECULAR METABOLISM
(2022)
Article
Oncology
Marine Dupont, Mathilde Huart, Claire Lauvinerie, Audrey Bidet, Amelie Valerie Guitart, Arnaud Villacreces, Isabelle Vigon, Vanessa Desplat, Ali El Habhab, Arnaud Pigneux, Zoran Ivanovic, Philippe Brunet De la Grange, Pierre-Yves Dumas, Jean-Max Pasquet
Summary: The mutation of fms-like receptor tyrosine kinase 3 is a common molecular abnormality in acute myeloid leukemia (AML), but targeting this mutation alone has not been able to prevent relapse. However, inhibiting autophagy by blocking PI3-kinase class III Vps34 offers a promising window for treating FLT3-ITD AML and reducing relapse. This study provides evidence that remission with low minimal residual disease in FLT3-ITD AML can be effectively treated with a combination of Vps34 inhibition and mobilization in order to target persistent leukemic stem cells.
Article
Cell & Tissue Engineering
Darija Loncaric, Laura Rodriguez, Christelle Debeissat, Nicolas Touya, Veronique Labat, Arnaud Villacreces, Anne-Karine Bouzier-Sore, Jean-Max Pasquet, Philippe Brunet de la Grange, Marija Vlaski-Lafarge, Sonja Pavlovic, Zoran Ivanovic
Summary: The data presented suggest that alpha-TOA positively impacts primitive cells within the mesenchymal stromal cell population by maintaining their proliferative capacity. This effect is likely achieved by decreasing the O-2 consumption rate of MStroC, although it does not lead to a compensatory increase in glycolysis activity. The moderate enhancement of mtROS upon alpha-TOA treatment also appears to be a factor, with potential implications for the inactivity of HIF-1 alpha and the maintenance of stemness.
STEM CELL REVIEWS AND REPORTS
(2021)
