Article
Multidisciplinary Sciences
Dinh Hoa Hoang, Dandan Zhao, Sergio Branciamore, Davide Maestrini, Ivan R. Rodriguez, Ya-Huei Kuo, Russell Rockne, Samer K. Khaled, Bin Zhang, Le Xuan Truong Nguyen, Guido Marcucci
Summary: In acute myeloid leukemia (AML), FLT3-ITD regulates the biogenesis of miR-126 and miR-155. FLT3-ITD induces the expression of miR-155, which down-regulates SHIP1 and increases AKT activity, leading to increased cell cycle progression. Additionally, miR-155 down-regulates SPRED1 and blocks the biogenesis of miR-126, resulting in decreased levels of mature miR-126.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Oncology
Kailong Jiang, Xuemei Li, Chang Wang, Xiaobei Hu, Peipei Wang, Lexian Tong, Yutong Tu, Beijing Chen, Tingting Jin, Tao Wang, Hanlin Wang, Yubing Han, Renzhao Gui, Jianmin Yang, Tao Liu, Jia Li, Yubo Zhou
Summary: FLT3 inhibitors (FLT3i) are widely used for AML treatment, but adaptive and acquired resistance remains a challenge. This study found that CHK1 inhibitors can synergistically enhance the therapeutic effect of FLT3i in FLT3-mutated AML cells, overcoming adaptive resistance. Simultaneous targeting of FLT3 and CHK1 may overcome acquired and adaptive resistance.
Letter
Oncology
Peihong Wang, Xinhua Xiao, Yuyin Zhang, Baoyuan Zhang, Donghe Li, Mingzhu Liu, Xi Xie, Chenxuan Liu, Ping Liu, Ruibao Ren
Summary: Research has identified KX2-391 as a promising FLT3 inhibitor for treating AML patients, especially those with drug-resistant FLT3-ITD-TKD mutations, showing significant efficacy in inhibiting FLT3 phosphorylation and enhancing apoptosis in AML cell lines.
JOURNAL OF HEMATOLOGY & ONCOLOGY
(2021)
Article
Oncology
Corinna Spohr, Teresa Poggio, Geoffroy Andrieux, Katharina Schoenberger, Nina Cabezas-Wallscheid, Melanie Boerries, Sebastian Halbach, Anna L. Illert, Tilman Brummer
Summary: The presence of internal tandem duplications (ITD) in FMS-like tyrosine kinase 3 (FLT3) combined with DNMT3A mutations in acute myeloid leukemia (AML) leads to poor prognosis. Studies have shown that GAB2 is essential for the development of Flt3-ITD driven AML, with Gab2 deficient mice displaying prolonged survival and reduced pathology. Gab2 increases signaling of receptor tyrosine kinases, promoting AML aggressiveness and drug resistance, making it a promising biomarker and therapeutic target in human AML.
Article
Medicine, Research & Experimental
Dan Xu, Yishan Chen, Ying Yang, Zhao Yin, Changfen Huang, Qiang Wang, Ling Jiang, Xuejie Jiang, Changxin Yin, Qifa Liu, Guopan Yu
Summary: Autophagy plays a critical role in drug resistance in FLT3-ITD-positive AML. It can be activated by acquired mutation or bone marrow micro-environment (BME) and mediates resistance to FLT3 inhibitors. Inhibiting autophagy could be a promising strategy to overcome resistance.
JOURNAL OF TRANSLATIONAL MEDICINE
(2022)
Article
Pharmacology & Pharmacy
Fangfang Wang, Jingcao Huang, Tingting Guo, Yuhuan Zheng, Li Zhang, Dan Zhang, Fujue Wang, Duolan Naren, Yushan Cui, Xiaoyan Liu, Ying Qu, Hongmei Luo, Yan Yang, Haichen Wei, Yong Guo
Summary: The combination treatment of HHT with quizartinib has shown synergistic effects on inhibiting cell growth, inducing apoptosis, and prolonging survival in mice with FLT3-ITD AML, suggesting it as a promising therapeutic strategy.
BIOCHEMICAL PHARMACOLOGY
(2021)
Article
Hematology
Shota Yokoyama, Masahiro Onozawa, Shota Yoshida, Naoki Miyashita, Hiroyuki Kimura, Shogo Takahashi, Toshihiro Matsukawa, Hideki Goto, Shinichi Fujisawa, Kosuke Miki, Daisuke Hidaka, Junichi Hashiguchi, Kentaro Wakasa, Makoto Ibata, Yukari Takeda, Akio Shigematsu, Katsuya Fujimoto, Yutaka Tsutsumi, Akio Mori, Toshimichi Ishihara, Yasutaka Kakinoki, Takeshi Kondo, Daigo Hashimoto, Takanori Teshima
Summary: Recent advances in next-generation sequencing have allowed for the detection of subclinical minute FLT3-ITD. We found that the molecular characteristics of minute FLT3-ITD were similar to clinically relevant FLT3-ITD, and the relapse rate was significantly higher in cases with minute FLT3-ITD. We observed the expansion of minute FLT3-ITD to become a dominant clone at relapse in clinically FLT3-ITD-negative AML.
BRITISH JOURNAL OF HAEMATOLOGY
(2023)
Article
Multidisciplinary Sciences
Kun-Yin Qiu, Xiong-Yu Liao, Yong Liu, Ke Huang, Yang Li, Jian-Pei Fang, Dun-Hua Zhou
Summary: This study explores the relationship between FLT3/ITD allelic ratio and prognosis in pediatric AML patients and identifies an optimal threshold value, highlighting the importance of individualized treatment for pediatric AML.
NATURE COMMUNICATIONS
(2022)
Article
Oncology
Stefan Bjelosevic, Emily Gruber, Andrea Newbold, Carolyn Shembrey, Jennifer R. Devlin, Simon J. Hogg, Lev Kats, Izabela Todorovski, Zheng Fan, Thomas C. Abrehart, Giovanna Pomilio, Andrew Wei, Gareth P. Gregory, Stephin J. Vervoort, Kristin K. Brown, Ricky W. Johnstone
Summary: FLT3-ITD promotes serine synthesis in AML, making FLT3-ITD-driven leukemias dependent on serine for proliferation and survival. Pharmacologically exploiting this metabolic dependency can sensitize FLT3-ITD-driven AML to chemotherapy.
Article
Medicine, Research & Experimental
Ying Xu, Ping Wang, Mengyuan Li, Zhaoxing Wu, Xian Li, Jianping Shen, Rongzhen Xu
Summary: Triptonide is a natural small molecule that can efficiently inhibit FLT3-ITD-driven AML in vitro and in vivo, targeting the Hedgehog/FLT3 signaling pathway. This study identifies Hedgehog/FLT3 axis as a novel target for treating FLT3-ITD-driven leukemia and demonstrates that triptonide is an active lead compound with good efficacy and tolerability for killing FLT3-ITD-driven leukemia cells.
BIOMEDICINE & PHARMACOTHERAPY
(2021)
Article
Oncology
Xinhua Xiao, Peihong Wang, Weina Zhang, Jiayi Wang, Mansi Cai, Hua Jiang, Yingli Wu, Huizhuang Shan
Summary: Our study revealed that GNF-7 is a potent FLT3-ITD inhibitor, exhibiting strong anti-leukemia activity against primary FLT3-ITD AML samples. GNF-7 binds to FLT3 protein and inhibits downstream signaling pathways, including STAT5, PI3K/AKT, and MAPK/ERK. It also shows potent inhibitory activity against FLT3-ITD/F691L that confers resistance to quizartinib or gilteritinib. Additionally, GNF-7 exhibits cytotoxic effect on leukemic stem cells, significantly extends survival in a PDX model, and shows comparable therapeutic effects to gilteritinib.
CANCER CELL INTERNATIONAL
(2023)
Article
Health Care Sciences & Services
David J. Wooten, Melat Gebru, Hong-Gang Wang, Reka Albert
Summary: The study investigated the gene expression changes in FLT3-mutant AML cell lines in response to drug treatment, identifying seven gene programs involved in AML drug-induced changes. By constructing a network of FLT3-ITD AML and applying the BooleaBayes algorithm, a probabilistic, data-driven dynamical model of acquired resistance to drugs was created, revealing potential interventions to disrupt the drug response system and prevent resistance.
JOURNAL OF PERSONALIZED MEDICINE
(2021)
Article
Oncology
Jong-Mi Lee, Silvia Park, Insik Hwang, Dain Kang, Byung Sik Cho, Hee-Je Kim, Ari Ahn, Myungshin Kim, Yonggoo Kim
Summary: This article presents an ITD-tracing algorithm based on NGS method for monitoring MRD in AML patients. The assay shows high sensitivity and superior performance, and demonstrates prognostic value in AML patients undergoing allogeneic hematopoietic stem cell transplantation.
Review
Oncology
Tobias R. Haage, Burkhart Schraven, Dimitrios Mougiakakos, Thomas Fischer
Summary: Mutations of the FLT3 gene are common in AML, occurring as internal tandem duplications (FLT3-ITD) in approximately 30% of cases. The specific insertion sites of FLT3-ITD show significant heterogeneity in biological and clinical features. Non-juxtamembrane domain (non-JMD) FLT3-ITD insertions have been associated with worse clinical outcomes and resistance to treatment. This review highlights the importance of considering non-JMD FLT3-ITD mutations in risk stratification and developing targeted therapies for AML.
Article
Oncology
Javier Bregante, Anna Schoenbichler, Daniel Poeloeske, Lina Degenfeld-Schonburg, Garazi Monzo Contreras, Emir Hadzijusufovic, Elvin D. de Araujo, Peter Valent, Richard Moriggl, Anna Orlova
Summary: FLT3-ITD mutations are common and detrimental in AML, with AML cells quickly developing resistance to FLT3 kinase inhibitors. Through a drug screen, new potential therapeutics like ispinesib, WS6, ponatinib, and cabozantinib have been identified for FLT3-ITD+ AML. Combination therapy with cabozantinib and ispinesib shows strong efficacy against FLT3-ITD+ AML, suggesting promising novel treatment options for this clinical challenge.
Article
Hematology
Rudy Birsen, Clement Larrue, Justine Decroocq, Natacha Johnson, Nathan Guiraud, Mathilde Gotanegre, Lilia Cantero-Aguilar, Eric Grignano, Tony Huynh, Michaela Fontenay, Olivier Kosmider, Patrick Mayeux, Nicolas Chapuis, Jean Emmanuel Sarry, Jerome Tamburini, Didier Bouscary
Summary: APR 246 is a promising therapeutic agent for myelodysplastic syndromes and acute myeloid leukemia that targets p53 mutated proteins. It has been found to reactivate the transcriptional activity of p53 mutants and induce p53-independent cell death. The study also demonstrates the association between APR 246 and ferroptosis, a recently described cell death process. The detoxification capacity of AML cells to maintain glutathione biosynthesis may play a key role in determining sensitivity to APR 246.
Article
Oncology
Shan Lin, Clement Larrue, Nastassja K. Scheidegger, Bo Kyung A. Seong, Neekesh Dharia, Miljan Kuljanin, Caroline S. Wechsler, Guillaume Kugener, Amanda L. Robichaud, Amy Saur Conway, Thelma Mashaka, Sarah Mouche, Biniam Adane, Jeremy A. Ryan, Joseph D. Mancias, Scott T. Younger, Federica Piccioni, Lynn H. Lee, Mark Wunderlich, Anthony Letai, Jerome Tamburini, Kimberly Stegmaier
Summary: This study utilized CRISPR screening to identify and validate AML-specific dependencies in vivo, including metabolic vulnerability and apoptosis regulator, providing an important strategy for discovering and prioritizing AML therapeutic targets.
Article
Hematology
Marion Haas, Gersende Caron, Fabrice Chatonnet, Stephane Manenti, Elina Alaterre, Julie Devin, Celine Delaloy, Giulia Bertolin, Roselyne Viel, Amandine Pignarre, Francisco Llamas-Gutierrez, Anne Marchalot, Olivier Decaux, Karin Tarte, Laurent Delpy, Jerome Moreaux, Thierry Fest
Summary: The kinase PIM2 plays a crucial role in the differentiation of B cells and in the survival of mature normal and malignant plasma cells. PIM2 regulates the cell cycle and apoptotic processes, affecting the secretion ability and adaptability of plasma cells.
Article
Hematology
Soledad Henriquez, Jeremie Zerbit, Timothee Bruel, Amani Ouedrani, Delphine Planas, Paul Deschamps, Isabelle Staropoli, Jerome Hadjadj, Bruno Varet, Natalia Ermak, Didier Bouscary, Lise Willems, Guillemette Fouquet, Justine Decroocq, Patricia Franchi, Benedicte Deau-Fischer, Benjamin Terrier, Jerome Tamburini, Lucienne Chatenoud, Olivier Schwartz, Marguerite Vignon
Letter
Hematology
Amira Marouf, Anne Segolene Cottereau, Salim Kanoun, Paul Deschamps, Michel Meignan, Patricia Franchi, David Sibon, Clara Antoine, Thomas Gastinne, Cecile Borel, Mohammad Hammoud, Guillaume Sicard, Romane Gille, Doriane Cavalieri, Aspasia Stamatoullas, Lauriane Filliatre-Clement, Julien Lazarovici, Adrien Chauchet, Luc-Matthieu Fornecker, Sandy Amorin, Mathieu Rocquet, Nicole Raus, Barbara Burroni, Marie Therese Rubio, Didier Bouscary, Philippe Quittet, Rene Olivier Casasnovas, Pauline Brice, Herve Ghesquieres, Jerome Tamburini, Benedicte Deau
Article
Cell Biology
Adrien Grenier, Laury Poulain, Johanna Mondesir, Arnaud Jacquel, Claudie Bosc, Lucille Stuani, Sarah Mouche, Clement Larrue, Ambrine Sahal, Rudy Birsen, Victoria Ghesquier, Justine Decroocq, Fetta Mazed, Mireille Lambert, Mamy Andrianteranagna, Benoit Viollet, Patrick Auberger, Andrew A. Lane, Pierre Sujobert, Didier Bouscary, Jean-Emmanuel Sarry, Jerome Tamburini
Summary: AMPK activation in AML cells triggers the unfolded protein response, leading to repression of oxidative phosphorylation, TCA cycle, and pyrimidine biosynthesis, as well as enhanced mitochondrial apoptotic signaling. Combination therapy with the AMPK activator GSK621 and the Bcl-2 inhibitor venetoclax shows synergistic effects, suggesting therapeutic potential in AML.
Article
Obstetrics & Gynecology
Pascal Froment, Ingrid Plotton, Cecilia Giulivi, Stephane Fabre, Rita Khoueiry, Nizar Mourad, Sandrine Horman, Christelle Rame, Charlene Rouillon, Jeremy Grandhaye, Yves Bigot, Claire Chevaleyre, Remy Le Guevel, Patricia Mallegol, Ramaroson Andriantsitohaina, Fabrice Guerif, Jerome Tamburini, Benoit Viollet, Marc Foretz, Joelle Dupont
Summary: The lack of alpha 1AMPK in granulosa cells impacts various biological processes and leads to a hyperandrogenic response.
HUMAN REPRODUCTION
(2022)
Article
Oncology
Morgane Le Bras, Noah Gorelick, Sylvain Pautet, Betty Tyler, Stephane Manenti, Nicolas Skuli, Stefania Millevoi, Anne Cammas
Summary: This study investigates the molecular mechanisms underlying protein synthesis deregulation in glioblastoma (GBM) and its impact on tumor progression and resistance to therapy. The results reveal the crucial role of RNA-binding proteins hnRNP H/F in controlling protein synthesis in GBM through overlapping mechanisms. Furthermore, hnRNP H/F are shown to potentiate cellular processes that contribute to the aggressive and resistant phenotype of GBMs, indicating their potential as therapeutic targets.
Letter
Oncology
A. Pradier, A. C. Mamez, C. Stephan, F. Giannotti, S. Masouridi-Levrat, S. Wang, S. Morin, D. Neofytos, D. L. Vu, A. Melotti, I. Arm, C. S. Eberhardt, J. Tamburini, L. Kaiser, Y. Chalandon, F. Simonetta
ANNALS OF ONCOLOGY
(2022)
Article
Oncology
Clement Larrue, Sarah Mouche, Shan Lin, Federico Simonetta, Nastassja K. Scheidegger, Laury Poulain, Rudy Birsen, Jean-Emmanuel Sarry, Kimberly Stegmaier, Jerome Tamburini
Summary: Mitochondrial fusion is a critical dependency in acute myeloid leukemia (AML). Inhibition of mitochondrial fusion through genetic depletion or pharmacological inhibition showed significant anti-leukemic activity in patient-derived xenograft (PDX) models, without impacting normal hematopoietic cells. Mechanistically, disruption of mitochondrial fusion led to cell cycle arrest and impaired mitochondrial respiration and reactive oxygen species production. These findings suggest that inhibition of mitochondrial fusion holds promise as a therapeutic approach for AML.
Article
Hematology
J. Dufour, S. Choquet, K. Hoang-Xuan, A. Schmitt, G. Ahle, R. Houot, L. Taillandier, R. Gressin, O. Casasnovas, J. P. Marolleau, J. Tamburini, C. Serrier, E. Perez, J. Paillassa, E. Gyan, A. Chauchet, R. Ursu, A. Kas, C. Soussain, C. Houillier
Summary: This nationwide population-based study found rare extracerebral relapses of primary central nervous system lymphomas (PCNSL). The extracerebral relapses were mainly found in visceral organs (particularly testis and breast) and the peripheral nervous system. The prognosis was worse for mixed relapses. The study suggests the use of PET-CT in diagnosis and paired tumor analysis at diagnosis/relapse to better understand the underlying molecular mechanisms.
ANNALS OF HEMATOLOGY
(2023)
Article
Hematology
A. Marouf, N. Molinari, D. Sibon, A. S. Cottereau, S. Kanoun, C. Antoine, P. E. Debureaux, D. Cavalieri, L. M. Fornecker, R. O. Casasnovas, C. Herbaux, S. Amorim, C. Rossi, D. Bouscary, P. Brice, H. Ghesquieres, J. Tamburini, B. Deau
Summary: Autologous hematopoietic stem cell transplant (ASCT) is the standard curative treatment for high-risk relapsed/refractory Hodgkin lymphoma (R/R HL) patients. Maintenance therapy with Brentuximab Vedotin (BV) after ASCT has been shown to improve survival in BV-naive patients. In this study, BV maintenance was compared to tandem transplant strategies and was found to be associated with better survival outcomes in patients with high-risk R/R HL.
BRITISH JOURNAL OF HAEMATOLOGY
(2023)
Article
Oncology
Marie Sabatier, Rudy Birsen, Laura Lauture, Sarah Mouche, Paolo Angelino, Jonas Dehairs, Ismael Boussaid, Mael Heiblig, Emeline Boet, Ambrine Sahal, Estelle Saland, Juliana C. Santos, Marc Armengol, Miranda Fernandez-Serrano, Thomas Farge, Guillaume Cognet, Federico Simonetta, Corentin Pignon, Antoine Graffeuil, Celine Mazzotti, Herve Avet-Loiseau, Oceane Delos, Justine Bertrand-Michel, Amelie Chedru, Vilma Dembitz, Paolo Gallipoli, Natasha S. Anstee, Sun Loo, Andrew H. Wei, Martin Carroll, Armelle Goubard, Remy Castellano, Yves Collette, Francois Vergez, Veronique Mansat-De Mas, Sarah Bertoli, Suzanne Tavitian, Muriel Picard, Christian Recher, Nathalie Bourges-Abella, Fanny Granat, Olivier Kosmider, Pierre Sujobert, Benoit Colsch, Carine Joffre, Lucille Stuani, Johannes V. Swinnen, Herve Guillou, Gael Roue, Nawad Hakim, Anne S. Dejean, Petros Tsantoulis, Clement Larrue, Didier Bouscary, Jerome Tamburini, Jean-Emmanuel Sarry
Summary: Although the role of CCAAT-enhancer binding protein α (C/EBPα) in cancer cell and metabolic homeostasis is largely unknown, this study reveals its coordination with FLT3 in lipid anabolism and its regulation of fatty acid biosynthesis and desaturation. Furthermore, FLT3 or C/EBPα inactivation decreases monounsaturated fatty acid incorporation and renders FLT3-mutant AML cells vulnerable to ferroptosis. This finding suggests a promising therapeutic potential for targeting FLT3-mutant AML cells.
Letter
Hematology
Maya Belhadj, Barbara Burroni, Olivier Kosmider, Lise Willems, Marie Temple, Sarah Bertoli, Corentin Orvain, Pierre-Yves Dumas, Celine Berthon, Ludovic Gabellier, Ambroise Marcais, Emmanuel Raffoux, Cecile Pautas, Alexis Genthon, Justine Decroocq, Rudy Birsen, Jerome Tamburini, Didier Bouscary, Adrien Contejean
BRITISH JOURNAL OF HAEMATOLOGY
(2023)
Article
Oncology
Charly Courdy, Loic Platteeuw, Charlotte Ducau, Isabelle De Araujo, Emeline Boet, Ambrine Sahal, Estelle Saland, Valerie Edmond, Suzanne Tavitian, Sarah Bertoli, Pierre Cougoul, Fanny Granat, Laura Poillet, Caroline Marty, Isabelle Plo, Jean-Emmanuel Sarry, Stephane Manenti, Veronique Mansat-De Mas, Carine Joffre
Summary: This study demonstrates that ruxolitinib induces autophagy through the activation of PP2A in JAK2(V617F) cells, and inhibiting autophagy or PP2A activity enhances the inhibitory effect of ruxolitinib on MPN cells. Additionally, a novel autophagy inhibitor, Lys05, improves the sensitivity to ruxolitinib and enhances the treatment efficacy for MPN patients.
BLOOD CANCER JOURNAL
(2023)
