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.
Article
Pathology
Ing S. Tiong, Nikky Andrieska, Phuong Dang, Piers Blombery, Ella Thompson, Michelle McBean, Kate Jones
Summary: FLT3 internal tandem duplication (ITD) quantitation is crucial for predicting prognosis in acute myeloid leukaemia (AML). The number of polymerase chain reaction (PCR) cycles used can influence the allelic ratio (AR) and potentially impact risk categorisation in AML. Two FLT3-ITD assays, Huang and RATIFY, were compared and found to be highly concordant under standard conditions. However, the RATIFY assay showed a progressive decrease in AR when PCR cycles were increased, while the Huang assay showed minimal change in AR. Therefore, the effect of PCR cycle number on FLT3-ITD quantitation is assay-dependent and may have implications for risk stratification in AML.
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)
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.
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
Julhash U. Kazi, Lina Al Ashiri, Rituraj Purohit, Lars Ronnstrand
Summary: This study investigated the impact of FLT3 mutations on its function and interaction with therapeutic drugs in acute myeloid leukemia (AML). The findings provide insights for tailored treatments and highlight the significance of customized medical approaches in AML therapy.
Article
Hematology
Kaosheng Lv, Jian-Gang Ren, Xu Han, Jun Gui, Chujie Gong, Wei Tong
Summary: FLT3-ITD is S-palmitoylated by ZDHHC6 and disruption of palmitoylation redirects FLT3-ITD signaling, with depalmitoylation inhibition synergizing with FLT3 kinase inhibitor in treating FLT3-ITD+ AML. These findings suggest potential therapeutic strategy targeting depalmitoylation in FLT3-ITD+ leukemias.
Article
Oncology
Marie Schwarz, Sophie Rizzo, Walter Espinoza Paz, Anne Kresinsky, Damien Thevenin, Joerg P. Mueller
Summary: This study demonstrates that mutations in PTPRJ can increase its activity and impair FLT3 activity in acute myeloid leukemia cells, thereby restricting the transformation and proliferation abilities of leukemic cells.
FRONTIERS IN ONCOLOGY
(2022)
Article
Chemistry, Medicinal
Sheng Cao, Lan Ma, Yulin Liu, Mingming Wei, Yuhong Yao, Chen Li, Ruonan Wang, Ning Liu, Zhiqiang Dong, Xuechun Li, Ming Li, Xiaoji Wang, Cheng Yang, Guang Yang
Summary: In this study, dovitinib was chemically modified into CRBN-recruiting PROTACs, resulting in two active compounds with enhanced antiproliferative effects against FLT3-ITD+ AML cells and the ability to induce degradation of FLT3-ITD and KIT proteins while blocking their downstream signaling pathways. This study presents a promising strategy for developing novel therapies for FLT3-ITD+ AML.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
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
Biochemistry & Molecular Biology
Monika Tomanova, Karolina Kozlanska, Radek Jorda, Lukas Jedinak, Tereza Havlikova, Eva Reznickova, Miroslav Perina, Pavel Klener, Alexandra Dolnikova, Petr Cankar, Vladimir Krystof
Summary: The therapy of FLT3-positive acute myeloid leukemia remains complicated, despite the availability of newly approved kinase inhibitors. This study reports the development of a new FLT3 inhibitor and provides structure-activity relationship studies. Cellular analyses and in vivo experiments demonstrate the inhibitory activity of the compound.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
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
Gabriele Lo Iudice, Eleonora De Bellis, Arianna Savi, Luca Guarnera, Alice Massacci, Francesca De Nicola, Frauke Goeman, Tiziana Ottone, Mariadomenica Divona, Matteo Pallocca, Maurizio Fanciulli, Maria Teresa Voso, Gennaro Ciliberto
Summary: The article discusses a case of Acute Myeloid Leukaemia with both CBFB-MYH11 rearrangement and FLT3-ITD gene mutation, resulting in an extremely aggressive phenotype. Somatic and germline Whole Exome Sequencing revealed additional mutations in LTK, BCAS2, and LGAS9, but they were unlikely to be causative of the observed clinical phenotype.
JOURNAL OF TRANSLATIONAL MEDICINE
(2022)
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)
Review
Cell Biology
Yongfeng Chen, Zhenyou Zou, Mihnea-Alexandru Gaman, Linglong Xu, Jing Li
Summary: FLT3-ITD is the most common genetic change in acute myeloid leukemia (AML), and about 30% of all AMLs have a FLT3-ITD mutation. FLT3 inhibitors have shown promising effects in FLT3-ITD-mutated AML, but drug resistance limits the clinical response. Evidence suggests that FLT3-ITD triggers oxidative stress signaling, which plays a pivotal role in drug resistance. Downstream pathways of FLT3-ITD, including STAT5, PI3K/AKT, and RAS/MAPK, are major oxidative stress signaling pathways.
CELL DEATH DISCOVERY
(2023)