Article
Multidisciplinary Sciences
Jarno Kivioja, Disha Malani, Ashwini Kumar, Mika Kontro, Alun Parsons, Olli Kallioniemi, Caroline A. Heckman
Summary: The study demonstrated a significant association between FLT3 internal tandem duplication allelic ratio (ITD-AR) and ex vivo response to FLT3 inhibitors in adult AML, while ITD length showed no correlation. Patients with high HLF gene expression and ITD-AR had better clinical response to the FLT3 inhibitor sorafenib compared to those with low ITD-AR and HLF expression.
SCIENTIFIC REPORTS
(2021)
Article
Biophysics
Feng-Ming Tien, Cheng-Hong Tsai, Sheng-Chuan Huang, Jia-Hau Liu, Chien-Yuan Chen, Yuan-Yeh Kuo, Yi-Kuang Chuang, Mei-Hsuan Tseng, Yen-Ling Peng, Ming-Chih Liu, Chia-Wen Liu, Xiu-Wen Liao, Liang-In Lin, Yu-Sin Wu, Mei-Fang Hou, Shang-Ju Wu, Szu-Chun Hsu, Bor-Sheng Ko, Wen-Chien Chou, Ming Yao, Hsin-An Hou, Jih-Luh Tang, Hwei-Fang Tien
Summary: The study found that FLT3-ITDlow in AML patients is associated with negative enrichment of leukemic stem cell features, marked enrichment of the RAS pathway, and higher frequencies of RAS pathway mutations, different from FLT3-ITDhigh. Concurrent CEBPA double mutations are favorable prognostic factors, while MLL-PTD and mutations in splicing factors are unfavorable prognostic factors in FLT3-ITDlow patients. Allo-HSCT in CR1 significantly prolongs overall survival and event-free survival in FLT3-ITDlow patients.
BONE MARROW TRANSPLANTATION
(2022)
Article
Oncology
Jiquan Jiang, Jing Feng, Xiangnan Song, Qing Yang, Hongbo Zhao, Rui Zhao, Xinrui He, Yaoyao Tian, Lianjie Wang, Yanhong Liu
Summary: The FLT3-ITD mutation in acute myeloid leukemia (AML) poses a serious threat to human health, with a poor prognosis and high risk of recurrence. Ferroptosis, an iron-dependent regulated cell death, plays a role in the development and progression of AML. This study identified a circRNA, hsa_circ_0015278, that regulates ferroptosis-related genes through miRNA sponge, promoting FLT3-ITD AML progression. This finding contributes to the identification of biomarkers for diagnosis and prognosis, and provides insights into the pathogenesis and therapeutic targets of AML with FLT3-ITD mutation.
Letter
Biophysics
Emily C. Liang, Connie Chen, Rong Lu, Gabriel N. Mannis, Lori Muffly
Summary: Measurable residual disease is associated with poor prognosis in AML, and new NGS methods are highly sensitive in detecting MRD. The use of FLT3 inhibitors post-HCT is crucial for maintaining remission. Early post-HCT MRD negatively impacts PFS, while maintenance FLT3 inhibitors lead to superior PFS and OS for both MRD-negative and MRD-positive patients.
BONE MARROW TRANSPLANTATION
(2021)
Article
Cell Biology
Jun Long, Xinjie Chen, Yan Shen, Yichen Lei, Lili Mu, Zhen Wang, Rufang Xiang, Wenhui Gao, Lining Wang, Ling Wang, Jieling Jiang, Wenjun Zhang, Huina Lu, Yan Dong, Yi Ding, Honghu Zhu, Dengli Hong, Yi Eve Sun, Jiong Hu, Aibin Liang
Summary: FLT3 inhibitors reduce the stability of the anti-cancer protein p53, leading to drug resistance. Blocking p53 degradation with proteasome inhibitors restores p53 protein levels and, when combined with FLT3-ITD inhibitors, shows superior therapeutic effects, suggesting a promising treatment strategy.
CELL REPORTS MEDICINE
(2023)
Article
Oncology
Anna Wojtuszkiewicz, Inge van der Werf, Stephan Hutter, Wencke Walter, Constance Baer, Wolfgang Kern, Jeroen J. W. M. Janssen, Gert J. Ossenkoppele, Claudia Haferlach, Jacqueline Cloos, Torsten Haferlach
Summary: This study explored differential splicing profiles associated with two common aberrations in AML, FLT3-ITD and NPM1 mutations. The co-occurrence of FLT3-ITD and mutated NPM1 was found to be associated with differential splicing of gene sets specific to FAB types, affecting cell cycle control and DNA damage response. Interestingly, differential expression mainly impacted genes involved in hematopoietic differentiation, indicating potential oncogenic relevance in FLT3-ITD+/NPM1+ samples.
Article
Oncology
Megan E. Zavorka Thomas, Xiyuan Lu, Zahra Talebi, Jae Yoon Jeon, Daelynn R. Buelow, Alice A. Gibson, Muhammad Erfan Uddin, Lindsey T. Brinton, Julie Nguyen, Meghan Collins, Alessia Lodi, Shannon R. Sweeney, Moray J. Campbell, Douglas H. Sweet, Alex Sparreboom, Rosa Lapalombella, Stefano Tiziani, Sharyn D. Baker
Summary: This study identified a novel metabolic pathway downstream of SLC38A1 that is sensitive to gilteritinib, leading to decreased glutaminolysis and disruption of redox homeostasis in leukemic cells. The combination treatment of gilteritinib with the glutaminase inhibitor CB-839 showed enhanced antileukemic effect in AML cells.
MOLECULAR CANCER THERAPEUTICS
(2021)
Article
Multidisciplinary Sciences
Tamara Castano-Bonilla, Juan M. Alonso-Dominguez, Eva Barragan, Rebeca Rodriguez-Veiga, Claudia Sargas, Cristina Gil, Carmen Chillon, Maria B. Vidriales, Raimundo Garcia, Joaquin Martinez-Lopez, Rosa Ayala, Maria J. Larrayoz, Eduardo Anguita, Rebeca Cuello, Alberto Cantalapiedra, Estrella Carrillo, Elena Soria-Saldise, Jorge Labrador, Isabel Recio, Lorenzo Algarra, Carlos Rodriguez-Medina, Cristina Bilbao-Syeiro, Juan A. Lopez-Lopez, Josefina Serrano, Erik De Cabo, Maria J. Sayas, Maria T. Olave, Joaquin Sanchez-Garcia, Mamen Mateos, Carlos Blas, Jose L. Lopez-Lorenzo, Daniel Lainez-Gonzalez, Juana Serrano, David Martinez-Cuadron, Miguel A. Sanz, Pau Montesinos
Summary: This study aimed to assess the prognostic impact of FLT3-ITD length and insertion site on complete remission rates, overall survival, and relapse-free survival of AML patients. The results suggest that FLT3-ITD length lacks prognostic value and clinical applicability.
SCIENTIFIC REPORTS
(2021)
Article
Biochemistry & Molecular Biology
Sankaranarayan Kannan, Mary E. Irwin, Shelley M. Herbrich, Tiewei Cheng, LaNisha L. Patterson, Marisa J. L. Aitken, Kapil Bhalla, M. James You, Marina Konopleva, Patrick A. Zweidler-McKay, Joya Chandra
Summary: AML patients with FLT3-ITD mutations have elevated levels of HO-1, which contributes to TKI resistance. Inhibiting HO-1 can increase sensitivity to TKI and genetic or pharmacological suppression of NRF2, a key driver of the pathway, results in decreased HO-1 levels and reduced AML resistance.
Article
Oncology
Christoph Rummelt, Sivahari P. Gorantla, Manja Meggendorfer, Anne Charlet, Cornelia Endres, Konstanze Doehner, Florian H. Heidel, Thomas Fischer, Torsten Haferlach, Justus Duyster, Nikolas von Bubnoff
Summary: One important limitation of FLT3 tyrosine kinase inhibitors in FLT3-ITD positive AML is the development of resistance. Research has found that JAK1 V658F mutation leads to reactivation of the CSF2RB-STAT5 pathway, while JAK family activating mutations induce resistance to FLT3-ITD inhibition, which can be overcome by dual FLT3/JAK inhibition.
Article
Cell Biology
Panpan Feng, Jingru Zhang, Juan Zhang, Xiaomin Liu, Lina Pan, Dawei Chen, Min Ji, Fei Lu, Peng Li, Guosheng Li, Tao Sun, Jingxin Li, Jingjing Ye, Chunyan Ji
Summary: The FLT3-ITD mutation is frequently observed in acute myeloid leukemia (AML) and is associated with poor prognosis. This study identifies YAP1 as a tumor suppressor in FLT3-ITD+ AML and demonstrates the role of the HDAC10-YAP1-PARP1 axis in mediating AML cell resistance to therapy. Targeting this axis, specifically with HDAC10 inhibitors, shows potential for improving clinical outcomes in FLT3-ITD+ AML patients.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Article
Oncology
Anamarija Pfeiffer, Giulia Franciosa, Marie Locard-Paulet, Ilaria Piga, Kristian Reckzeh, Vidyasiri Vemulapalli, Stephen C. Blacklow, Kim Theilgaard-Monch, Lars J. Jensen, Jesper V. Olsen
Summary: The protein tyrosine phosphatase SHP2 plays a crucial role in the oncogenic transformation of AML cells. By stabilizing SHP2 in its autoinhibited conformation, allosteric inhibitors show promise in inhibiting the RAS-ERK pathway and preventing cell proliferation and survival. Combination therapies that target SHP2 and other key enzymes can prevent the development of resistance.
Article
Oncology
Paola Minetto, Anna Candoni, Fabio Guolo, Marino Clavio, Maria Elena Zannier, Maurizio Miglino, Maria Vittoria Dubbini, Enrico Carminati, Anna Sicuranza, Sara Ciofini, Nicoletta Colombo, Girolamo Pugliese, Riccardo Marcolin, Adele Santoni, Filippo Ballerini, Luca Lanino, Michele Cea, Marco Gobbi, Monica Bocchia, Renato Fanin, Roberto Massimo Lemoli
Summary: In this study, the efficacy of FLAI induction therapy in younger AML patients with NPM1mut was investigated, showing potential to overcome the prognostic impact of FLT3-ITD co-mutations. The results suggest that FLAI may reduce the need for early consolidation with allogeneic transplant in double-mutated patients, supporting it as an ideal backbone for combination with innovative targeted drugs. The role of HSCT in first CR for NPM1mut patients with concomitant FLT3-ITD needs further evaluation.
Article
Chemistry, Multidisciplinary
Miao Yu, Zhi-xiao Fang, Wei-wei Wang, Ying Zhang, Zhi-lei Bu, Meng Liu, Xin-hua Xiao, Zi-lu Zhang, Xing-ming Zhang, Yang Cao, Ying-ying Wang, Hu Lei, Han-zhang Xu, Yun-zhao Wu, Wei Liu, Ying-li Wu
Summary: The novel USP10 inhibitor Wu-5 induces degradation of FLT3-ITD protein, selectively inhibits FLT3-ITD-positive AML cells, especially those resistant to FLT3 inhibitors. Combined treatment of Wu-5 and crenolanib synergistically enhances anti-AML effect by targeting FLT3 and AMPK alpha pathway.
ACTA PHARMACOLOGICA SINICA
(2021)
Editorial Material
Hematology
Sara E. Meyer
Summary: In this issue of Blood, Li et al.1 explore the role of FLT3 internal tandem duplication (ITD) in orchestrating transcriptional and epigenetic programs in myeloid progenitor cells, resulting in distinct functional outputs.