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
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
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
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.
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
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
Oncology
Jad Othman, Nicola Potter, Katya Mokretar, David Taussig, Anjum Khan, Pramila Krishnamurthy, Anne-Louise Latif, Paul Cahalin, James Aries, Mariam Amer, Edward Belsham, Eibhlin Conneally, Charles Craddock, Dominic Culligan, Mike Dennis, Caroline Duncan, Sylvie D. Freeman, Caroline Furness, Amanda Gilkes, Paraskevi Gkreka, Katherine Hodgson, Wendy Ingram, Manish Jain, Andrew King, Steven Knapper, Panagiotis Kottaridis, Mary Frances McMullin, Unmesh Mohite, Loretta Ngu, Jenny O'Nions, Katharine Patrick, Tom Rider, Wing Roberts, Marianne Tang Severinsen, Neill Storrar, Tom Taylor, Nigel H. Russell, Richard Dillon
Summary: Patients with FLT3-mutated AML are at high risk of relapse and poor outcomes. Monitoring measurable residual disease (MRD) can help identify patients destined to relapse, providing an opportunity for pre-emptive intervention. In this study, 56 patients with molecular failure were treated with FLT3 inhibitors (FLT3i), resulting in a molecular response rate of 60% and an overall survival rate of 80% at 2 years. High-sensitivity next-generation sequencing identified patients more likely to benefit from FLT3i monotherapy. Further prospective studies are warranted to evaluate this promising treatment strategy.
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
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
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
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.
Editorial Material
Oncology
Raffaele Palmieri, Luca Maurillo, Maria Ilaria Del Principe, Giovangiacinto Paterno, Roland Bruno Walter, Adriano Venditti, Francesco Buccisano
Article
Hematology
Luca Guarnera, Gentiana Elena Trotta, Valentina Boldrini, Lucia Cardillo, Ilaria Cerroni, Valeria Mezzanotte, Gianmario Pasqualone, Arianna Savi, Beatrice Borsellino, Elisa Buzzatti, Raffaele Palmieri, Giovangiacinto Paterno, Luca Maurillo, Francesco Buccisano, Adriano Venditti, Maria Ilaria Del Principe
Summary: Colonization by multidrug-resistant organisms (MDRO) is a frequent complication in hematologic departments, which puts patients at risk of life-threatening bacterial sepsis. Fever of unknown origin (FUO) is a condition related to the delivery of chemotherapy in hematologic malignancies, in which the use of antibiotics is debated. The incidence, risk factors, and influence on the outcome of these conditions in patients with acute myeloid leukemia (AML) are not clearly defined.
MEDITERRANEAN JOURNAL OF HEMATOLOGY AND INFECTIOUS DISEASES
(2023)
Letter
Hematology
Luca Guarnera, Elisa Buzzatti, Fabrizio Bonanni, Giovangiacinto Paterno, Antonella Riccitelli, Vittorio Forte, Adriano Venditti, Maria Ilaria Del Principe
ANNALS OF HEMATOLOGY
(2023)
Review
Biochemistry & Molecular Biology
Elisa Meddi, Arianna Savi, Federico Moretti, Flavia Mallegni, Raffaele Palmieri, Giovangiacinto Paterno, Elisa Buzzatti, Maria Ilaria Del Principe, Francesco Buccisano, Adriano Venditti, Luca Maurillo
Summary: In acute myeloid leukemia (AML), many patients experience relapse despite achieving complete remission. Traditional morphologic criteria are inadequate for assessing treatment response. Quantification of measurable residual disease (MRD) is a strong prognostic marker in AML, with MRD-negative patients having lower relapse rates and better survival. Different techniques for detecting MRD are available, and their use in guiding post-remission therapy is being actively investigated. Despite controversy, the prognostic value of MRD shows promise in supporting drug development and potentially expediting regulatory approval of new agents.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Oncology
Gianfranco Catalano, Alessandra Zaza, Cristina Banella, Elvira Pelosi, Germana Castelli, Elisabetta de Marinis, Ariela Smigliani, Serena Travaglini, Tiziana Ottone, Mariadomenica Divona, Maria Ilaria Del Principe, Francesco Buccisano, Luca Maurillo, Emanuele Ammatuna, Ugo Testa, Clara Nervi, Adriano Venditti, Maria Teresa Voso, Nelida Ines Noguera
Summary: We characterized the metabolic background in different types of Acute Myeloid Leukemia (AML) by comparing the metabolism of primary AML blasts with that of normal hematopoietic progenitors. The AML blasts showed lower respiratory and glycolytic capacities compared to hematopoietic precursors. AML blasts can be grouped based on Proton Leak values, and the group with high Proton Leak and high respiratory capacity had shorter overall survival time and overexpression of MCL1 protein. MCL1 was found to directly bind to HK2 on the outer mitochondrial membrane, suggesting its role in inducing glycolysis and promoting resistance to therapy in AML cells.
Article
Oncology
L. Maurillo, A. Spagnoli, A. Candoni, C. Papayannidis, E. Borlenghi, D. Lazzarotto, L. Fianchi, M. Sciume, M. E. Zannier, F. Buccisano, M. I. Del Principe, V. Mancini, M. Breccia, R. Fanin, E. Todisco, M. Lunghi, R. Palmieri, N. Fracchiolla, P. Musto, G. Rossi, A. Venditti
Summary: This study compared the efficacy of azacitidine and decitabine in elderly patients with untreated AML. The results showed similar outcomes in terms of complete remission, overall survival, and disease free survival between the two groups.
Letter
Medicine, General & Internal
Luca Guarnera, Elisa Buzzatti, Francesco Marchesi, Daniele Armiento, Carla Mazzone, Saveria Capria, Emilia Scalzulli, Francesco Malfona, Sabina Chiaretti, Raffaele Palmieri, Giovangiacinto Paterno, Chiara Franzese, Fabrizio Bonanni, Arianna Savi, Gianmario Pasqualone, Federico Moretti, Luca Maurillo, Francesco Buccisano, Adriano Venditti, Maria Ilaria Del Principe
Article
Oncology
Silvia Calabria, Giulia Ronconi, Letizia Dondi, Carlo Piccinni, Antonella Pedrini, Immacolata Esposito, Alice Addesi, Giuseppe Rossi, Felicetto Ferrara, Adriano Venditti, Nello Martini
Summary: This study aimed to identify newly diagnosed patients with acute myeloid leukemia in 2017 in Italy, and assess their probability of receiving allogeneic stem cell transplantation and survival. From the Italian National Health Service database, adults with in-hospital diagnosis of acute myeloid leukemia in 2017 were selected. Results showed that only patients treated with intensive chemotherapy underwent allogeneic stem cell transplantation and had higher survival rates.
Review
Hematology
Adriano Venditti, Roberto Cairoli, Morena Caira, Paola Finsinger, Fabio Finocchiaro, Benedetta Neri, Daniela De Benedittis, Giuseppe Rossi, Felicetto Ferrara
Summary: Age alone is no longer the sole indicator to determine eligibility for intensive chemotherapy in patients with acute myeloid leukemia (AML). The evaluation of comorbidities and overall performance status is also important in tailoring therapeutic options. Consensus criteria have been proposed to define eligibility for intensive and nonintensive chemotherapy in AML patients, and assessment of fitness is now essential in selecting the most appropriate treatment.
EXPERT REVIEW OF HEMATOLOGY
(2023)
Article
Oncology
T. Ottone, G. Silvestrini, R. Piazza, S. Travaglini, C. Gurnari, F. Marchesi, A. M. Nardozza, E. Fabiani, E. Attardi, L. Guarnera, M. Divona, P. Ricci, M. A. Irno Consalvo, S. Ienzi, R. Arcese, A. Biagi, L. Fiori, M. Novello, A. Mauriello, A. Venditti, L. Anemona, M. T. Voso
Summary: By analyzing the transcriptome profile of AML patients, researchers found that TWIST1, ECM-receptor interaction, and focal-adhesion pathways were significantly deregulated. The study also showed that metformin can interfere with these processes.
Review
Oncology
Anna Aureli, Beatrice Marziani, Adriano Venditti, Tommaso Sconocchia, Giuseppe Sconocchia
Summary: The emergence of targeted therapies has revolutionized the management of B-lineage acute lymphoblastic leukemia, allowing for optimism in replacing traditional treatments. However, few patients currently benefit from these therapies, necessitating further research to improve outcomes, particularly in patients resistant to current treatments. This review discusses new therapeutic options, including bispecific antibodies, antibody-drug conjugates, and CAR-based therapies.
Review
Oncology
Maria Christina Cox, Fabiana Esposito, Massimiliano Postorino, Adriano Venditti, Arianna Di Napoli
Summary: This systematic review explores the clinical impact of serum paraprotein (PP) in low- and high-grade mature B-cell malignancies. The analysis shows that serum PP is consistently associated with high-risk biological and clinical features, as well as poor outcome. Screening for serum PP should be included in the diagnostic work-up of all mature B-cell malignancies.
Letter
Health Care Sciences & Services
Mario Luppi, Elena Bandieri, Adriano Venditti, Paolo Corradini
BMJ SUPPORTIVE & PALLIATIVE CARE
(2023)
Article
Hematology
Jorge Sierra, Pau Montesinos, Xavier Thomas, Laimonas Griskevicius, Thomas Cluzeau, Denis Caillot, Ollivier Legrand, Clara Minotti, Mario Luppi, Firas Farkas, Bourras-Rezki Bengoudifa, Geralyn Gilotti, Sejla Hodzic, Alessandro Rambaldi, Adriano Venditti
Summary: The pivotal RATIFY study demonstrated that midostaurin combined with standard chemotherapy significantly reduced mortality in adult patients with newly diagnosed FLT3(mut) acute myeloid leukemia. This open-label, multicenter phase 3b trial aimed to further assess the safety and efficacy of midostaurin plus chemotherapy in different age groups. The results showed that the safety and efficacy of midostaurin remained consistent with previous findings regardless of age, sex, or induction regimen.
Article
Hematology
Michael Luebbert, Pierre W. Wijermans, Michal Kicinski, Sylvain Chantepie, Walter J. F. M. Van der Velden, Richard Noppeney, Laimonas Griskevicius, Andreas Neubauer, Martina Crysandt, Radovan Vrhovac, Mario Luppi, Stephan Fuhrmann, Ernesta Audisio, Anna Candoni, Olivier Legrand, Robin Foa, Gianluca Gaidano, Danielle van Lammeren-Venema, Eduardus F. M. Posthuma, Mels Hoogendoorn, Anne Giraut, Marian Stevens-Kroef, Joop H. Jansen, Aniek O. de Graaf, Fabio Efficace, Emanuele Ammatuna, Jean-Pierre Vilque, Ralph Waesch, Heiko Becker, Nicole Blijlevens, Ulrich Duehrsen, Frederic Baron, Stefan Suciu, Sergio Amadori, Adriano Venditti, Gerwin Huls
Summary: This study compares the efficacy and safety of decitabine monotherapy with intensive chemotherapy in older patients with acute myeloid leukemia. The results show that 10-day decitabine monotherapy is as effective and safer than 3 + 7 chemotherapy in older patients.
LANCET HAEMATOLOGY
(2023)