492 results on '"Ilaria Iacobucci"'
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2. Defining the condensate landscape of fusion oncoproteins
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Swarnendu Tripathi, Hazheen K. Shirnekhi, Scott D. Gorman, Bappaditya Chandra, David W. Baggett, Cheon-Gil Park, Ramiz Somjee, Benjamin Lang, Seyed Mohammad Hadi Hosseini, Brittany J. Pioso, Yongsheng Li, Ilaria Iacobucci, Qingsong Gao, Michael N. Edmonson, Stephen V. Rice, Xin Zhou, John Bollinger, Diana M. Mitrea, Michael R. White, Daniel J. McGrail, Daniel F. Jarosz, S. Stephen Yi, M. Madan Babu, Charles G. Mullighan, Jinghui Zhang, Nidhi Sahni, and Richard W. Kriwacki
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Science - Abstract
Abstract Fusion oncoproteins (FOs) arise from chromosomal translocations in ~17% of cancers and are often oncogenic drivers. Although some FOs can promote oncogenesis by undergoing liquid-liquid phase separation (LLPS) to form aberrant biomolecular condensates, the generality of this phenomenon is unknown. We explored this question by testing 166 FOs in HeLa cells and found that 58% formed condensates. The condensate-forming FOs displayed physicochemical features distinct from those of condensate-negative FOs and segregated into distinct feature-based groups that aligned with their sub-cellular localization and biological function. Using Machine Learning, we developed a predictor of FO condensation behavior, and discovered that 67% of ~3000 additional FOs likely form condensates, with 35% of those predicted to function by altering gene expression. 47% of the predicted condensate-negative FOs were associated with cell signaling functions, suggesting a functional dichotomy between condensate-positive and -negative FOs. Our Datasets and reagents are rich resources to interrogate FO condensation in the future.
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- 2023
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3. Thymic Stromal Lymphopoietin (TSLP) Is Cleaved by Human Mast Cell Tryptase and Chymase
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Luisa Canè, Remo Poto, Francesco Palestra, Ilaria Iacobucci, Marinella Pirozzi, Seetharaman Parashuraman, Anne Lise Ferrara, Amalia Illiano, Antonello La Rocca, Edoardo Mercadante, Piero Pucci, Gianni Marone, Giuseppe Spadaro, Stefania Loffredo, Maria Monti, and Gilda Varricchi
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airway remodeling ,asthma ,chymase ,epithelial cells ,macrophage ,mast cell ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Thymic stromal lymphopoietin (TSLP), mainly expressed by epithelial cells, plays a central role in asthma. In humans, TSLP exists in two variants: the long form TSLP (lfTSLP) and a shorter TSLP isoform (sfTSLP). Macrophages (HLMs) and mast cells (HLMCs) are in close proximity in the human lung and play key roles in asthma. We evaluated the early proteolytic effects of tryptase and chymase released by HLMCs on TSLP by mass spectrometry. We also investigated whether TSLP and its fragments generated by these enzymes induce angiogenic factor release from HLMs. Mass spectrometry (MS) allowed the identification of TSLP cleavage sites caused by tryptase and chymase. Recombinant human TSLP treated with recombinant tryptase showed the production of 1-97 and 98-132 fragments. Recombinant chymase treatment of TSLP generated two peptides, 1-36 and 37-132. lfTSLP induced the release of VEGF-A, the most potent angiogenic factor, from HLMs. By contrast, the four TSLP fragments generated by tryptase and chymase failed to activate HLMs. Long-term TSLP incubation with furin generated two peptides devoid of activating property on HLMs. These results unveil an intricate interplay between mast cell-derived proteases and TSLP. These findings have potential relevance in understanding novel aspects of asthma pathobiology.
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- 2024
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4. Proteomic signature profiling in the cortex of dairy cattle unravels the physiology of brain aging
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Flora Cozzolino, Luisa Canè, Maria Claudia Gatto, Ilaria Iacobucci, Luigi Sacchettino, Davide De Biase, Evaristo Di Napoli, Orlando Paciello, Luigi Avallone, Maria Monti, Danila d’Angelo, and Francesco Napolitano
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bovine ,brain ,cortex ,aging ,proteomics ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
IntroductionAging is a physiological process occurring in all living organisms. It is characterized by a progressive deterioration of the physiological and cognitive functions of the organism, accompanied by a gradual impairment of mechanisms involved in the regulation of tissue and organ homeostasis, thus exacerbating the risk of developing pathologies, including cancer and neurodegenerative disorders.MethodsIn the present work, for the first time, the influence of aging has been investigated in the brain cortex of the Podolica cattle breed, through LC–MS/MS-based differential proteomics and the bioinformatic analysis approach (data are available via ProteomeXchange with identifier PXD044108), with the aim of identifying potential aging or longevity markers, also associated with a specific lifestyle.Results and discussionWe found a significant down-regulation of proteins involved in cellular respiration, dendric spine development, synaptic vesicle transport, and myelination. On the other hand, together with a reduction of the neurofilament light chain, we observed an up-regulation of both GFAP and vimentin in the aged samples. In conclusion, our data pave the way for a better understanding of molecular mechanisms underlying brain aging in grazing cattle, which could allow strategies to be developed that are aimed at improving animal welfare and husbandry practices of dairy cattle from intensive livestock.
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- 2023
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5. Preliminary evaluation of the proteomic profiling in the hippocampus of aged grazing cattle
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Flora Cozzolino, Luisa Canè, Luigi Sacchettino, Maria Claudia Gatto, Ilaria Iacobucci, Claudia Gatta, Davide De Biase, Evaristo Di Napoli, Orlando Paciello, Luigi Avallone, Maria Monti, Danila d’Angelo, and Francesco Napolitano
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aging ,bovine ,brain ,hippocampus ,proteomics ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Brain aging is a physiological process associated with physical and cognitive decline; however, in both humans and animals, it can be regarded as a risk factor for neurodegenerative disorders, such as Alzheimer’s disease. Among several brain regions, hippocampus appears to be more susceptible to detrimental effects of aging. Hippocampus belongs to limbic system and is mainly involved in declarative memories and context-dependent spatial-learning, whose integrity is compromised in an age-dependent manner. In the present work, taking advantage of liquid chromatography–tandem mass spectrometry (LC–MS/MS)-based proteomics, we sought to identify proteins differentially expressed in the hippocampus of the aged grazing milk cows. Our exploratory findings showed that, out of 707 identified proteins, 112 were significantly altered in old cattle, when compared to the adult controls, and functional clusterization highlighted their involvement in myelination, synaptic vesicle, metabolism, and calcium-related biological pathways. Overall, our preliminary data pave the way for the future studies, aimed at better characterizing the role of such a subcortical brain region in the age-dependent cognitive decline, as well as identifying early aging markers to improve animal welfare and husbandry practices of dairy cattle from intensive livestock.
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- 2023
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6. Stromal-induced epithelial-mesenchymal transition induces targetable drug resistance in acute lymphoblastic leukemia
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Chun Shik Park, Hiroki Yoshihara, Qingsong Gao, Chunxu Qu, Ilaria Iacobucci, Pankaj S. Ghate, Jon P. Connelly, Shondra M. Pruett-Miller, Ben Wagner, Camenzind G. Robinson, Ashutosh Mishra, Junmin Peng, Lei Yang, Zoran Rankovic, David Finkelstein, Selina Luger, Mark Litzow, Elisabeth M. Paietta, Nikhil Hebbar, M. Paulina Velasquez, and Charles G. Mullighan
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CP: Cancer ,Biology (General) ,QH301-705.5 - Abstract
Summary: The bone marrow microenvironment (BME) drives drug resistance in acute lymphoblastic leukemia (ALL) through leukemic cell interactions with bone marrow (BM) niches, but the underlying mechanisms remain unclear. Here, we show that the interaction between ALL and mesenchymal stem cells (MSCs) through integrin β1 induces an epithelial-mesenchymal transition (EMT)-like program in MSC-adherent ALL cells, resulting in drug resistance and enhanced survival. Moreover, single-cell RNA sequencing analysis of ALL-MSC co-culture identifies a hybrid cluster of MSC-adherent ALL cells expressing both B-ALL and MSC signature genes, orchestrated by a WNT/β-catenin-mediated EMT-like program. Blockade of interaction between β-catenin and CREB binding protein impairs the survival and drug resistance of MSC-adherent ALL cells in vitro and results in a reduction in leukemic burden in vivo. Targeting of this WNT/β-catenin-mediated EMT-like program is a potential therapeutic approach to overcome cell extrinsically acquired drug resistance in ALL.
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- 2023
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7. From the Discovery of Targets to Delivery Systems: How to Decipher and Improve the Metallodrugs’ Actions at a Molecular Level
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Ilaria Iacobucci, Sara La Manna, Irene Cipollone, Vittoria Monaco, Luisa Canè, and Flora Cozzolino
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metallodrugs ,medicinal chemistry ,chemoproteomics ,thermal proteome profiling ,pro-metallodrugs ,delivery systems ,Pharmacy and materia medica ,RS1-441 - Abstract
Metals are indispensable for the life of all organisms, and their dysregulation leads to various disorders due to the disruption of their homeostasis. Nowadays, various transition metals are used in pharmaceutical products as diagnostic and therapeutic agents because their electronic structure allows them to adjust the properties of molecules differently from organic molecules. Therefore, interest in the study of metal–drug complexes from different aspects has been aroused, and numerous approaches have been developed to characterize, activate, deliver, and clarify molecular mechanisms. The integration of these different approaches, ranging from chemoproteomics to nanoparticle systems and various activation strategies, enables the understanding of the cellular responses to metal drugs, which may form the basis for the development of new drugs and/or the modification of currently used drugs. The purpose of this review is to briefly summarize the recent advances in this field by describing the technological platforms and their potential applications for identifying protein targets for discovering the mechanisms of action of metallodrugs and improving their efficiency during delivery.
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- 2023
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8. Lysosome purinergic receptor P2X4 regulates neoangiogenesis induced by microvesicles from sarcoma patients
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Wulf Palinski, Maria Monti, Rosa Camerlingo, Ilaria Iacobucci, Serena Bocella, Federica Pinto, Clara Iannuzzi, Gelsomina Mansueto, Sara Pignatiello, Flavio Fazioli, Michele Gallo, Laura Marra, Flora Cozzolino, Annarosaria De Chiara, Piero Pucci, Antonio Bilancio, and Filomena de Nigris
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Cytology ,QH573-671 - Abstract
Abstract The tumor microenvironment modulates cancer growth. Extracellular vesicles (EVs) have been identified as key mediators of intercellular communication, but their role in tumor growth is largely unexplored. Here, we demonstrate that EVs from sarcoma patients promote neoangiogenesis via a purinergic X receptor 4 (P2XR4) -dependent mechanism in vitro and in vivo. Using a proteomic approach, we analyzed the protein content of plasma EVs and identified critical activated pathways in human umbilical vein endothelial cells (HUVECs) and human progenitor hematopoietic cells (CD34+). We then showed that vessel formation was due to rapid mitochondrial activation, intracellular Ca2+ mobilization, increased extracellular ATP, and trafficking of the lysosomal P2XR4 to the cell membrane, which is required for cell motility and formation of stable branching vascular networks. Cell membrane translocation of P2XR4 was induced by proteins and chemokines contained in EVs (e.g. Del-1 and SDF-1). Del-1 was found expressed in many EVs from sarcoma tumors and several tumor types. P2XR4 blockade reduced EVs-induced vessels in angioreactors, as well as intratumor vascularization in mouse xenografts. Together, these findings identify P2XR4 as a key mediator of EVs-induced tumor angiogenesis via a signaling mediated by mitochondria-lysosome-sensing response in endothelial cells, and indicate a novel target for therapeutic interventions.
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- 2021
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9. Spike S1 domain interactome in non-pulmonary systems: A role beyond the receptor recognition
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Ilaria Iacobucci, Vittoria Monaco, Luisa Canè, Francesca Bibbò, Valentina Cioffi, Flora Cozzolino, Alfredo Guarino, Massimo Zollo, and Maria Monti
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SARS-CoV-2 ,proteomics ,interactomics ,host-virus interaction ,COVID-19 ,spike protein ,Biology (General) ,QH301-705.5 - Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes Coronavirus Disease 2019 (COVID-19), which, since 2019 in China, has rapidly become a worldwide pandemic. The aggressiveness and global spread were enhanced by the many SARS-CoV-2 variants that have been isolated up to now. These mutations affect mostly the viral glycoprotein Spike (S), the capsid protein mainly involved in the early stages of viral entry processes, through the recognition of specific receptors on the host cell surface. In particular, the subunit S1 of the Spike glycoprotein contains the Receptor Binding Domain (RBD) and it is responsible for the interaction with the angiotensin-converting enzyme 2 (ACE2). Although ACE2 is the primary Spike host receptor currently studied, it has been demonstrated that SARS-CoV-2 is also able to infect cells expressing low levels of ACE2, indicating that the virus may have alternative receptors on the host cells. The identification of the alternative receptors can better elucidate the pathogenicity and the tropism of SARS-CoV-2. Therefore, we investigated the Spike S1 interactomes, starting from host membrane proteins of non-pulmonary cell lines, such as human kidney (HK-2), normal colon (NCM460D), and colorectal adenocarcinoma (Caco-2). We employed an affinity purification-mass spectrometry (AP-MS) to pull down, from the membrane protein extracts of all cell lines, the protein partners of the recombinant form of the Spike S1 domain. The purified interactors were identified by a shotgun proteomics approach. The lists of S1 potential interacting proteins were then clusterized according to cellular localization, biological processes, and pathways, highlighting new possible S1 intracellular functions, crucial not only for the entrance mechanisms but also for viral replication and propagation processes.
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- 2022
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10. The endogenous HBZ interactome in ATL leukemic cells reveals an unprecedented complexity of host interacting partners involved in RNA splicing
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Mariam Shallak, Tiziana Alberio, Mauro Fasano, Maria Monti, Ilaria Iacobucci, Julien Ladet, Franck Mortreux, Roberto S. Accolla, and Greta Forlani
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HTLV-1 ,HBZ ,ATL ,interactome ,alternative splicing ,protein network ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Adult T-cell leukemia/lymphoma (ATL) is a T-cell lymphoproliferative neoplasm caused by the human T-cell leukemia virus type 1 (HTLV-1). Two viral proteins, Tax-1 and HBZ play important roles in HTLV-1 infectivity and in HTLV-1-associated pathologies by altering key pathways of cell homeostasis. However, the molecular mechanisms through which the two viral proteins, particularly HBZ, induce and/or sustain the oncogenic process are still largely elusive. Previous results suggested that HBZ interaction with nuclear factors may alter cell cycle and cell proliferation. To have a more complete picture of the HBZ interactions, we investigated in detail the endogenous HBZ interactome in leukemic cells by immunoprecipitating the HBZ-interacting complexes of ATL-2 leukemic cells, followed by tandem mass spectrometry analyses. RNA seq analysis was performed to decipher the differential gene expression and splicing modifications related to HTLV-1. Here we compared ATL-2 with MOLT-4, a non HTLV-1 derived leukemic T cell line and further compared with HBZ-induced modifications in an isogenic system composed by Jurkat T cells and stably HBZ transfected Jurkat derivatives. The endogenous HBZ interactome of ATL-2 cells identified 249 interactors covering three main clusters corresponding to protein families mainly involved in mRNA splicing, nonsense-mediated RNA decay (NMD) and JAK-STAT signaling pathway. Here we analyzed in detail the cluster involved in RNA splicing. RNAseq analysis showed that HBZ specifically altered the transcription of many genes, including crucial oncogenes, by affecting different splicing events. Consistently, the two RNA helicases, members of the RNA splicing family, DDX5 and its paralog DDX17, recently shown to be involved in alternative splicing of cellular genes after NF-κB activation by HTLV-1 Tax-1, interacted and partially co-localized with HBZ. For the first time, a complete picture of the endogenous HBZ interactome was elucidated. The wide interaction of HBZ with molecules involved in RNA splicing and the subsequent transcriptome alteration strongly suggests an unprecedented complex role of the viral oncogene in the establishment of the leukemic state.
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- 2022
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11. Enzyme Replacement Therapy for FABRY Disease: Possible Strategies to Improve Its Efficacy
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Ilaria Iacobucci, Bruno Hay Mele, Flora Cozzolino, Vittoria Monaco, Chiara Cimmaruta, Maria Monti, Giuseppina Andreotti, and Maria Monticelli
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Fabry disease ,drug repositioning ,interactome ,GLA ,Fabrazyme ,Replagal ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Enzyme replacement therapy is the only therapeutic option for Fabry patients with completely absent AGAL activity. However, the treatment has side effects, is costly, and requires conspicuous amounts of recombinant human protein (rh-AGAL). Thus, its optimization would benefit patients and welfare/health services (i.e., society at large). In this brief report, we describe preliminary results paving the way for two possible approaches: i. the combination of enzyme replacement therapy with pharmacological chaperones; and ii. the identification of AGAL interactors as possible therapeutic targets on which to act. We first showed that galactose, a low-affinity pharmacological chaperone, can prolong AGAL half-life in patient-derived cells treated with rh-AGAL. Then, we analyzed the interactomes of intracellular AGAL on patient-derived AGAL-defective fibroblasts treated with the two rh-AGALs approved for therapeutic purposes and compared the obtained interactomes to the one associated with endogenously produced AGAL (data available as PXD039168 on ProteomeXchange). Common interactors were aggregated and screened for sensitivity to known drugs. Such an interactor-drug list represents a starting point to deeply screen approved drugs and identify those that can affect (positively or negatively) enzyme replacement therapy.
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- 2023
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12. Therapeutic potential of ruxolitinib and ponatinib in patients with EPOR-rearranged Philadelphia chromosome-like acute lymphoblastic leukemia
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Lisa M. Niswander, Joseph P. Loftus, Élodie Lainey, Aurélie Caye-Eude, Morgane Pondrom, David A. Hottman, Ilaria Iacobucci, Charles G. Mullighan, Nitin Jain, Marina Konopleva, Hélène Cavé, André Baruchel, Pierre S. Rohrlich, and Sarah K. Tasian
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2021
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13. Protein-Based Delivery Systems for Anticancer Metallodrugs: Structure and Biological Activity of the Oxaliplatin/β-Lactoglobulin Adduct
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Daria Maria Monti, Domenico Loreto, Ilaria Iacobucci, Giarita Ferraro, Alessandro Pratesi, Luigi D’Elia, Maria Monti, and Antonello Merlino
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delivery system ,protein ,metallodrug ,anticancer ,protein metalation ,Medicine ,Pharmacy and materia medica ,RS1-441 - Abstract
β-lactoglobulin is the major component of whey. Here, the adduct formed upon the reaction of the protein with oxaliplatin (OXA) has been prepared, structurally characterized by X-ray crystallography and electrospray ionization–mass spectrometry, and evaluated as a cytotoxic agent. The data demonstrate that OXA rapidly binds β-lactoglobulin via coordination with a Met7 side chain upon release of the oxalate ligand. The adduct is significantly more cytotoxic than the free drug and induces apoptosis in cancer cells. Overall, our results suggest that metallodrug/β-lactoglobulin adducts can be used as anticancer agents and that the protein can be used as a metallodrug delivery system.
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- 2022
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14. New label-free methods for protein relative quantification applied to the investigation of an animal model of Huntington Disease.
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Flora Cozzolino, Alfredo Landolfi, Ilaria Iacobucci, Vittoria Monaco, Marianna Caterino, Simona Celentano, Chiara Zuccato, Elena Cattaneo, and Maria Monti
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Medicine ,Science - Abstract
Spectral Counts approaches (SpCs) are largely employed for the comparison of protein expression profiles in label-free (LF) differential proteomics applications. Similarly, to other comparative methods, also SpCs based approaches require a normalization procedure before Fold Changes (FC) calculation. Here, we propose new Complexity Based Normalization (CBN) methods that introduced a variable adjustment factor (f), related to the complexity of the sample, both in terms of total number of identified proteins (CBN(P)) and as total number of spectral counts (CBN(S)). Both these new methods were compared with the Normalized Spectral Abundance Factor (NSAF) and the Spectral Counts log Ratio (Rsc), by using standard protein mixtures. Finally, to test the robustness and the effectiveness of the CBNs methods, they were employed for the comparative analysis of cortical protein extract from zQ175 mouse brains, model of Huntington Disease (HD), and control animals (raw data available via ProteomeXchange with identifier PXD017471). LF data were also validated by western blot and MRM based experiments. On standard mixtures, both CBN methods showed an excellent behavior in terms of reproducibility and coefficients of variation (CVs) in comparison to the other SpCs approaches. Overall, the CBN(P) method was demonstrated to be the most reliable and sensitive in detecting small differences in protein amounts when applied to biological samples.
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- 2020
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15. Targeting WEE1 to enhance conventional therapies for acute lymphoblastic leukemia
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Andrea Ghelli Luserna Di Rorà, Neil Beeharry, Enrica Imbrogno, Anna Ferrari, Valentina Robustelli, Simona Righi, Elena Sabattini, Maria Vittoria Verga Falzacappa, Chiara Ronchini, Nicoletta Testoni, Carmen Baldazzi, Cristina Papayannidis, Maria Chiara Abbenante, Giovanni Marconi, Stefania Paolini, Sarah Parisi, Chiara Sartor, Maria Chiara Fontana, Serena De Matteis, Ilaria Iacobucci, Pier Giuseppe Pelicci, Michele Cavo, Timothy J. Yen, and Giovanni Martinelli
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Acute lymphoblastic leukemia ,WEE1 inhibitor ,Chemo-sensitizer agent ,G2/M checkpoint ,Diseases of the blood and blood-forming organs ,RC633-647.5 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Despite the recent progress that has been made in the understanding and treatment of acute lymphoblastic leukemia (ALL), the outcome is still dismal in adult ALL cases. Several studies in solid tumors identified high expression of WEE1 kinase as a poor prognostic factor and reported its role as a cancer-conserving oncogene that protects cancer cells from DNA damage. Therefore, the targeted inhibition of WEE1 kinase has emerged as a rational strategy to sensitize cancer cells to antineoplastic compounds, which we evaluate in this study. Methods The effectiveness of the selective WEE1 inhibitor AZD-1775 as a single agent and in combination with different antineoplastic agents in B and T cell precursor ALL (B/T-ALL) was evaluated in vitro and ex vivo studies. The efficacy of the compound in terms of cytotoxicity, induction of apoptosis, and changes in gene and protein expression was assessed using different B/T-ALL cell lines and confirmed in primary ALL blasts. Results We showed that WEE1 was highly expressed in adult primary ALL bone marrow and peripheral blood blasts (n = 58) compared to normal mononuclear cells isolated from the peripheral blood of healthy donors (p = 0.004). Thus, we hypothesized that WEE1 could be a rational target in ALL, and its inhibition could enhance the cytotoxicity of conventional therapies used for ALL. We evaluated the efficacy of AZD-1775 as a single agent and in combination with several antineoplastic agents, and we elucidated its mechanisms of action. AZD-1775 reduced cell viability in B/T-ALL cell lines by disrupting the G2/M checkpoint and inducing apoptosis. These findings were confirmed in human primary ALL bone marrow and peripheral blood blasts (n = 15). In both cell lines and primary leukemic cells, AZD-1775 significantly enhanced the efficacy of several tyrosine kinase inhibitors (TKIs) such as bosutinib, imatinib, and ponatinib, and of chemotherapeutic agents (clofarabine and doxorubicin) in terms of the reduction of cell viability, apoptosis induction, and inhibition of proliferation. Conclusions Our data suggest that WEE1 plays a role in ALL blast’s survival and is a bona fide target for therapeutic intervention. These data support the evaluation of the therapeutic potential of AZD-1775 as chemo-sensitizer agent for the treatment of B/T-ALL.
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- 2018
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16. Biologic and Therapeutic Implications of Genomic Alterations in Acute Lymphoblastic Leukemia
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Ilaria Iacobucci, Shunsuke Kimura, and Charles G. Mullighan
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B-ALL ,DUX4 ,IKZF1 ,PAX5 ,Ph-like ,ZNF384 ,Medicine - Abstract
Acute lymphoblastic leukemia (ALL) is the most successful paradigm of how risk-adapted therapy and detailed understanding of the genetic alterations driving leukemogenesis and therapeutic response may dramatically improve treatment outcomes, with cure rates now exceeding 90% in children. However, ALL still represents a leading cause of cancer-related death in the young, and the outcome for older adolescents and young adults with ALL remains poor. In the past decade, next generation sequencing has enabled critical advances in our understanding of leukemogenesis. These include the identification of risk-associated ALL subtypes (e.g., those with rearrangements of MEF2D, DUX4, NUTM1, ZNF384 and BCL11B; the PAX5 P80R and IKZF1 N159Y mutations; and genomic phenocopies such as Ph-like ALL) and the genomic basis of disease evolution. These advances have been complemented by the development of novel therapeutic approaches, including those that are of mutation-specific, such as tyrosine kinase inhibitors, and those that are mutation-agnostic, including antibody and cellular immunotherapies, and protein degradation strategies such as proteolysis-targeting chimeras. Herein, we review the genetic taxonomy of ALL with a focus on clinical implications and the implementation of genomic diagnostic approaches.
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- 2021
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17. What Antarctic Plants Can Tell Us about Climate Changes: Temperature as a Driver for Metabolic Reprogramming
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Laura Bertini, Flora Cozzolino, Silvia Proietti, Gaia Salvatore Falconieri, Ilaria Iacobucci, Rosanna Salvia, Patrizia Falabella, Maria Monti, and Carla Caruso
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Colobanthus quitensis ,differential proteomic analysis ,open top chambers ,response to stress ,temperature changes ,Microbiology ,QR1-502 - Abstract
Global warming is strongly affecting the maritime Antarctica climate and the consequent melting of perennial snow and ice covers resulted in increased colonization by plants. Colobanthus quitensis is a vascular plant highly adapted to the harsh environmental conditions of Antarctic Peninsula and understanding how the plant is responding to global warming is a new challenging target for modern cell physiology. To this aim, we performed differential proteomic analysis on C. quitensis plants grown in natural conditions compared to plants grown for one year inside open top chambers (OTCs) which determine an increase of about 4 °C at midday, mimicking the effect of global warming. A thorough analysis of the up- and downregulated proteins highlighted an extensive metabolism reprogramming leading to enhanced photoprotection and oxidative stress control as well as reduced content of cell wall components. Overall, OTCs growth seems to be advantageous for C. quitensis plants which could benefit from a better CO2 diffusion into the mesophyll and a reduced ROS-mediated photodamage.
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- 2021
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18. Genetic Alterations and Therapeutic Targeting of Philadelphia-Like Acute Lymphoblastic Leukemia
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Ilaria Iacobucci and Kathryn G. Roberts
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acute lymphoblastic leukemia (ALL) ,BCR-ABL1–like ALL ,Ph-like ALL ,cryptic rearrangements ,kinase signaling ,targeted therapy ,Genetics ,QH426-470 - Abstract
Philadelphia-like (Ph-like) acute lymphoblastic leukemia (ALL) is a subgroup of B-cell precursor ALL which by gene expression analysis clusters with Philadelphia-positive ALL although lacking the pathognomonic BCR-ABL1 oncoprotein. Its prevalence increases with age and similar to BCR-ABL1-positive ALL, Ph-like ALL is characterized by IKZF1 or other B-lymphoid transcription factor gene deletions and by poor outcome to conventional therapeutic approaches. Genetic alterations are highly heterogenous across patients and include gene fusions, sequence mutations, DNA copy number changes and cryptic rearrangements. These lesions drive constitutively active cytokine receptor and kinase signaling pathways which deregulate ABL1 or JAK signaling and more rarely other kinase-driven pathways. The presence of activated kinase alterations and cytokine receptors has led to the incorporation of targeted therapy to the chemotherapy backbone which has improved treatment outcome for this high-risk subtype. More recently, retrospective studies have shown the efficacy of immunotherapies including both antibody drug-conjugates and chimeric antigen receptor T cell therapy and as they are not dependent on a specific genetic alteration, it is likely their use will increase in prospective clinical trials. This review summarizes the genomic landscape, clinical features, diagnostic assays, and novel therapeutic approaches for patients with Ph-like ALL.
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- 2021
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19. Pharmacological Inhibition of WIP1 Sensitizes Acute Myeloid Leukemia Cells to the MDM2 Inhibitor Nutlin-3a
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Maria Chiara Fontana, Jacopo Nanni, Andrea Ghelli Luserna di Rorà, Elisabetta Petracci, Antonella Padella, Martina Ghetti, Anna Ferrari, Giovanni Marconi, Simona Soverini, Ilaria Iacobucci, Cristina Papayannidis, Antonio Curti, Ernesta Audisio, Maria Benedetta Giannini, Michela Rondoni, Francesco Lanza, Michele Cavo, Giovanni Martinelli, and Giorgia Simonetti
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AML ,novel therapeutic targets ,WIP1 ,MDM2 ,Biology (General) ,QH301-705.5 - Abstract
In acute myeloid leukemia (AML), the restoration of p53 activity through MDM2 inhibition proved efficacy in combinatorial therapies. WIP1, encoded from PPM1D, is a negative regulator of p53. We evaluated PPM1D expression and explored the therapeutic efficacy of WIP1 inhibitor (WIP1i) GSK2830371, in association with the MDM2 inhibitor Nutlin-3a (Nut-3a) in AML cell lines and primary samples. PPM1D transcript levels were higher in young patients compared with older ones and in core-binding-factor AML compared with other cytogenetic subgroups. In contrast, its expression was reduced in NPM1-mutated (mut, irrespective of FLT3-ITD status) or TP53-mut cases compared with wild-type (wt) ones. Either Nut-3a, and moderately WIP1i, as single agent decreased cell viability of TP53-wt cells (MV-4-11, MOLM-13, OCI-AML3) in a time/dosage-dependent manner, but not of TP53-mut cells (HEL, KASUMI-1, NOMO-1). The drug combination synergistically reduced viability and induced apoptosis in TP53-wt AML cell line and primary cells, but not in TP53-mut cells. Gene expression and immunoblotting analyses showed increased p53, MDM2 and p21 levels in treated TP53-wt cells and highlighted the enrichment of MYC, PI3K-AKT-mTOR and inflammation-related signatures upon WIP1i, Nut-3a and their combination, respectively, in the MV-4-11 TP53-wt model. This study demonstrated that WIP1 is a promising therapeutic target to enhance Nut-3a efficacy in TP53-wt AML.
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- 2021
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20. Genomic analyses identify recurrent MEF2D fusions in acute lymphoblastic leukaemia
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Zhaohui Gu, Michelle Churchman, Kathryn Roberts, Yongjin Li, Yu Liu, Richard C. Harvey, Kelly McCastlain, Shalini C. Reshmi, Debbie Payne-Turner, Ilaria Iacobucci, Ying Shao, I-Ming Chen, Marcus Valentine, Deqing Pei, Karen L. Mungall, Andrew J. Mungall, Yussanne Ma, Richard Moore, Marco Marra, Eileen Stonerock, Julie M. Gastier-Foster, Meenakshi Devidas, Yunfeng Dai, Brent Wood, Michael Borowitz, Eric E. Larsen, Kelly Maloney, Leonard A. Mattano Jr, Anne Angiolillo, Wanda L. Salzer, Michael J. Burke, Francesca Gianni, Orietta Spinelli, Jerald P. Radich, Mark D. Minden, Anthony V. Moorman, Bella Patel, Adele K. Fielding, Jacob M. Rowe, Selina M. Luger, Ravi Bhatia, Ibrahim Aldoss, Stephen J. Forman, Jessica Kohlschmidt, Krzysztof Mrózek, Guido Marcucci, Clara D. Bloomfield, Wendy Stock, Steven Kornblau, Hagop M. Kantarjian, Marina Konopleva, Elisabeth Paietta, Cheryl L. Willman, Mignon L. Loh, Stephen P. Hunger, and Charles G. Mullighan
- Subjects
Science - Abstract
Acute lymphoblastic leukaemia is characterized by chromosomal rearrangements. Here, the authors carry out RNA-sequencing on a large cohort of patients and identify recurrent rearrangements of MEF2D, which lead to increased transcriptional activity of the gene, and cellular transformation in vitro.
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- 2016
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21. A Comparative Study of the Effects of Platinum (II) Complexes on β-Amyloid Aggregation: Potential Neurodrug Applications
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Sara La Manna, Daniele Florio, Ilaria Iacobucci, Fabiana Napolitano, Ilaria De Benedictis, Anna Maria Malfitano, Maria Monti, Mauro Ravera, Elisabetta Gabano, and Daniela Marasco
- Subjects
amyloid aggregation ,metallodrugs ,platinum (II) compounds ,anti-aggregation properties ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Herein the effects of three platinum complexes, namely (SP-4-2)-(2,2′-bipyridine)dichloridoplatinum(II), Pt-bpy, (SP-4-2)-dichlorido(1,10-phenanthroline) platinum(II), Pt-phen, and (SP-4-2)-chlorido(2,2′:6′,2′′-terpyridine)platinum(II) chloride, Pt-terpy, on the aggregation of an amyloid model system derived from the C-terminal domain of Aβ peptide (Aβ21–40) were investigated. Thioflavin T (ThT) binding assays revealed the ability of Pt(II) compounds to repress amyloid aggregation in a dose-dependent way, whereas the ability of Aβ21–40 peptide to interfere with ligand field of metal complexes was analyzed through UV-Vis absorption spectroscopy and electrospray ionization mass spectrometry. Spectroscopic data provided micromolar EC50 values and allowed to assess that the observed inhibition of amyloid aggregation is due to the formation of adducts between Aβ21–40 peptide and complexes upon the release of labile ligands as chloride and that they can explore different modes of coordination toward Aβ21–40 with respect to the entire Aβ1–40 polypeptide. In addition, conformational studies through circular dichroism (CD) spectroscopy suggested that Pt-terpy induces soluble β-structures of monomeric Aβ21–40, thus limiting self-recognition. Noticeably, Pt-terpy demonstrated the ability to reduce the cytotoxicity of amyloid peptide in human SH-SY5Y neuroblastoma cells. Presented data corroborate the hypothesis to enlarge the application field of already known metal-based agents to neurodegenerative diseases, as potential neurodrugs.
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- 2021
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22. Lysines Acetylome and Methylome Profiling of H3 and H4 Histones in Trichostatin A—Treated Stem Cells
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Flora Cozzolino, Ilaria Iacobucci, Vittoria Monaco, Tiziana Angrisano, and Maria Monti
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histone PTMs ,limited proteolysis ,mass spectrometry ,TSA ,activation of differentiation ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Trichostatin A ([R-(E,E)]-7-[4-(dimethylamino) phenyl]-N-hydroxy- 4,6-dimethyl- 7-oxo-2,4-heptadienamide, TSA) affects chromatin state through its potent histone deacetylase inhibitory activity. Interfering with the removal of acetyl groups from lysine residues in histones is one of many epigenetic regulatory processes that control gene expression. Histone deacetylase inhibition drives cells toward the differentiation stage, favoring the activation of specific genes. In this paper, we investigated the effects of TSA on H3 and H4 lysine acetylome and methylome profiling in mice embryonic stem cells (ES14), treated with trichostatin A (TSA) by using a new, untargeted approach, consisting of trypsin-limited proteolysis experiments coupled with MALDI-MS and LC-MS/MS analyses. The method was firstly set up on standard chicken core histones to probe the optimized conditions in terms of enzyme:substrate (E:S) ratio and time of proteolysis and, then, applied to investigate the global variations of the acetylation and methylation state of lysine residues of H3 and H4 histone in the embryonic stem cells (ES14) stimulated by TSA and addressed to differentiation. The proposed strategy was found in its simplicity to be extremely effective in achieving the identification and relative quantification of some of the most significant epigenetic modifications, such as acetylation and lysine methylation. Therefore, we believe that it can be used with equal success in wider studies concerning the characterization of all epigenetic modifications.
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- 2021
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23. Modulation of Amyloidogenic Peptide Aggregation by Photoactivatable CO-Releasing Ruthenium(II) Complexes
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Daniele Florio, Maria Cuomo, Ilaria Iacobucci, Giarita Ferraro, Ahmed M. Mansour, Maria Monti, Antonello Merlino, and Daniela Marasco
- Subjects
modulators of amyloid peptide aggregation ,metallodrugs ,ruthenium(II) compounds ,CO releasing molecules ,Medicine ,Pharmacy and materia medica ,RS1-441 - Abstract
Three Ru(II)-based CO-releasing molecules featuring bidentate benzimidazole and terpyridine derivatives as ligands were investigated for their ability to modulate the aggregation process of the second helix of the C-terminal domain of nucleophosmin 1, namely nucleophosmin 1 (NPM1)264–277, a model amyloidogenic system, before and after irradiation at 365 nm. Thioflavin T (ThT) binding assays and UV/Vis absorption spectra indicate that binding of the compounds to the peptide inhibits its aggregation and that the inhibitory effect increases upon irradiation (half maximal effective concentration (EC50) values in the high micromolar range). Electrospray ionization mass spectrometry data of the peptide in the presence of one of these compounds confirm that the modulation of amyloid aggregation relies on the formation of adducts obtained when the Ru compounds react with the peptide upon releasing of labile ligands, like chloride and carbon monoxide. This mechanism of action explains the subtle different behavior of the three compounds observed in ThT experiments. Overall, data support the hypothesis that metal-based CO releasing molecules can be used to develop metal-based drugs with potential application as anti-amyloidogenic agents.
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- 2020
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24. Role of the Metal Center in the Modulation of the Aggregation Process of Amyloid Model Systems by Square Planar Complexes Bearing 2-(2′-pyridyl)benzimidazole Ligands
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Daniele Florio, Ilaria Iacobucci, Giarita Ferraro, Ahmed M. Mansour, Giancarlo Morelli, Maria Monti, Antonello Merlino, and Daniela Marasco
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amyloid aggregation ,metallodrugs ,gold(iii) compounds ,platinum(ii) compounds ,palladium(ii) compounds ,anti-aggregation properties ,Medicine ,Pharmacy and materia medica ,RS1-441 - Abstract
The effect of analogue Pd(II)-, Pt(II)-, and Au(III) compounds featuring 2-(2′-pyridyl)benzimidazole on the aggregation propensity of amyloid-like peptides derived from Aβ and from the C-terminal domain of nucleophosmin 1 was investigated. Kinetic profiles of aggregation were evaluated using thioflavin binding assays, whereas the interactions of the compounds with the peptides were studied by UV-Vis absorption spectroscopy and electrospray ionization mass spectrometry. The results indicate that the compounds modulate the aggregation of the investigated peptides using different mechanisms, suggesting that the reactivity of the metal center and the physicochemical properties of the metals (rather than those of the ligands and the geometry of the metal compounds) play a crucial role in determining the anti-aggregation properties.
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- 2019
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25. Epigenetically induced ectopic expression of UNCX impairs the proliferation and differentiation of myeloid cells
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Giulia Daniele, Giorgia Simonetti, Caterina Fusilli, Ilaria Iacobucci, Angelo Lonoce, Antonio Palazzo, Mariana Lomiento, Fabiana Mammoli, Renè Massimiliano Marsano, Elena Marasco, Vilma Mantovani, Hilmar Quentmeier, Hans G Drexler, Jie Ding, Orazio Palumbo, Massimo Carella, Niroshan Nadarajah, Margherita Perricone, Emanuela Ottaviani, Carmen Baldazzi, Nicoletta Testoni, Cristina Papayannidis, Sergio Ferrari, Tommaso Mazza, Giovanni Martinelli, and Clelia Tiziana Storlazzi
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
We here describe a leukemogenic role of the homeobox gene UNCX, activated by epigenetic modifications in acute myeloid leukemia (AML). We found the ectopic activation of UNCX in a leukemia patient harboring a t(7;10)(p22;p14) translocation, in 22 of 61 of additional cases [a total of 23 positive patients out of 62 (37.1%)], and in 6 of 75 (8%) of AML cell lines. UNCX is embedded within a low-methylation region (canyon) and encodes for a transcription factor involved in somitogenesis and neurogenesis, with specific expression in the eye, brain, and kidney. UNCX expression turned out to be associated, and significantly correlated, with DNA methylation increase at its canyon borders based on data in our patients and in archived data of patients from The Cancer Genome Atlas. UNCX-positive and -negative patients displayed significant differences in their gene expression profiles. An enrichment of genes involved in cell proliferation and differentiation, such as MAP2K1 and CCNA1, was revealed. Similar results were obtained in UNCX-transduced CD34+ cells, associated with low proliferation and differentiation arrest. Accordingly, we showed that UNCX expression characterizes leukemia cells at their early stage of differentiation, mainly M2 and M3 subtypes carrying wild-type NPM1. We also observed that UNCX expression significantly associates with an increased frequency of acute promyelocytic leukemia with PML-RARA and AML with t(8;21)(q22;q22.1); RUNX1-RUNX1T1 classes, according to the World Health Organization disease classification. In summary, our findings suggest a novel leukemogenic role of UNCX, associated with epigenetic modifications and with impaired cell proliferation and differentiation in AML.
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- 2017
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26. Platinum(II) O,S Complexes Inhibit the Aggregation of Amyloid Model Systems
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Daniele Florio, Anna Maria Malfitano, Sarah Di Somma, Carolin Mügge, Wolfgang Weigand, Giarita Ferraro, Ilaria Iacobucci, Maria Monti, Giancarlo Morelli, Antonello Merlino, and Daniela Marasco
- Subjects
amyloid aggregation ,platinum complexes ,anti-aggregation properties ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Platinum(II) complexes with different cinnamic acid derivatives as ligands were investigated for their ability to inhibit the aggregation process of amyloid systems derived from Aβ, Yeast Prion Protein Sup35p and the C-terminal domain of nucleophosmin 1. Thioflavin T binding assays and circular dichroism data indicate that these compounds strongly inhibit the aggregation of investigated peptides exhibiting IC50 values in the micromolar range. MS analysis confirms the formation of adducts between peptides and Pt(II) complexes that are also able to reduce amyloid cytotoxicity in human SH-SY5Y neuroblastoma cells. Overall data suggests that bidentate ligands based on β-hydroxy dithiocinnamic esters can be used to develop platinum or platinoid compounds with anti-amyloid aggregation properties.
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- 2019
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27. Three novel fusion transcripts of the paired box 5 gene in B-cell precursor acute lymphoblastic leukemia
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Grazia Fazio, Giulia Daniele, Valeria Cazzaniga, Luciana Impera, Marco Severgnini, Ilaria Iacobucci, Marta Galbiati, Anna Leszl, Ingrid Cifola, Gianluca De Bellis, Paola Bresciani, Giovanni Martinelli, Giuseppe Basso, Andrea Biondi, Clelia Tiziana Storlazzi, and Giovanni Cazzaniga
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2015
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28. Posterior reversible encephalopathy syndrome in a B-cell acute lymphoblastic leukemia young adult patient treated with a pediatric-like chemotherapeutic schedule
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Cristina Papayannidis, Francesca Volpato, Ilaria Iacobucci, Maria Chiara Abbenante, Chiara Sartor, and Giovanni Martinelli
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posterior reversible encephalopathy syndrome, acute lymphoblastic leukemia, methotrexate, seizure, brain magnetic resonance imaging ,Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
We report here the case of a young adult affected by pre B-cell acute lymphoblastic leukemia (ALL), who developed, during a pediatric-like chemotherapy consolidation schedule with high dosage of Methotrexate, a severe neurological toxicity. Clinical presentation and neuroimaging data were diagnostic for posterior reversible encephalopathy syndrome (PRES). A complete resolution was quickly obtained with medical blood pressure control and anticonvulsants administration. To the best of our knowledge, this is the first case of PRES described in the adult ALL setting. Currently, the clinical management of this aggressive disease is moving towards a pediatric-like approach also in adult patients, due to the better outcome reached with intensive chemotherapeutic regimens in children population. However, therapy-related toxicities have to be taken into account, since their onset may adversely affect patients’ clinical outcome.
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- 2014
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29. Rationale for a pediatric-inspired approach in the adolescent and young adult population with acute lymphoblastic leukemia, with a focus on asparaginase treatment
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Carmelo Rizzari, Maria Caterina Putti, Antonella Colombini, Sara Casagranda, Giulia Maria Ferrari, Cristina Papayannidis, Ilaria Iacobucci, Maria Chiara Abbenante, Chiara Sartor, and Giovanni Martinelli
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asparaginase, acute lymphoblastic leukemia, adolescent, young adult ,Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
In the last two decades great improvements have been made in the treatment of childhood acute lymphoblastic leukemia, with 5-year overall survival rates currently approaching almost 90%. In comparison, results reported in adolescents and young adults (AYAs) are relatively poor. In adults, results have improved, but are still lagging behind those obtained in children. Possible reasons for this different pattern of results include an increased incidence of unfavorable and a decreased incidence of favorable cytogenetic abnormalities in AYAs compared with children. Furthermore, in AYAs less intensive treatments (especially lower cumulative doses of drugs such as asparaginase, corticosteroids and methotrexate) and longer gaps between courses of chemotherapy are planned compared to those in children. However, although favorable results obtained in AYAs receiving pediatric protocols have been consistently reported in several international collaborative trials, physicians must also be aware of the specific toxicity pattern associated with increased success in AYAs, since an excess of toxicity may compromise overall treatment schedule intensity. Cooperative efforts between pediatric and adult hematologists in designing specific protocols for AYAs are warranted.
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- 2014
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30. A case report of acute myeloid leukemia and neurofibromatosis 1
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Chiara Sartor, Cristina Papayannidis, Maria Chiara Abbenante, Antonio Curti, Nicola Polverelli, Emanuela Ottaviani, Ilaria Iacobucci, Viviana Guadagnuolo, and Giovanni Martinelli
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acute myeloid leukemia, neurofibromatosis type 1, NF1, Von Recklinghausen disease ,Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
We report a case of a 65-year old patient affected by neurofibromatosis 1, documented by the presence of germ-line mutation on the NF1 gene, who developed various hyperproliferative malignant and benign diseases. He was brought to our attention for the diagnosis of acute myeloid leukemia revealed by major fatigue and dyspnea. The disease characteristics at diagnosis were hyperleukocytosis and complex karyotype with the inversion of the chromosome 16, classifying as a high-risk leukemia. The association between leukemia and neurofibromatosis 1 is controversial and needs to be further investigated. Nevertheless, such patients present a wide number of comorbidities that make therapeutic strategies most difficult.
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- 2013
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31. Recurrent gastrointestinal hemorrhage in treatment with dasatinib in a patient showing SMAD4 mutation with acute lymphoblastic leukemia Philadelphia positive and juvenile polyposis hereditary hemorrhagic telangiectasia syndrome
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Chiara Sartor, Cristina Papayannidis, Maria Chiara Abbenante, Ilaria Iacobucci, Alessandro Broccoli, Claudia Venturi, Nicoletta Testoni, Anna Ferrari, and Giovanni Martinelli
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juvenile poyposis, hereditary hemorrhagic telangiectasia, acute lymphoblastic leukemia, SMAD4, Philadelphia chromosome, dasatinib, hemorrhage ,Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
We report a case of a patient affected by juvenile polyposis and hereditary hemorrhagic telangiectasia linked to a SMAD4 mutation who developed acute lymphoblastic leukemia positive for the Philadelphia chromosome translocation and with a complex karyotype. During the treatment with the tyrosine kinase inhibitor dasatinib the patient presented recurrent severe gastrointestinal hemorrhages linked to the genetic background and aggravated by thrombocytopenia.
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- 2013
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32. Association between imatinib transporters and metabolizing enzymes genotype and response in newly diagnosed chronic myeloid leukemia patients receiving imatinib therapy
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Sabrina Angelini, Simona Soverini, Gloria Ravegnini, Matt Barnett, Eleonora Turrini, Mark Thornquist, Fabrizio Pane, Timothy P. Hughes, Deborah L. White, Jerald Radich, Dong Wook Kim, Giuseppe Saglio, Daniela Cilloni, Ilaria Iacobucci, Giovanni Perini, Richard Woodman, Giorgio Cantelli-Forti, Michele Baccarani, Patrizia Hrelia, and Giovanni Martinelli
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Imatinib has so far been the first-choice treatment in chronic myeloid leukemia with excellent results. However, only a proportion of patients achieve major molecular response – hence the need to find biological predictors of outcome to select the optimal therapeutic strategy now that more potent inhibitors are available. We investigated a panel of 20 polymorphisms in seven genes, potentially associated with the pharmacogenetics of imatinib, in a subset of 189 patients with newly diagnosed chronic myeloid leukemia enrolled in the TOPS trial. The analysis included polymorphisms in the transporters hOCT1, MDR1, ABCG2, OCTN1, and OATP1A2, and in the metabolizing genes CYP3A4 and CYP3A5. In the overall population, the OCTN1 C allele (rs1050152), a simple combination of polymorphisms in the hOCT1 gene and another combination in the genes involved in imatinib uptake were significantly associated with major molecular response. The combination of polymorphisms in imatinib uptake was also significantly associated with complete molecular response. Analyses restricted to Caucasians highlighted the significant association of MDR1 CC (rs60023214) genotype with complete molecular response. We demonstrate the usefulness of a pharmacogenetic approach for stratifying patients with chronic myeloid leukemia according to their likelihood of achieving a major or complete molecular response to imatinib. This represents an attractive opportunity for therapy optimization, worth testing in clinical trials.
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- 2013
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33. A novel t(2;10)(q31;p12) balanced translocation in acute myeloid leukemia
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Luciana Impera, Giulia Daniele, Luisa Marra, Carmen Baldazzi, Ilaria Iacobucci, Giovanni Martinelli, Nicoletta Testoni, and Clelia Tiziana Storlazzi
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chromosome, translocation, FISH, acute myeloid leukemia, HNRNA3, NFE2L2, MPP7 ,Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
We describe a case of acute myeloid leukemia M5 showing a balanced t(2;10)(q31;p12) translocation. This has never been described before as the sole cytogenetic abnormality in a bone marrow cell clone at onset. Using fluorescence in situ hybridization with properly designed bacterial artificial chromosome probes, we mapped the breakpoint regions on both derivative chromosomes 2 and 10:der(2) and der(10), respectively. The MPP7 gene, disrupted by the breakpoint on chromosome 10, was juxtaposed upstream of both HNRNA3 and NFE2L2 genes on chromosome 2, without the formation of any fusion gene. Using real-time quantitative polymerase chain reaction, we tested the possible disregulation of any of the breakpoint-associated genes as a consequence of the translocation, but we found no statistically significant alteration. Considering the potential role of this clonal cytogenetic abnormality in leukemogenesis, we speculate that this translocation could have an impact on additional genes mapping outside the breakpoint regions. However, the limited amount of RNA material available prevented us from testing this hypothesis in this present case.
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- 2012
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34. IKAROS deletions dictate a unique gene expression signature in patients with adult B-cell acute lymphoblastic leukemia.
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Ilaria Iacobucci, Nunzio Iraci, Monica Messina, Annalisa Lonetti, Sabina Chiaretti, Emanuele Valli, Anna Ferrari, Cristina Papayannidis, Francesca Paoloni, Antonella Vitale, Clelia Tiziana Storlazzi, Emanuela Ottaviani, Viviana Guadagnuolo, Sandra Durante, Marco Vignetti, Simona Soverini, Fabrizio Pane, Robin Foà, Michele Baccarani, Markus Müschen, Giovanni Perini, and Giovanni Martinelli
- Subjects
Medicine ,Science - Abstract
Deletions of IKAROS (IKZF1) frequently occur in B-cell precursor acute lymphoblastic leukemia (B-ALL) but the mechanisms by which they influence pathogenesis are unclear. To address this issue, a cohort of 144 adult B-ALL patients (106 BCR-ABL1-positive and 38 B-ALL negative for known molecular rearrangements) was screened for IKZF1 deletions by single nucleotide polymorphism (SNP) arrays; a sub-cohort of these patients (44%) was then analyzed for gene expression profiling.Total or partial deletions of IKZF1 were more frequent in BCR-ABL1-positive than in BCR-ABL1-negative B-ALL cases (75% vs 58%, respectively, p = 0.04). Comparison of the gene expression signatures of patients carrying IKZF1 deletion vs those without showed a unique signature featured by down-regulation of B-cell lineage and DNA repair genes and up-regulation of genes involved in cell cycle, JAK-STAT signalling and stem cell self-renewal. Through chromatin immunoprecipitation and luciferase reporter assays we corroborated these findings both in vivo and in vitro, showing that Ikaros deleted isoforms lacked the ability to directly regulate a large group of the genes in the signature, such as IGLL1, BLK, EBF1, MSH2, BUB3, ETV6, YES1, CDKN1A (p21), CDKN2C (p18) and MCL1.Here we identified and validated for the first time molecular pathways specifically controlled by IKZF1, shedding light into IKZF1 role in B-ALL pathogenesis.
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- 2012
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35. Philadelphia-positive acute lymphoblastic leukemia patients already harbor BCR-ABL kinase domain mutations at low levels at the time of diagnosis
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Simona Soverini, Antonella Vitale, Angela Poerio, Alessandra Gnani, Sabrina Colarossi, Ilaria Iacobucci, Giuseppe Cimino, Loredana Elia, Annalisa Lonetti, Marco Vignetti, Stefania Paolini, Giovanna Meloni, Valeria di Maio, Cristina Papayannidis, Marilina Amabile, Anna Guarini, Michele Baccarani, Giovanni Martinelli, and Robin Foà
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Background In patients with Philadelphia-positive acute lymphoblastic leukemia, resistance to treatment with tyrosine kinase inhibitors is frequent and most often associated with the development of point mutations in the BCR-ABL kinase domain. We aimed to assess: (i) in how many patients BCR-ABL kinase domain mutations are already detectable at relatively low levels at the time of diagnosis, and (ii) whether mutation detection correlates with subsequent response to therapy.Design and Methods We retrospectively analyzed samples collected at diagnosis from 15 patients with Philadelphia-positive acute lymphoblastic leukemia who subsequently received tyrosine kinase inhibitor therapy (dasatinib) by cloning the BCR-ABL kinase domain in a bacterial vector and sequencing 200 independent clones per sample.Results Mutations at relatively low levels (2–4 clones out of 200) could be detected in all patients – eight who relapsed and seven who achieved persistent remission. Each patient had evidence of two to eight different mutations, the majority of which have never been reported in association with resistance to tyrosine kinase inhibitors. In two patients out of six who relapsed because of a mutation, the mutation (a T315I) was already detectable in a few clones at the time of diagnosis. On the other hand, a patient who was found to harbor an F317L mutation is in persistent remission on dasatinib.Conclusions Our results suggest that the BCR-ABL kinase domain is prone to randomly accumulate point mutations in Philadelphia-positive acute lymphoblastic leukemia, although the presence of these mutations in a relatively small leukemic subclone does not always preclude a primary response to tyrosine kinase inhibitors.
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- 2011
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36. The PAX5 gene is frequently rearranged in BCR-ABL1-positive acute lymphoblastic leukemia but is not associated with outcome. A report on behalf of the GIMEMA Acute Leukemia Working Party
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Ilaria Iacobucci, Annalisa Lonetti, Francesca Paoloni, Cristina Papayannidis, Anna Ferrari, Clelia Tiziana Storlazzi, Marco Vignetti, Daniela Cilloni, Francesca Messa, Viviana Guadagnuolo, Stefania Paolini, Loredana Elia, Monica Messina, Antonella Vitale, Giovanna Meloni, Simona Soverini, Fabrizio Pane, Michele Baccarani, Robin Foà, and Giovanni Martinelli
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Background Recently, in genome-wide analyses of DNA copy number abnormalities using single nucleotide polymorphism microarrays, genetic alterations targeting PAX5 were identified in over 30% of pediatric patients with acute lymphoblastic leukemia. So far the occurrence of PAX5 alterations and their clinical correlation have not been investigated in adults with BCR-ABL1-positive acute lymphoblastic leukemia.Design and Methods The aim of this study was to characterize the rearrangements on 9p involving PAX5 and their clinical significance in adults with BCR-ABL1-positive acute lymphoblastic leukemia. Eighty-nine adults with de novo BCR-ABL1-positive acute lymphoblastic leukemia were enrolled into institutional (n=15) or GIMEMA (Gruppo Italiano Malattie EMatologiche dell’Adulto) (n=74) clinical trials and, after obtaining informed consent, their genome was analyzed by single nucleotide polymorphism arrays (Affymetrix 250K NspI and SNP 6.0), genomic polymerase chain reaction analysis and re-sequencing.Results PAX5 genomic deletions were identified in 29 patients (33%) with the extent of deletions ranging from a complete loss of chromosome 9 to the loss of a subset of exons. In contrast to BCR-ABL1-negative acute lymphoblastic leukemia, no point mutations were found, suggesting that deletions are the main mechanism of inactivation of PAX5 in BCR-ABL1-positive acute lymphoblastic leukemia. The deletions were predicted to result in PAX5 haploinsufficiency or expression of PAX5 isoforms with impaired DNA-binding. Deletions of PAX5 were not significantly correlated with overall survival, disease-free survival or cumulative incidence of relapse, suggesting that PAX5 deletions are not associated with outcome.Conclusions PAX5 deletions are frequent in adult BCR-ABL1-positive acute lymphoblastic leukemia and are not associated with a poor outcome.
- Published
- 2010
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37. The response to imatinib and interferon-α is more rapid than the response to imatinib alone: a retrospective analysis of 495 Philadelphia-positive chronic myeloid leukemia patients in early chronic phase
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Francesca Palandri, Fausto Castagnetti, Ilaria Iacobucci, Giovanni Martinelli, Marilina Amabile, Gabriele Gugliotta, Angela Poerio, Nicoletta Testoni, Massimo Breccia, Monica Bocchia, Monica Crugnola, Giovanna Rege-Cambrin, Bruno Martino, Ivana Pierri, Franca Radaelli, Giorgina Specchia, Fabrizio Pane, Giuseppe Saglio, Gianantonio Rosti, and Michele Baccarani
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Before the introduction of imatinib, interferon α-based regimens were the gold standard for treatment of early chronic phase chronic myeloid leukemia patients. The combination of IFN-α with imatinib is currently being investigated in at least two large clinical trials, the German CML Study IV and the French SPIRIT trial.We reviewed the cytogenetic and molecular responses of 76 early chronic phase chronic myeloid leukemia patients who were treated with imatinib and interferon-α and of 419 early chronic phase chronic myeloid leukemia patients treated with imatinib alone front-line.The complete cytogenetic response rate was higher in the IM+IFN-α group than in the imatinib group at six months (60% vs. 42%; P=0.003), but not at 48 months (88% vs. 88%). The durability of the complete cytogenetic response was similar in the two groups with 94% and 91% of complete cytogenetic responders in continuous complete cytogenetic response at 48 months (P=0.56). The major molecular response rate was higher in the IM+IFN-α group at six months (58% vs. 34%; P=0.0001) and 12 months (67% vs. 47%; P=0.001) but not later on (65% vs. 57% at 48 months; P=0.25). Overall and progression free survival were comparable in the two groups; a significant trend to a better event free survival was observed in patients treated with PegIFNα (91% vs. 78%; P=0.02).These data suggest that the response to the combination treatment is more rapid. It is not yet known how much a rapid reduction will influence the longer-term overall and progression free survival, and the cure rate.
- Published
- 2010
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38. Aurora kinase inhibitors: which role in the treatment of chronic myelogenous leukemia patients resistant to imatinib?
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Giovanni Martinelli, Simona Soverini, Ilaria Iacobucci, Cristina Papayannidis, Daniela Cilloni, and Michele Baccarani
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Aurora kinase inhibitors ,Chronic Myelogenous Leukemia ,Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
At present, there are no compounds in clinical development in the field of chronic myeloid leukemia (CML) or Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL) that have been documented to harbor significant activity against the imatinib-resistant T315I mutation. Recent reports on the pre-clinical activity of some emerging tyrosine kinase inhibitors such as ON012380, VX-680 and PHA-739358 promise possible clinical efficacy against this specific Bcr-Abl mutant form. Here, we focus on the role of aurora kinase inhibitor VX-680 and PHA-739358 in blocking the leukemogenic pathways driven by wild-type and T315I-Bcr-Abl in CML or Ph+ ALL by reviewing recent research evidence. We also discuss the possibility of employing aurora kinase inhibitors as a promising new therapeutic approach in the treatment of CML and Ph+ ALL patients resistant to first and second generation TK inhibitors.
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- 2009
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39. Identification of different Ikaros cDNA transcripts in Philadelphia-positive adult acute lymphoblastic leukemia by a high-throughput capillary electrophoresis sizing method
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Ilaria Iacobucci, Annalisa Lonetti, Daniela Cilloni, Francesca Messa, Anna Ferrari, Roberta Zuntini, Simona Ferrari, Emanuela Ottaviani, Francesca Arruga, Stefania Paolini, Cristina Papayannidis, Pier Paolo Piccaluga, Simona Soverini, Giuseppe Saglio, Fabrizio Pane, Anna Baruzzi, Marco Vignetti, Giorgio Berton, Antonella Vitale, Sabina Chiaretti, Markus Müschen, Robin Foà, Michele Baccarani, and Giovanni Martinelli
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Background Ikaros is the prototypic member of a Kruppel-like zinc finger transcription factor subfamily that is required for normal hematopoietic cell differentiation and proliferation, particularly in the lymphoid lineages. Alternative splicing can generate multiple Ikaros isoforms that lack different numbers of exons and have different functions. Shorter isoforms, which lack the amino-terminal domain that mediates sequence-specific DNA binding, exert a dominant negative effect and inhibit the ability of longer heterodimer partners to bind DNA.Design and Methods In this study, we developed a high-throughput capillary electrophoresis sizing method to detect and quantify different Ikaros cDNA transcripts.Results We demonstrated that Philadelphia chromosome-positive acute lymphoblastic leukemia cells expressed high levels of the non-DNA-binding isoform Ik6 that was generated following IKZF1 genomic deletions (19/46 patients, 41%). Furthermore, a recurring 60 bp insertion immediately upstream of exon 5, at the exon 3/exon 5 junction, was frequently detected in the Ik2 and Ik4 isoforms. This insertion occurred either alone or together with an in-frame ten amino acid deletion that was due to a 30 bp loss at the end of exon 7. Both the alterations are due to the selection of alternative cryptic splice sites and have been suggested to cause impaired DNA-binding activity. Non-DNA-binding isoforms were localized in the cytoplasm whereas the DNA-binding isoforms were localized in the nucleus.Conclusions Our findings demonstrate that both aberrant splicing and genomic deletion leading to different non-DNA-binding Ikaros cDNA transcripts are common features of Philadelphia chromosome-positive acute lymphoblastic leukemia.
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- 2008
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40. Front-line treatment of Philadelphia positive chronic myeloid leukemia with imatinib and interferon-α: 5-year outcome
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Francesca Palandri, Ilaria Iacobucci, Fausto Castagnetti, Nicoletta Testoni, Angela Poerio, Marilina Amabile, Massimo Breccia, Tamara Intermesoli, Francesco Iuliano, Giovanna Rege-Cambrin, Mario Tiribelli, Maurizio Miglino, Fabrizio Pane, Giuseppe Saglio, Giovanni Martinelli, Gianantonio Rosti, Michele Baccarani, and on behalf of the GIMEMA Working Party on CML
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
In 2004, we reported the short-term results of a multicentric, phase 2 study of imatinib 400 mg daily and pegylated interferon-α in the treatment of 76 early chronic phase Philadelphia-positive chronic myeloid leukemia patients. In this report, we update the results with an observation time of five years. After two years of treatment, all but 10 patients (13%) had discontinued pegylated interferon-α. The complete cytogenetic response rate at five years was 87%, and 94% of complete cytogenetic responders maintained the complete cytogenetic response after five years. All but one complete cytogenetic response also achieved a major molecular response. These data confirm the excellent response to imatinib front-line and the stability of the complete cytogenetic response. Any possible additional benefit of the combination with interferon-α remains uncertain, due to low patient compliance.
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- 2008
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41. Long-term molecular responses to imatinib in patients with chronic myeloid leukemia: comparison between complete cytogenetic responders treated in early and in late chronic phase
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Francesca Palandri, Ilaria Iacobucci, Fabrizio Quarantelli, Fausto Castagnetti, Daniela Cilloni, and Michele Baccarani
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
CML patients who obtain a complete cytogenetic response (CCgR) may harbor different degrees of molecular disease, which are associated with different progression-free survival. We have compared the pattern and the magnitude of the molecular response (MolR) of 54 early chronic phase (ECP) and of 115 late CP patients who achieved a stable CCgR with IM 400 mg/daily. ECP patients obtained earlier, higher and more sustained MMolR.
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- 2007
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42. The efficacy of imatinib mesylate in patients with FIP1L1-PDGFRα-positive hypereosinophilic syndrome. Results of a multicenter prospective study
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Michele Baccarani, Daniela Cilloni, Michela Rondoni, Emanuela Ottaviani, Francesca Messa, Serena Merante, Mario Tiribelli, Francesco Buccisano, Nicoletta Testoni, Enrico Gottardi, Antonio de Vivo, Emilia Giugliano, Ilaria Iacobucci, Stefania Paolini, Simona Soverini, Gianantonio Rosti, Francesca Rancati, Cinzia Astolfi, Fabrizio Pane, Giuseppe Saglio, and Giovanni Martinelli
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Background and Objectives The hypereosinophilic syndrome (HES) may be associated with the fusion of the platelet derived growth factor receptor α (PDGFRα) gene with the FIP1L1 gene in chromosome 4 coding for a constitutively activated PDGFRα tyrosine kinase. These cases with FIP1L1-PDGFRα rearrangement have been reported to be very sensitive to the tyrosine kinase inhibitor imatinib mesylate.Design and Methods A prospective multicenter study of idiopathic or primary HES was established in 2001 (Study Protocol Registration no. NCT 0027 6929). One hundred and ninety-six patients were screened, of whom 72 where identified as having idiopathic or primary HES and 63 were treated with imatinib 100 to 400 mg daily.Results Twenty-seven male patients carried the FIP1L1-PDGFRα rearrangement. All 27 achieved a complete hematologic remission (CHR) and became negative for the fusion transcripts according to reverse transcriptase polymerase chain reaction (RT-PCR) analysis. With a median follow-up of 25 months (15–60 months) all 27 patients remain in CHR and RT-PCR negative, and continue treatment at a dose of 100 to 400 mg daily. In three patients imatinib treatment was discontinued for few months, the fusion transcript became rapidly detectable, and then again undetectable upon treatment reassumption. Thirty-six patients did not carry the rearrangement; of these, five (14%) achieved a CHR, which was lost in all cases after 1 to 15 months.Interpretation and Conclusions All patients meeting the criteria for idiopathic or primary HES should be screened for the FIP1L1-PDGFRα rearrangement. For all patients with this rearrangement, chronic imatinib treatment at doses as low as 100 mg daily ensures complete and durable responses.
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- 2007
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43. Targeted therapy and the T315I mutation in Philadelphia-positive leukemias
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Simona Soverini, Ilaria Iacobucci, Michele Baccarani, and Giovanni Martinelli
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2007
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44. Monitoring BCR-ABL transcript levels by real-time quantitative polymerase chain reaction: a linear regression equation to convert from BCR-ABL/B2M ratio to estimated BCR-ABL/ABL ratio
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Ilaria Iacobucci, Livia Galletti, Marilina Amabile, Simona Soverini, Michele Baccarani, and Giovanni Martinelli
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
In order to overcome the problem of different control genes for BCR-ABL normalization, we used a linear regression equation to compare our results previously obtained using B2M as the control gene with those calculated using the ABL gene and validated the slope as a factor to convert from B2M to ABL results.
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- 2007
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45. Resistance to dasatinib in Philadelphia-positive leukemia patients and the presence or the selection of mutations at residues 315 and 317 in the BCR-ABL kinase domain
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Simona Soverini, Sabrina Colarossi, Alessandra Gnani, Fausto Castagnetti, Gianantonio Rosti, Costanza Bosi, Stefania Paolini, Michela Rondoni, Pier Paolo Piccaluga, Francesca Palandri, Panagiota Giannoulia, Giulia Marzocchi, Simona Luatti, Nicoletta Testoni, Ilaria Iacobucci, Daniela Cilloni, Giuseppe Saglio, Michele Baccarani, and Giovanni Martinelli
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
The emergence of resistance to the Bcr-Abl inhibitor imatinib mesylate in patients with Philadelphia chromosome-positive (Ph+) leukemia has prompted the development of second-generation compounds active against several imatinib-insensitive mutant forms of Bcr-Abl, including dasatinib (BMS-354825; Bristol-Myers Squibb). In order to assess which pre-existent or emerging kinase domain mutations are associated with decreased clinical efficacy of desatinib, we analyzed BCR-ABL kinase sequences before and during treatment in 21 Ph+ patients who failed to respond to or relapsed during dasatinib therapy. In all patients but one, resistance to dasatinib was invariably found to be associated with mutations at residue 315 and/or at residue 317.
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- 2007
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46. Impact of age on the outcome of patients with chronic myeloid leukemia in late chronic phase: results of a phase II study of the GIMEMA CML Working Party
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Gianantonio Rosti, Ilaria Iacobucci, Simona Bassi, Fausto Castagnetti, Marilina Amabile, Daniela Cilloni, Angela Poerio, Simona Soverini, Francesca Palandri, Giovanna Rege Cambrin, Franco Iuliano, Giuliana Alimena, Roberto Latagliata, Nicoletta Testoni, Fabrizio Pane, Giuseppe Saglio, Michele Baccarani, and Giovanni Martinelli
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
To assess the effect of age on response and compliance to treatment in patients with chronic myeloid leukemia (CML) we performed a sub-analysis within a phase II trial of the GIMEMA CML Working Party (CML/002/STI571). Since the WHO cut-off age to define an older patient is 65 years, among the 284 patients considered, we identified 226 (80%) younger patients (below 65 years) and 58 (20%) older patients (above 65 years) before starting imatinib. Response rates (hematologic and cytogenetic) were lower in the older age group but the probabilities of progression-free survival and overall survival (median observation time 3 years) were the same. Moreover, among complete cytogenetic responders, no differences were found in the level of molecular response between the two age groups. As might be expected, older patients experienced more adverse events, both hematologic and non-hematologic: this worsened compliance did not, however, prevent a long-term outcome similar to that of younger patients.
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- 2007
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47. Single-cell analysis of acute lymphoblastic and lineage-ambiguous leukemia: approaches and molecular insights
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Charles Mullighan, Matthew Witkowski, and Ilaria Iacobucci
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Abstract
Despite recent progress in identifying the genetic drivers of acute lymphoblastic leukemia (ALL), prognosis remains poor for those individuals who experience disease recurrence. Moreover, acute leukemias of ambiguous lineage lack a biologically informed framework to guide classification and therapy. These needs have driven the adoption of multiple complementary single-cell sequencing approaches to explore key issues in the biology of these leukemias, including cell of origin, developmental hierarchy and ontogeny, and the molecular heterogeneity driving pathogenesis, progression, and therapeutic responsiveness. There are multiple single-cell techniques for profiling a specific modality, including RNA, DNA, chromatin accessibility and methylation; and an expanding range of approaches for simultaneous analysis of multiple modalities. Single-cell sequencing approaches have also enabled characterization of cell-intrinsic and -extrinsic features of ALL biology. In this review we describe these approaches and highlight the extensive heterogeneity that underpins ALL gene expression, cellular differentiation, and clonal architecture throughout disease pathogenesis and treatment resistance. In addition, we discuss the importance of the dynamic interactions that occur between leukemia cells and the nonleukemia microenvironment. We discuss potential opportunities and limitations of single-cell sequencing for the study of ALL biology and treatment responsiveness.
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- 2023
48. The genomic landscape of acute lymphoblastic leukemia with intrachromosomal amplification of chromosome 21
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Qingsong Gao, Sarra L Ryan, Ilaria Iacobucci, Pankaj S Ghate, Ruth E Cranston, Claire J Schwab, Abdelrahman H. Elsayed, Lei Shi, Stanley B Pounds, Shaohua Lei, Pradyumna Baviskar, Deqing Pei, Cheng Cheng, Matthew Bashton, Paul B Sinclair, David R Bentley, Mark Ross, Zoya Kingsbury, Terena James, Kathryn G Roberts, Meenakshi Devidas, Yiping Fan, Wenan Chen, Ti-Cheng Chang, Gang Wu, Andrew J. Carroll, Nyla A. Heerema, Virginia Valentine, Marcus B Valentine, Wenjian Yang, Jun J. Yang, Anthony V Moorman, Christine J Harrison, and Charles G. Mullighan
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Abstract
Intrachromosomal amplification of chromosome 21 defines a subtype of high-risk childhood acute lymphoblastic leukemia (iAMP21-ALL) characterized by copy number changes and complex rearrangements of chromosome 21. The genomic basis of iAMP21-ALL and the pathogenic role of the region of amplification of chromosome 21 to leukemogenesis remain incompletely understood. Here, using integrated whole genome and transcriptome sequencing of 124 iAMP21-ALL patients, including rare cases arising in the context of constitutional chromosomal aberrations, we identified subgroups of iAMP21-ALL according to patterns of copy number alteration and structural variation. This large dataset enabled formal delineation of a 7.8 Mb common region of amplification harboring 71 genes, 43 of which are differentially expressed compared to non-iAMP21-ALL cases, and including multiple genes implicated in the pathogenesis of acute leukemia: CHAF1B, DYRK1A, ERG, HMGN1 and RUNX1. Using multimodal single cell genomic profiling, including single cell whole genome sequencing of two cases, we documented clonal heterogeneity and genomic evolution, formally demonstrating that acquisition of the iAMP21-chromosome is an early event that may undergo progressive amplification during disease ontogeny. We show that UV mutational signatures and high mutation load are characteristic secondary genetic features. Although the genomic alterations of chromosome 21 are variable, these integrated genomic analyses and demonstration of an extended common minimal region of amplification broaden the definition of iAMP21-ALL for more precise diagnosis using cytogenetic or genomic methods to inform clinical management.
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- 2023
49. The orally bioavailable GSPT1/2 degrader SJ6986 exhibits in vivo efficacy in acute lymphoblastic leukemia
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Yunchao Chang, Fatemeh Keramatnia, Pankaj S Ghate, Gisele Nishiguchi, Qingsong Gao, Ilaria Iacobucci, Lei Yang, Divyabharathi Chepyala, Ashutosh Mishra, Anthony Andrew High, Hiroaki Goto, Koshi Akahane, Junmin Peng, Jun J. Yang, Marcus Fischer, Zoran Rankovic, and Charles G. Mullighan
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Abstract
Advancing cure rates for high-risk acute lymphoblastic leukemia (ALL) has been limited by the lack of agents that effectively kill leukemic cells sparing normal hematopoietic tissue. Molecular glues direct the cellular ubiquitin ligase cellular machinery to target neosubstrates for protein degradation. We developed a novel Cereblon modulator, SJ6986 that exhibited potent and selective degradation of GSPT1 and GSPT2, and cytotoxic activity against childhood cancer cell lines. Here we report in vitro and in vivo testing of the activity of this agent in a panel of ALL cell lines and xenografts. SJ6986 exhibited similar cytotoxicity to the previously described GSPT1 degrader CC-90009 in a panel of leukemia cell lines in vitro, resulting in apoptosis and perturbation of cell cycle progression. SJ6986 was more effective than CC-90009 in suppressing leukemic cell growth in vivo, partly attributable to favorable pharmacokinetic properties, and did not significantly impair differentiation of human CD34+ cells ex vivo. Genome wide CRISPR/Cas9 screening of ALL cell lines treated with SJ6986 confirmed components of the CRL4CRBN complex, associated adaptors, regulators and effectors were integral in mediating the action of SJ6986. SJ6986 is a potent, selective, orally bioavailable GSPT1/2 degrader that shows broad antileukemic activity and has potential for clinical development.
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- 2023
50. Data from Integrated Genomic Analysis Identifies UBTF Tandem Duplications as a Recurrent Lesion in Pediatric Acute Myeloid Leukemia
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Jeffery M. Klco, Xiaotu Ma, Soheil Meshinchi, Jeffrey E. Rubnitz, Jinghui Zhang, M. Madan Babu, Stanley Pounds, Charles G. Mullighan, James R. Downing, Todd A. Alonzo, Yi-Cheng Wang, Hiroto Inaba, Gang Wu, Michael Rusch, Delaram Rahbarinia, Evadnie Rampersaud, Jason R. Myers, Jonathan Miller, Ryan Hiltenbrand, Ilaria Iacobucci, Evan Parganas, Jenny L. Smith, Rhonda E. Ries, Yen-Chun Liu, Marcus B. Valentine, Virginia Valentine, Huiyun Wu, John Easton, Bengsheng Ju, Amanda R. Leonti, Andrew B. Kleist, Jamie L. Maciaszek, Scott G. Foy, Quang Tran, Pandurang Kolekar, Xiaolong Chen, Yanling Liu, Liqing Tian, Guangchun Song, Michael P. Walsh, Melvin E. Thomas, Juan M. Barajas, Sherif Abdelhamed, Tamara Westover, Kohei Hagiwara, Benjamin J. Huang, Jing Ma, and Masayuki Umeda
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The genetics of relapsed pediatric acute myeloid leukemia (AML) has yet to be comprehensively defined. Here, we present the spectrum of genomic alterations in 136 relapsed pediatric AMLs. We identified recurrent exon 13 tandem duplications (TD) in upstream binding transcription factor (UBTF) in 9% of relapsed AML cases. UBTF-TD AMLs commonly have normal karyotype or trisomy 8 with cooccurring WT1 mutations or FLT3-ITD but not other known oncogenic fusions. These UBTF-TD events are stable during disease progression and are present in the founding clone. In addition, we observed that UBTF-TD AMLs account for approximately 4% of all de novo pediatric AMLs, are less common in adults, and are associated with poor outcomes and MRD positivity. Expression of UBTF-TD in primary hematopoietic cells is sufficient to enhance serial clonogenic activity and to drive a similar transcriptional program to UBTF-TD AMLs. Collectively, these clinical, genomic, and functional data establish UBTF-TD as a new recurrent mutation in AML.Significance:We defined the spectrum of mutations in relapsed pediatric AML and identified UBTF-TDs as a new recurrent genetic alteration. These duplications are more common in children and define a group of AMLs with intermediate-risk cytogenetic abnormalities, FLT3-ITD and WT1 alterations, and are associated with poor outcomes.See related commentary by Hasserjian and Nardi, p. 173.This article is highlighted in the In This Issue feature, p. 171.
- Published
- 2023
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