44 results on '"Vukovic P"'
Search Results
2. Thrombotic and Bleeding Complications in Patients with Chronic Lymphocytic Leukemia and Severe COVID-19: A Study of Eric, the European Research Initiative on CLL
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Antic, Darko, Milic, Natasa, Chatzikonstantinou, Thomas, Scarfò, Lydia, Otasevic, Vladimir, Rajovic, Nina, Allsup, David, Cabrero, Alejandro Alonso, Andres, Martin, Baile Gonzales, Monica, Capasso, Antonella, Collado, Rosa, Cordoba, Raul, Cuéllar-García, Carolina, Correa, Juan Gonzalo, De Paoli, Lorenzo, De Paolis, Maria Rosaria, Del Poeta, Giovanni, Dimou, Maria, Doubek, Michael, Efstathopoulou, Maria, El-Ashwah, Shaimaa, Enrico, Alicia, Espinet, Blanca, Farina, Lucia, Ferrari, Angela, Foglietta, Myriam, Lopez-Garcia, Alberto, Garcia-Marco, Jose A., García-Serra, Rocío, Gentile, Massimo, Gimeno, Eva, Gomes da Silva, Maria, Gutwein, Odit, Hakobyan, Yervand, Herishanu, Yair, Hernández-Rivas, José Ángel, Herold, Tobias, Itchaki, Gilad, Jaksic, Ozren, Janssens, Ann, Kalashnikova, Оlga B., Kalicińska, Elżbieta, Kater, Arnon P., Kersting, Sabina, Koren-Michowitz, Maya, Gomez, Jorge Labrador, Lad, Deepesh, Laurenti, Luca, Fresa, Alberto, Levin, Mark-David, Mayor Bastida, Carlota, Malerba, Lara, Marasca, Roberto, Marchetti, Monia, Marquet, Juan, Mihaljevic, Biljana, Milosevic, Ivana, Mirás, Fatima, Morawska, Marta, Motta, Marina, Munir, Talha, Murru, Roberta, Nunes, Raquel, Olivieri, Jacopo, Pavlovsky, Miguel Arturo, Piskunova, Inga S., Popov, Viola Maria, Quaglia, Francesca Maria, Quaresmini, Giulia, Reda, Gianluigi, Rigolin, Gian Matteo, Shrestha, Amit, Šimkovič, Martin, Smirnova, Svetlana, Špaček, Martin, Sportoletti, Paolo, Stanca, Oana, Stavroyianni, Niki, Te Raa, Doreen, Tomic, Kristina, Tonino, Sanne, Trentin, Livio, Van Der Spek, Ellen, van Gelder, Michel, Varettoni, Marzia, Visentin, Andrea, Vitale, Candida, Vukovic, Vojin, Wasik-Szczepanek, Ewa, Wróbel, Tomasz, Yanez San Segundo, Lucrecia, Yassin, Mohamed A, Coscia, Marta, Rambaldi, Alessandro, Montserrat, Emili, Foà, Robin, Cuneo, Antonio, Carrier, Marc, Ghia, Paolo, and Stamatopoulos, Kostas
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- 2022
- Full Text
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3. Thrombotic and Bleeding Complications in Patients with Chronic Lymphocytic Leukemia and Severe COVID-19: A Study of Eric, the European Research Initiative on CLL
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Antic, Darko, Milic, Natasa, Chatzikonstantinou, Thomas, Scarfò, Lydia, Otasevic, Vladimir, Rajovic, Nina, Allsup, David, Cabrero, Alejandro Alonso, Andres, Martin, Baile Gonzales, Monica, Capasso, Antonella, Collado, Rosa, Cordoba, Raul, Cuéllar-García, Carolina, Correa, Juan Gonzalo, De Paoli, Lorenzo, De Paolis, Maria Rosaria, Del Poeta, Giovanni, Dimou, Maria, Doubek, Michael, Efstathopoulou, Maria, El-Ashwah, Shaimaa, Enrico, Alicia, Espinet, Blanca, Farina, Lucia, Ferrari, Angela, Foglietta, Myriam, Lopez-Garcia, Alberto, Garcia-Marco, Jose A., García-Serra, Rocío, Gentile, Massimo, Gimeno, Eva, Gomes da Silva, Maria, Gutwein, Odit, Hakobyan, Yervand, Herishanu, Yair, Hernández-Rivas, José Ángel, Herold, Tobias, Itchaki, Gilad, Jaksic, Ozren, Janssens, Ann, Kalashnikova, Оlga B., Kalicińska, Elżbieta, Kater, Arnon P., Kersting, Sabina, Koren-Michowitz, Maya, Gomez, Jorge Labrador, Lad, Deepesh, Laurenti, Luca, Fresa, Alberto, Levin, Mark-David, Mayor Bastida, Carlota, Malerba, Lara, Marasca, Roberto, Marchetti, Monia, Marquet, Juan, Mihaljevic, Biljana, Milosevic, Ivana, Mirás, Fatima, Morawska, Marta, Motta, Marina, Munir, Talha, Murru, Roberta, Nunes, Raquel, Olivieri, Jacopo, Pavlovsky, Miguel Arturo, Piskunova, Inga S., Popov, Viola Maria, Quaglia, Francesca Maria, Quaresmini, Giulia, Reda, Gianluigi, Rigolin, Gian Matteo, Shrestha, Amit, Šimkovič, Martin, Smirnova, Svetlana, Špaček, Martin, Sportoletti, Paolo, Stanca, Oana, Stavroyianni, Niki, Te Raa, Doreen, Tomic, Kristina, Tonino, Sanne, Trentin, Livio, Van Der Spek, Ellen, van Gelder, Michel, Varettoni, Marzia, Visentin, Andrea, Vitale, Candida, Vukovic, Vojin, Wasik-Szczepanek, Ewa, Wróbel, Tomasz, Yanez San Segundo, Lucrecia, Yassin, Mohamed A, Coscia, Marta, Rambaldi, Alessandro, Montserrat, Emili, Foà, Robin, Cuneo, Antonio, Carrier, Marc, Ghia, Paolo, and Stamatopoulos, Kostas
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- 2022
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4. Donor bone marrow–derived macrophage MHC II drives neuroinflammation and altered behavior during chronic GVHD in mice
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Adams, Rachael C., Carter-Cusack, Dylan, Shaikh, Samreen N., Llanes, Genesis T., Johnston, Rebecca L., Quaife-Ryan, Gregory, Boyle, Glen, Koufariotis, Lambros T., Möller, Andreas, Blazar, Bruce R., Vukovic, Jana, and MacDonald, Kelli P. A.
- Abstract
Graft-versus-host disease (GVHD) remains the leading cause of nonrelapse mortality after allogeneic stem cell transplantation for hematological malignancies. Manifestations of GVHD in the central nervous system (CNS) present as neurocognitive dysfunction in up to 60% of patients; however, the mechanisms driving chronic GVHD (cGVHD) in the CNS are yet to be elucidated. Our studies of murine cGVHD revealed behavioral deficits associated with broad neuroinflammation and persistent Ifng upregulation. By flow cytometry, we observed a proportional shift in the donor-derived T-cell population in the cGVHD brain from early CD8 dominance to later CD4 sequestration. RNA sequencing of the hippocampus identified perturbations to structural and functional synapse-related gene expression, together with the upregulation of genes associated with interferon-γ responses and antigen presentation. Neuroinflammation in the cortex of mice and humans during acute GVHD was recently shown to be mediated by resident microglia-derived tumor necrosis factor. In contrast, infiltration of proinflammatory major histocompatibility complex (MHC) class II+ donor bone marrow (BM)–derived macrophages (BMDMs) was identified as a distinguishing feature of CNS cGVHD. Donor BMDMs, which composed up to 50% of the CNS myeloid population, exhibited a transcriptional signature distinct from resident microglia. Recipients of MHC class II knockout BM grafts exhibited attenuated neuroinflammation and behavior comparable to controls, suggestive of a critical role of donor BMDM MHC class II expression in CNS cGVHD. Our identification of disease mediators distinct from those in the acute phase indicates the necessity to pursue alternative therapeutic targets for late-stage neurological manifestations.
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- 2022
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5. Donor bone marrow–derived macrophage MHC II drives neuroinflammation and altered behavior during chronic GVHD in mice
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Adams, Rachael C., Carter-Cusack, Dylan, Shaikh, Samreen N., Llanes, Genesis T., Johnston, Rebecca L., Quaife-Ryan, Gregory, Boyle, Glen, Koufariotis, Lambros T., Möller, Andreas, Blazar, Bruce R., Vukovic, Jana, and MacDonald, Kelli P.A.
- Abstract
Graft-versus-host disease (GVHD) remains the leading cause of nonrelapse mortality after allogeneic stem cell transplantation for hematological malignancies. Manifestations of GVHD in the central nervous system (CNS) present as neurocognitive dysfunction in up to 60% of patients; however, the mechanisms driving chronic GVHD (cGVHD) in the CNS are yet to be elucidated. Our studies of murine cGVHD revealed behavioral deficits associated with broad neuroinflammation and persistent Ifngupregulation. By flow cytometry, we observed a proportional shift in the donor-derived T-cell population in the cGVHD brain from early CD8 dominance to later CD4 sequestration. RNA sequencing of the hippocampus identified perturbations to structural and functional synapse-related gene expression, together with the upregulation of genes associated with interferon-γ responses and antigen presentation. Neuroinflammation in the cortex of mice and humans during acute GVHD was recently shown to be mediated by resident microglia-derived tumor necrosis factor. In contrast, infiltration of proinflammatory major histocompatibility complex (MHC) class II+donor bone marrow (BM)–derived macrophages (BMDMs) was identified as a distinguishing feature of CNS cGVHD. Donor BMDMs, which composed up to 50% of the CNS myeloid population, exhibited a transcriptional signature distinct from resident microglia. Recipients of MHC class II knockout BM grafts exhibited attenuated neuroinflammation and behavior comparable to controls, suggestive of a critical role of donor BMDM MHC class II expression in CNS cGVHD. Our identification of disease mediators distinct from those in the acute phase indicates the necessity to pursue alternative therapeutic targets for late-stage neurological manifestations.
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- 2022
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6. CSF1R Inhibition Promotes Neuroinflammation and Behavioural Deficits during Graft-Versus-Host Disease in Mice
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Adams, Rachael C, Carter-Cusack, Dylan, Llanes, Genesis T, Hunter, Christopher R, Vinnakota, Janaki Manoja, Ruitenberg, Marc, Vukovic, Jana, Bertolino, Patrick, Chand, Kirat K., Wixey, Julie A., Nayler, Samuel P, Hill, Geoffrey R, Furlan, Scott N, Zeiser, Robert, and MacDonald, Kelli PA
- Abstract
Chronic graft-versus-host disease (cGVHD) remains a significant complication of allogeneic hematopoietic stem cell transplantation. Central nervous system (CNS) involvement is becoming increasingly recognised, where brain-infiltrating donor MHC class II +bone marrow-derived macrophages (BMDM) are implicated mediators of pathology. Colony-stimulating factor 1 receptor (CSF1R)-dependent BMDM are established mediators of cutaneous and pulmonary cGVHD, and clinical trials assessing the efficacy of CSF1R antibody blockade to deplete macrophages are promising. We hypothesized that CSF1R antibody blockade may also be a useful strategy to prevent/treat CNS cGVHD.
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- 2023
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7. Non-O Blood Group and Pretreatment Risk of Venous Thromboembolism in Patients with Diffuse Large B-Cell Lymphoma
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Otasevic, Vladimir, Ivanovic, Jelena, Vukovic, Vojin, Milic, Natasa, Kozarac, Sofija, Pesic, Andrej, Mihaljevic, Biljana, Fareed, Jawed, and Antic, Darko
- Abstract
Introduction:Diffuse large B-cell lymphoma (DLBCL) is the most frequent aggressive non-Hodgkin lymphoma (NHL). It has been extensively documented that the risk of venous thromboembolism (VTE) is augmented in patients with aggressive lymphomas. The timing of VTE occurrence in this group of patients is highly variable and depends on diverse risk factors. Lately, it has been observed that ABO blood group type can have a prognostic impact on both thrombosis development and survival outcomes in patients with cancer. Therefore, the study aimed to examine the ABO blood group as a risk factor for VTE development in patients with DLBCL, to examine the relation between ABO blood groups and the timing of VTE development, and to investigate the association between ABO group type and treatment and survival outcomes.
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- 2023
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8. Identifying Novel Coagulation Biomarkers for Thrombosis in Patients with Lymphoma
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Antic, Darko, Otasevic, Vladimir, Mitrovic-Ajtic, Olivera, Djikic, Dragoslava, Zivkovic, Emilija, Dragojevic, Teodora, Ivanovic, Jelena, Stanisavljevic, Dejana, Milic, Natasa, Vukotic, Milica, Suboticki, Tijana, Diklic, Milos, Santibanez, Juan F., Vukovic, Vojin, Kozarac, Sofija, Pesic, Andrej, Mihaljevic, Biljana, Fareed, Jawed, and Cokic, Vladan P.
- Abstract
Thromboembolic events are a common complication of lymphoma, influenced by a number of factors, including status of the disease, patient characteristics and treatment modalities. Recent studies demonstrated presence of hemostatic dysregulation in lymphoma patients with the possible involvement of tissue factor (TF) in the development of thrombotic events; however, more data are needed to link coagulation biomarkers' levels with clinical data and increased thrombotic risk. TF initiates blood coagulation and expressed by nonvascular cells plays a major role in hemostasis, while TF expressed by vascular cells induces intravascular thrombosis. In this study, we aimed to profile coagulation biomarkers and determine the roles of neutrophils, monocytes, platelets and endothelial cells and their interactions in thrombus formation in patients with lymphoma.
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- 2023
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9. Tissue Factor Positive Extracellular Vesicles and Risk of Thromboembolism in Diffuse Large B-Cell Lymphoma: A Prospective Exploratory Study
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Otasevic, Vladimir, Gran, Charlotte, Milic, Natasa, Vukovic, Vojin, Mihaljevic, Biljana, Fareed, Jawed, Mahmoud Hourani Soutari, Nida, Antovic, Jovan, and Antic, Darko
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- 2022
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10. Tissue Factor Positive Extracellular Vesicles and Risk of Thromboembolism in Diffuse Large B-Cell Lymphoma: A Prospective Exploratory Study
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Otasevic, Vladimir, Gran, Charlotte, Milic, Natasa, Vukovic, Vojin, Mihaljevic, Biljana, Fareed, Jawed, Mahmoud Hourani Soutari, Nida, Antovic, Jovan, and Antic, Darko
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- 2022
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11. Adult hematopoietic stem cells lacking Hif-1α self-renew normally
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Vukovic, Milica, Sepulveda, Catarina, Subramani, Chithra, Guitart, Amélie V., Mohr, Jasmine, Allen, Lewis, Panagopoulou, Theano I., Paris, Jasmin, Lawson, Hannah, Villacreces, Arnaud, Armesilla-Diaz, Alejandro, Gezer, Deniz, Holyoake, Tessa L., Ratcliffe, Peter J., and Kranc, Kamil R.
- Abstract
The hematopoietic stem cell (HSC) pool is maintained under hypoxic conditions within the bone marrow microenvironment. Cellular responses to hypoxia are largely mediated by the hypoxia-inducible factors, Hif-1 and Hif-2. The oxygen-regulated α subunits of Hif-1 and Hif-2 (namely, Hif-1α and Hif-2α) form dimers with their stably expressed β subunits and control the transcription of downstream hypoxia-responsive genes to facilitate adaptation to low oxygen tension. An initial study concluded that Hif-1α is essential for HSC maintenance, whereby Hif-1α–deficient HSCs lost their ability to self-renew in serial transplantation assays. In another study, we demonstrated that Hif-2α is dispensable for cell-autonomous HSC maintenance, both under steady-state conditions and following transplantation. Given these unexpected findings, we set out to revisit the role of Hif-1α in cell-autonomous HSC functions. Here we demonstrate that inducible acute deletion of Hif-1α has no impact on HSC survival. Notably, unstressed HSCs lacking Hif-1α efficiently self-renew and sustain long-term multilineage hematopoiesis upon serial transplantation. Finally, Hif-1α–deficient HSCs recover normally after hematopoietic injury induced by serial administration of 5-fluorouracil. We therefore conclude that despite the hypoxic nature of the bone marrow microenvironment, Hif-1α is dispensable for cell-autonomous HSC maintenance.
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- 2016
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12. Adult hematopoietic stem cells lacking Hif-1α self-renew normally
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Vukovic, Milica, Sepulveda, Catarina, Subramani, Chithra, Guitart, Amélie V., Mohr, Jasmine, Allen, Lewis, Panagopoulou, Theano I., Paris, Jasmin, Lawson, Hannah, Villacreces, Arnaud, Armesilla-Diaz, Alejandro, Gezer, Deniz, Holyoake, Tessa L., Ratcliffe, Peter J., and Kranc, Kamil R.
- Abstract
The hematopoietic stem cell (HSC) pool is maintained under hypoxic conditions within the bone marrow microenvironment. Cellular responses to hypoxia are largely mediated by the hypoxia-inducible factors, Hif-1 and Hif-2. The oxygen-regulated α subunits of Hif-1 and Hif-2 (namely, Hif-1α and Hif-2α) form dimers with their stably expressed β subunits and control the transcription of downstream hypoxia-responsive genes to facilitate adaptation to low oxygen tension. An initial study concluded that Hif-1αis essential for HSC maintenance, whereby Hif-1α–deficient HSCs lost their ability to self-renew in serial transplantation assays. In another study, we demonstrated that Hif-2αis dispensable for cell-autonomous HSC maintenance, both under steady-state conditions and following transplantation. Given these unexpected findings, we set out to revisit the role of Hif-1αin cell-autonomous HSC functions. Here we demonstrate that inducible acute deletion of Hif-1αhas no impact on HSC survival. Notably, unstressed HSCs lacking Hif-1αefficiently self-renew and sustain long-term multilineage hematopoiesis upon serial transplantation. Finally, Hif-1α–deficient HSCs recover normally after hematopoietic injury induced by serial administration of 5-fluorouracil. We therefore conclude that despite the hypoxic nature of the bone marrow microenvironment, Hif-1αis dispensable for cell-autonomous HSC maintenance.
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- 2016
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13. Chromatin looping defines expression of TAL1, its flanking genes, and regulation in T-ALL
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Zhou, Yan, Kurukuti, Sreenivasulu, Saffrey, Peter, Vukovic, Milica, Michie, Alison M., Strogantsev, Ruslan, West, Adam G., and Vetrie, David
- Abstract
TAL1 is an important regulator of hematopoiesis and its expression is tightly controlled despite complexities in its genomic organization. It is frequently misregulated in T-cell acute lymphoblastic leukemia (T-ALL), often due to deletions between TAL1 and the neighboring STIL gene. To better understand the events that lead to TAL1 expression in hematopoiesis and in T-ALL, we studied looping interactions at the TAL1 locus. In TAL1-expressing erythroid cells, the locus adopts a looping “hub” which brings into close physical proximity all known TAL1 cis-regulatory elements including CTCF-bound insulators. Loss of GATA1 results in disassembly of the hub and loss of CTCF/RAD21 from one of its insulators. Genes flanking TAL1 are partly dependent on hub integrity for their transcriptional regulation. We identified looping patterns unique to TAL1-expressing T-ALL cells, and, intriguingly, loops occurring between the TAL1 and STIL genes at the common TAL1/STIL breakpoints found in T-ALL. These findings redefine how TAL1 and neighboring genes communicate within the nucleus, and indicate that looping facilitates both normal and aberrant TAL1 expression and may predispose to structural rearrangements in T-ALL. We also propose that GATA1-dependent looping mechanisms may facilitate the conservation of TAL1 regulation despite cis-regulatory remodeling during vertebrate evolution.
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- 2013
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14. Chromatin looping defines expression of TAL1, its flanking genes, and regulation in T-ALL
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Zhou, Yan, Kurukuti, Sreenivasulu, Saffrey, Peter, Vukovic, Milica, Michie, Alison M., Strogantsev, Ruslan, West, Adam G., and Vetrie, David
- Abstract
TAL1 is an important regulator of hematopoiesis and its expression is tightly controlled despite complexities in its genomic organization. It is frequently misregulated in T-cell acute lymphoblastic leukemia (T-ALL), often due to deletions between TAL1and the neighboring STILgene. To better understand the events that lead to TAL1 expression in hematopoiesis and in T-ALL, we studied looping interactions at the TAL1locus. In TAL1-expressing erythroid cells, the locus adopts a looping “hub” which brings into close physical proximity all known TAL1 cis-regulatory elements including CTCF-bound insulators. Loss of GATA1 results in disassembly of the hub and loss of CTCF/RAD21 from one of its insulators. Genes flanking TAL1are partly dependent on hub integrity for their transcriptional regulation. We identified looping patterns unique to TAL1-expressing T-ALL cells, and, intriguingly, loops occurring between the TAL1and STILgenes at the common TAL1/STILbreakpoints found in T-ALL. These findings redefine how TAL1and neighboring genes communicate within the nucleus, and indicate that looping facilitates both normal and aberrant TAL1 expression and may predispose to structural rearrangements in T-ALL. We also propose that GATA1-dependent looping mechanisms may facilitate the conservation of TAL1regulation despite cis-regulatory remodeling during vertebrate evolution.
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- 2013
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15. Hif-2α is not essential for cell-autonomous hematopoietic stem cell maintenance
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Guitart, Amelie V., Subramani, Chithra, Armesilla-Diaz, Alejandro, Smith, Gillian, Sepulveda, Catarina, Gezer, Deniz, Vukovic, Milica, Dunn, Karen, Pollard, Patrick, Holyoake, Tessa L., Enver, Tariq, Ratcliffe, Peter J., and Kranc, Kamil R.
- Abstract
Local hypoxia in hematopoietic stem cell (HSC) niches is thought to regulate HSC functions. Hypoxia-inducible factor-1 (Hif-1) and Hif-2 are key mediators of cellular responses to hypoxia. Although oxygen-regulated α-subunits of Hifs, namely Hif-1α and Hif-2α, are closely related, they play overlapping and also distinct functions in nonhematopoietic tissues. Although Hif-1α–deficient HSCs lose their activity on serial transplantation, the role for Hif-2α in cell-autonomous HSC maintenance remains unknown. Here, we demonstrate that constitutive or inducible hematopoiesis-specific Hif-2α deletion does not affect HSC numbers and steady-state hematopoiesis. Furthermore, using serial transplantations and 5-fluorouracil treatment, we demonstrate that HSCs do not require Hif-2α to self-renew and recover after hematopoietic injury. Finally, we show that Hif-1α deletion has no major impact on steady-state maintenance of Hif-2α–deficient HSCs and their ability to repopulate primary recipients, indicating that Hif-1α expression does not account for normal behavior of Hif-2α–deficient HSCs.
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- 2013
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16. Hif-2α is not essential for cell-autonomous hematopoietic stem cell maintenance
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Guitart, Amelie V., Subramani, Chithra, Armesilla-Diaz, Alejandro, Smith, Gillian, Sepulveda, Catarina, Gezer, Deniz, Vukovic, Milica, Dunn, Karen, Pollard, Patrick, Holyoake, Tessa L., Enver, Tariq, Ratcliffe, Peter J., and Kranc, Kamil R.
- Abstract
Local hypoxia in hematopoietic stem cell (HSC) niches is thought to regulate HSC functions. Hypoxia-inducible factor-1 (Hif-1) and Hif-2 are key mediators of cellular responses to hypoxia. Although oxygen-regulated α-subunits of Hifs, namely Hif-1α and Hif-2α, are closely related, they play overlapping and also distinct functions in nonhematopoietic tissues. Although Hif-1α–deficient HSCs lose their activity on serial transplantation, the role for Hif-2αin cell-autonomous HSC maintenance remains unknown. Here, we demonstrate that constitutive or inducible hematopoiesis-specific Hif-2αdeletion does not affect HSC numbers and steady-state hematopoiesis. Furthermore, using serial transplantations and 5-fluorouracil treatment, we demonstrate that HSCs do not require Hif-2αto self-renew and recover after hematopoietic injury. Finally, we show that Hif-1αdeletion has no major impact on steady-state maintenance of Hif-2α–deficient HSCs and their ability to repopulate primary recipients, indicating that Hif-1αexpression does not account for normal behavior of Hif-2α–deficient HSCs.
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- 2013
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17. Megakaryocytes assemble podosomes that degrade matrix and protrude through basement membrane
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Schachtner, Hannah, Calaminus, Simon D. J., Sinclair, Amy, Monypenny, James, Blundell, Michael P., Leon, Catherine, Holyoake, Tessa L., Thrasher, Adrian J., Michie, Alison M., Vukovic, Milica, Gachet, Christian, Jones, Gareth E., Thomas, Steven G., Watson, Steve P., and Machesky, Laura M.
- Abstract
Megakaryocytes give rise to platelets via extension of proplatelet arms, which are released through the vascular sinusoids into the bloodstream. Megakaryocytes and their precursors undergo varying interactions with the extracellular environment in the bone marrow during their maturation and positioning in the vascular niche. We demonstrate that podosomes are abundant in primary murine megakaryocytes adherent on multiple extracellular matrix substrates, including native basement membrane. Megakaryocyte podosome lifetime and density, but not podosome size, are dependent on the type of matrix, with podosome lifetime dramatically increased on collagen fibers compared with fibrinogen. Podosome stability and dynamics depend on actin cytoskeletal dynamics but not matrix metalloproteases. However, podosomes degrade matrix and appear to be important for megakaryocytes to extend protrusions across a native basement membrane. We thus demonstrate for the first time a fundamental requirement for podosomes in megakaryocyte process extension across a basement membrane, and our results suggest that podosomes may have a role in proplatelet arm extension or penetration of basement membrane.
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- 2013
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18. Megakaryocytes assemble podosomes that degrade matrix and protrude through basement membrane
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Schachtner, Hannah, Calaminus, Simon D.J., Sinclair, Amy, Monypenny, James, Blundell, Michael P., Leon, Catherine, Holyoake, Tessa L., Thrasher, Adrian J., Michie, Alison M., Vukovic, Milica, Gachet, Christian, Jones, Gareth E., Thomas, Steven G., Watson, Steve P., and Machesky, Laura M.
- Abstract
Megakaryocytes give rise to platelets via extension of proplatelet arms, which are released through the vascular sinusoids into the bloodstream. Megakaryocytes and their precursors undergo varying interactions with the extracellular environment in the bone marrow during their maturation and positioning in the vascular niche. We demonstrate that podosomes are abundant in primary murine megakaryocytes adherent on multiple extracellular matrix substrates, including native basement membrane. Megakaryocyte podosome lifetime and density, but not podosome size, are dependent on the type of matrix, with podosome lifetime dramatically increased on collagen fibers compared with fibrinogen. Podosome stability and dynamics depend on actin cytoskeletal dynamics but not matrix metalloproteases. However, podosomes degrade matrix and appear to be important for megakaryocytes to extend protrusions across a native basement membrane. We thus demonstrate for the first time a fundamental requirement for podosomes in megakaryocyte process extension across a basement membrane, and our results suggest that podosomes may have a role in proplatelet arm extension or penetration of basement membrane.
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- 2013
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19. Properties of CD34+ CML stem/progenitor cells that correlate with different clinical responses to imatinib mesylate
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Jiang, Xiaoyan, Forrest, Donna, Nicolini, Franck, Turhan, Ali, Guilhot, Joelle, Yip, Calvin, Holyoake, Tessa, Jorgensen, Heather, Lambie, Karen, Saw, Kyi Min, Pang, Emily, Vukovic, Ranko, Lehn, Paeta, Ringrose, Ashley, Yu, Miao, Brinkman, Ryan R., Smith, Clay, Eaves, Allen, and Eaves, Connie
- Abstract
Imatinib mesylate (IM) induces clinical remissions in chronic-phase chronic myeloid leukemia (CML) patients but IM resistance remains a problem. We recently identified several features of CML CD34+ stem/progenitor cells expected to confer resistance to BCR-ABL-targeted therapeutics. From a study of 25 initially chronic-phase patients, we now demonstrate that some, but not all, of these parameters correlate with subsequent clinical response to IM therapy. CD34+ cells from the 14 IM nonresponders demonstrated greater resistance to IM than the 11 IM responders in colony-forming cell assays in vitro (P < .001) and direct sequencing of cloned transcripts from CD34+ cells further revealed a higher incidence of BCR-ABL kinase domain mutations in the IM nonresponders (10%-40% vs 0%-20% in IM responders, P < .003). In contrast, CD34+ cells from IM nonresponders and IM responders were not distinguished by differences in BCR-ABL or transporter gene expression. Interestingly, one BCR-ABL mutation (V304D), predicted to destabilize the interaction between p210BCR-ABL and IM, was detectable in 14 of 20 patients. T315I mutant CD34+ cells found before IM treatment in 2 of 20 patients examined were preferentially amplified after IM treatment. Thus, 2 properties of pretreatment CML stem/progenitor cells correlate with subsequent response to IM therapy. Prospective assessment of these properties may allow improved patient management.
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- 2010
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20. Properties of CD34+CML stem/progenitor cells that correlate with different clinical responses to imatinib mesylate
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Jiang, Xiaoyan, Forrest, Donna, Nicolini, Franck, Turhan, Ali, Guilhot, Joelle, Yip, Calvin, Holyoake, Tessa, Jorgensen, Heather, Lambie, Karen, Saw, Kyi Min, Pang, Emily, Vukovic, Ranko, Lehn, Paeta, Ringrose, Ashley, Yu, Miao, Brinkman, Ryan R., Smith, Clay, Eaves, Allen, and Eaves, Connie
- Abstract
Imatinib mesylate (IM) induces clinical remissions in chronic-phase chronic myeloid leukemia (CML) patients but IM resistance remains a problem. We recently identified several features of CML CD34+stem/progenitor cells expected to confer resistance to BCR-ABL-targeted therapeutics. From a study of 25 initially chronic-phase patients, we now demonstrate that some, but not all, of these parameters correlate with subsequent clinical response to IM therapy. CD34+cells from the 14 IM nonresponders demonstrated greater resistance to IM than the 11 IM responders in colony-forming cell assays in vitro (P< .001) and direct sequencing of cloned transcripts from CD34+cells further revealed a higher incidence of BCR-ABLkinase domain mutations in the IM nonresponders (10%-40% vs 0%-20% in IM responders, P< .003). In contrast, CD34+cells from IM nonresponders and IM responders were not distinguished by differences in BCR-ABLor transporter gene expression. Interestingly, one BCR-ABLmutation (V304D), predicted to destabilize the interaction between p210BCR-ABLand IM, was detectable in 14 of 20 patients. T315I mutant CD34+cells found before IM treatment in 2 of 20 patients examined were preferentially amplified after IM treatment. Thus, 2 properties of pretreatment CML stem/progenitor cells correlate with subsequent response to IM therapy. Prospective assessment of these properties may allow improved patient management.
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- 2010
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21. Real-World Evidence on Therapeutic Strategies and Treatment-Sequencing in Patients with Chronic Lymphocytic Leukemia: An International Study of Eric, the European Research Initiative on CLL
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Chatzikonstantinou, Thomas, Scarfo, Lydia, Demosthenous, Christos, Kotaskova, Jana, Iacoboni, Gloria, Minga, Evangelia, Chammou, Dimitra, Karakatsoulis, Georgios, Albi, Elisa, Alcoceba, Miguel, El-Ashwah, Shaimaa, Bacchiarri, Francesca, Khan, Mehreen Ali, Aurran, Thérèse, Calleja, Anne, Cassin, Ramona, Chatzileontiadou, Sofia, Christian, Amy, Claus, Rainer, Collado, Rosa, De Deus Santos, Marcos Daniel, Davis, Zadie, Dimou, Maria, Donaldson, David, Dos Santos, Gimena, Dreta, Barbara, Efstathopoulou, Maria, Enrico, Alicia, Fresa, Alberto, Galimberti, Sara, García-Serra, Rocío, González-Gascón Y Marín, Isabel, Gozzetti, Alessandro, Guarente, Valerio, Harrop, Sean, Hatzimichael, Eleftheria, Herishanu, Yair, Inchiappa, Luca, Iskas, Michalis, Jaksic, Ozren, Janssen, Susanne R., Kalicinska, Elzbieta, Karakus, Volkan, Kater, Arnon P., Kho, Bonnie, Konstantinou, Iliana, Longval, Thomas, Koren-Michowitz, Maya, Kotsianidis, Ioannis, Kreitman, Robert J., Nath, Uttam Kumar, Labrador, Jorge, Lad, Deepesh, Laribi, Kamel, Levy, Ilana, Lopez-Garcia, Alberto, Marquet Palomanes, Juan, Maslejova, Stanislava, Mayor-Bastida, Carlota, Merabet, Fatiha, Mihaljevic, Biljana, Milosevic, Ivana, Miras, Fatima, Moia, Riccardo, Morawska, Marta, Navarro-Bailón, Almudena, Oscier, David, Olivieri, Jacopo, Papajík, Tomáš, Papaioannou, Maria, Pierie, Cheyenne, Puiggros, Anna, Reda, Gianluigi, Rigolin, Gian Matteo, Ruchlemer, Rosa, Schiattone, Luana, Sevindik, Omur Gokmen, Shen, Yandong, Šimkovič, Martin, Smirnova, Svetlana, Soliman, Dina Sameh, Špaček, Martin, Schiwitza, Annett, Tadmor, Tamar, Tourjeman, Liat, Tse, Eric, Visentin, Andrea, Tomic, Kristina, Van Gelder, Michel, Vassilakopoulos, Theodoros P., Vitale, Candida, Vrachiolias, George, Vukovic, Vojin, Xu, Zhenshu, Yáñez, Lucrecia, Yagci, Munci, Yassin, Mohamed A, Zuchnicka, Jana, Angelopoulou, Maria K., Antic, Darko, Biderman, Bella V., Catherwood, Mark, Coscia, Marta, Cuneo, Antonio, Demirkan, Fatih, Espinet, Blanca, Gaidano, Gianluca, Guièze, Romain, Kalashnikova, Olga, Laurenti, Luca, Mulligan, Stephen, Murru, Roberta, Nikitin, Eugene A., Panayiotidis, Panayiotis, Pangalis, Gerasimos, Panovska, Irina, Popov, Viola Maria, Pospíšilová, Šárka, Smolej, Lukas, Sportoletti, Paolo, Stavroyianni, Niki, Tam, Constantine S., Trentin, Livio, Trněný, Marek, Bosch Albareda, Francesc, Doubek, Michael, Chatzidimitriou, Anastasia, Ghia, Paolo, and Stamatopoulos, Kostas
- Abstract
The use of novel small molecule inhibitors alone or in combination with anti-CD20 monoclonal antibodies for chronic lymphocytic leukemia (CLL) has raised a number of questions on efficacy, tolerability, long-term treatment adherence in patients with heterogeneous clinical features. To fill this gap, we designed a study focusing on treatment sequencing in patients with CLL in order to (i) compare the outcome of patients treated with chemoimmunotherapy (CIT) combinations in first-line versus those receiving Bruton's tyrosine kinase inhibitors (BTKi); (ii) characterize the efficacy and tolerability of venetoclax-based regimens; (ii) understand the impact of treatment sequencing when it comes to chemo-free options including venetoclax after BTKi and vice versa. Data from consecutive sets of patients diagnosed with CLL between 2000-2020 attended at 77 institutions affiliated with ERIC were collected and analyzed. Collected variables included: demographics, clinical stage at diagnosis, IGHV gene somatic hypermutation status; cytogenetic status for chromosomes 11q, 13q 17p and 12 determined by fluorescence in situhybridization; TP53gene mutation status; treatment; treatment response; discontinuation; reason for discontinuation; death. We included 9173 patients with a diagnosis of CLL who received at least one line of treatment. The median age at diagnosis was 67 years with a male:female ratio of 1.9. The median follow-up was 78 months (IQR, 48-120 months). Regarding novel targeted agents, 1860/9173 (20.2%) patients had received at least one line of treatment with BTKi (ibrutinib, n=1788; acalabrutinib, n=72) over the disease course; 631/9173 (6.9%) with venetoclax; and, 447/9173 (4.9%) with the PI3K inhibitor idelalisib. Seventy-nine patients were treated with both BTKi and venetoclax (59 BTKi followed by BCL2i, 20 vice versa). At last follow-up, 5870/9173 patients (64.0%) were alive, 3229/9173 (35.2%) died and 74/9173 (0.8%) were lost to follow-up. Patients treated with BTKi in first-line were enriched for TP53aberrations [del(17p) 27.6%, TP53mutation 26.3%] and unmutated IGHV genes (69%) and obtained an ORR of 87.7%. Of these, 136 (26.3%) discontinued treatment after a median of 1.2 years (0.07-5.98); main reasons of discontinuation were toxicity (40.5%) and failure (26.2%). Among 631 patients treated with venetoclax at any line, 100 (15.8%) received BCL2 +/- anti-CD20 as first-line; 170 (26.9%) as second line (125 previously treated with CIT, 27 with BTKi); and, 361 as third or subsequent line. ORR ranged between 71.5% (≥3 lines) with 30.5% CR/CRi to 90.3% (first-line) with 68.1% CR/CRi. Treatment discontinuation was due to toxicity in 28.6% of patients treated in the first-line, and 17.6% and 21.8% of patients treated in second and third-or-higher-line, respectively. Disease progression led to treatment discontinuation in 14.3%, 20.6% and 33.6% in first, second and third-or-higher line, respectively. CIT was used as front-line treatment in 5465 patients (59.6%). Of these, 2070 (37.9%) and 1018 (18.6%) patients received a second and third line of treatment, respectively. The great majority (865/1086 cases, 79.7%) of patients who received a second line before 2014 were retreated with CIT, most commonly Bendamustine-Rituximab (284/1086, 26.1%) and Fludarabine-Cyclophosphamide-Rituximab (252/1086, 23.2%); alemtuzumab monotherapy was used in 55/1086 (5%) of patients. After 2014, 415/984 patients (42.1%) were retreated with BTKi; 93 (9.5%) with venetoclax; 70 (7.2%) with idelalisib; 50 (5%) with Alemtuzumab monotherapy, and 315 (32%) with CIT. Similarly, in the third-or-higher line of treatment, most patients (86.3%) were retreated with CIT before 2014, while BTKi, BCL2i, and PI3Ki were mainly used after 2014 (in 43.1%, 15.7% and 14.7% of cases, respectively). Finally, our cohort included 1075 patients with TP53aberrations. The ORR of patients receiving BTKis (n=171) as first-line of treatment was 86.5% (22.2 CR+64.3 PR), while the ORR with venetoclax +/- anti-CD20 (n=15) was 91% (45.5% CR+45.5 PR). Patients treated with CIT (n=694) had an ORR of 68.7% (28.3% CR+40.4% PR). In conclusion, in a large international study we provide real world data regarding the selection and sequencing of treatment in CLL, charting a major shift in treatment patterns before and after the introduction of novel trargeted agents and confirming their efficacy even in high-risk CLL.
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- 2021
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22. Alrn-6924, a Dual Inhibitor of MDMX and MDM2, Transiently Induces Cell Cycle Arrest in Bone Marrow and Prevents Toxicity in Mouse Models of Acute Radiation Injury
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Annis, Allen, Sutton, David, Aivado, Manuel, and Vukovic, Vojislav
- Abstract
Background: Myelosuppression is a common sequela of acute radiation injury due to sensitivity of proliferating bone marrow cells to ionizing radiation. ALRN-6924 is a clinical-stage, first-in-class, stabilized cell-permeating alpha-helical peptide drug that disrupts the interaction of the p53 tumor suppressor protein with its endogenous inhibitors, MDMX and MDM2, to induce transient, dose-dependent cell cycle arrest in p53-wild-type tissues. ALRN-6924 is being evaluated in clinical trials as a selective chemoprotection agent for patients with p53-mutant cancers to protect healthy normal cells from chemotherapy while not protecting p53-mutant cancer cells. We tested whether ALRN-6924 may similarly protect against radiation-induced toxicity in mouse models of acute radiation injury.
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- 2021
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23. Alrn-6924, a Dual Inhibitor of MDMX and MDM2, Transiently Induces Cell Cycle Arrest in Bone Marrow and Prevents Toxicity in Mouse Models of Acute Radiation Injury
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Annis, Allen, Sutton, David, Aivado, Manuel, and Vukovic, Vojislav
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Annis: Aileron Therapeutics, Inc.: Current Employment. Sutton: Aileron Therapeutics, Inc.: Consultancy; Kriya Therapeutics: Consultancy; First Light Pharmaceuticals: Consultancy; Cygnal Therapeutics: Consultancy. Aivado: Aileron Therapeutics, Inc.: Current Employment. Vukovic: Aileron Therapeutics, Inc.: Current Employment.
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- 2021
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24. Real-World Evidence on Therapeutic Strategies and Treatment-Sequencing in Patients with Chronic Lymphocytic Leukemia: An International Study of Eric, the European Research Initiative on CLL
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Chatzikonstantinou, Thomas, Scarfo, Lydia, Demosthenous, Christos, Kotaskova, Jana, Iacoboni, Gloria, Minga, Evangelia, Chammou, Dimitra, Karakatsoulis, Georgios, Albi, Elisa, Alcoceba, Miguel, El-Ashwah, Shaimaa, Bacchiarri, Francesca, Khan, Mehreen Ali, Aurran, Thérèse, Calleja, Anne, Cassin, Ramona, Chatzileontiadou, Sofia, Christian, Amy, Claus, Rainer, Collado, Rosa, De Deus Santos, Marcos Daniel, Davis, Zadie, Dimou, Maria, Donaldson, David, Dos Santos, Gimena, Dreta, Barbara, Efstathopoulou, Maria, Enrico, Alicia, Fresa, Alberto, Galimberti, Sara, García-Serra, Rocío, González-Gascón Y Marín, Isabel, Gozzetti, Alessandro, Guarente, Valerio, Harrop, Sean, Hatzimichael, Eleftheria, Herishanu, Yair, Inchiappa, Luca, Iskas, Michalis, Jaksic, Ozren, Janssen, Susanne R., Kalicinska, Elzbieta, Karakus, Volkan, Kater, Arnon P., Kho, Bonnie, Konstantinou, Iliana, Longval, Thomas, Koren-Michowitz, Maya, Kotsianidis, Ioannis, Kreitman, Robert J., Nath, Uttam Kumar, Labrador, Jorge, Lad, Deepesh, Laribi, Kamel, Levy, Ilana, Lopez-Garcia, Alberto, Marquet Palomanes, Juan, Maslejova, Stanislava, Mayor-Bastida, Carlota, Merabet, Fatiha, Mihaljevic, Biljana, Milosevic, Ivana, Miras, Fatima, Moia, Riccardo, Morawska, Marta, Navarro-Bailón, Almudena, Oscier, David, Olivieri, Jacopo, Papajík, Tomáš, Papaioannou, Maria, Pierie, Cheyenne, Puiggros, Anna, Reda, Gianluigi, Rigolin, Gian Matteo, Ruchlemer, Rosa, Schiattone, Luana, Sevindik, Omur Gokmen, Shen, Yandong, Šimkovič, Martin, Smirnova, Svetlana, Soliman, Dina Sameh, Špaček, Martin, Schiwitza, Annett, Tadmor, Tamar, Tourjeman, Liat, Tse, Eric, Visentin, Andrea, Tomic, Kristina, Van Gelder, Michel, Vassilakopoulos, Theodoros P., Vitale, Candida, Vrachiolias, George, Vukovic, Vojin, Xu, Zhenshu, Yáñez, Lucrecia, Yagci, Munci, Yassin, Mohamed A, Zuchnicka, Jana, Angelopoulou, Maria K., Antic, Darko, Biderman, Bella V., Catherwood, Mark, Coscia, Marta, Cuneo, Antonio, Demirkan, Fatih, Espinet, Blanca, Gaidano, Gianluca, Guièze, Romain, Kalashnikova, Olga, Laurenti, Luca, Mulligan, Stephen, Murru, Roberta, Nikitin, Eugene A., Panayiotidis, Panayiotis, Pangalis, Gerasimos, Panovska, Irina, Popov, Viola Maria, Pospíšilová, Šárka, Smolej, Lukas, Sportoletti, Paolo, Stavroyianni, Niki, Tam, Constantine S., Trentin, Livio, Trněný, Marek, Bosch Albareda, Francesc, Doubek, Michael, Chatzidimitriou, Anastasia, Ghia, Paolo, and Stamatopoulos, Kostas
- Abstract
Scarfo: Janssen: Honoraria, Other: Travel grants; Astra Zeneca: Honoraria; Abbvie: Honoraria. Iacoboni: BMS/Celgene, Gilead, Novartis, Janssen, Roche: Honoraria. Collado: Abbvie,: Other: pharmaceutical Company, Research Funding; Janssen: Other: Pharmaceutical Company, Research Funding. Galimberti: AbbVie, Janssen: Honoraria, Other: Travel grants; Incyte: Speakers Bureau. García-Serra: AbbVie: Other: Educational grands; Janssen: Other: Educational grants; Novartis: Other: Educational grants. Gozzetti: Janssen: Honoraria; AbbVie: Honoraria. Hatzimichael: Amgen, Roche, Genesis, Novartis, Bristol Mayer Squibb, Celgene, Pfizer: Consultancy; Abbvie, Amgen, Bristol Mayer Squibb, MSD, Gilead, Janssen Cilag, Genesis Pharma, Roche, Takeda: Honoraria. Herishanu: AbbVie: Honoraria, Research Funding; Janssen: Honoraria; Roche: Honoraria; Medison: Honoraria. Jaksic: Roche, Oktal-Pharma/Celtrion, Sandoz: Consultancy, Honoraria. Kater: Janssen, AstraZeneca: Other: Ad Board, steering committee, Research Funding; Abbvie: Honoraria, Other: Ad Board, Research Funding; BMS, Roche/Genentech: Other: Ad Board, , Research Funding; Genmab, LAVA: Other: Ad Board, Steering Committee. Kotsianidis: Astellas: Other: NONE, Research Funding, Speakers Bureau; Genesis: Consultancy, Other: NONE; Janssen Hellas: Consultancy, Other: NONE, Speakers Bureau; Bristol Hellas: Consultancy, Other: NONE, Research Funding, Speakers Bureau; Novartis Hellas: Consultancy, Other: NONE, Research Funding, Speakers Bureau; Abbvie: Consultancy, Other: NONE, Research Funding, Speakers Bureau. Kreitman: NIH: Patents & Royalties: Moxetumomab Pasudotox; Genentech: Research Funding; Teva: Research Funding; AstraZeneca/MedImmune: Research Funding; Innate: Research Funding; GSK/Novartis: Research Funding; Array BioPharma/Pfizer: Research Funding. Laribi: BeiGene: Other: Personal Fees; Jansen: Research Funding; Novartis: Other: Personal Fees, Research Funding; Astellas Phama, Inc.: Other: Personal Fees; AstraZeneca: Other: Personal Fees; Le Mans Hospital: Research Funding; Takeda: Other: Personal Fees, Research Funding; AbbVie: Other: Personal Fees, Research Funding; IQONE: Other: Personal Fees. Lopez-Garcia: Roche: Other: Speaker Honoraria, Travel and accommodation grants; Novonordisk: Other: Speaker Honoraria; Fresenius: Other: Speaker Honoraria; Celgene: Other: Speaker Honoraria; Abbvie: Other: Speaker Honoraria, Advisor, Travel and accommodation grants; Janssen: Other: Speaker Honoraria, Advisor, Travel and accommodation grants, Research Funding. Milosevic: Roche: Honoraria; Abbvie,: Honoraria; Janssen: Honoraria; Sandoz: Honoraria. Reda: Beigene: Consultancy; Astra Zeneca: Consultancy; Abbvie: Consultancy; Janssen: Consultancy. Ruchlemer: AbbVie: Consultancy, Honoraria, Research Funding. Šimkovič: Janssen, Gilead, Roche, AstraZeneca, and AbbVie: Other: consultancy fees, advisory board participation fees, travel grants, and honoraria; University Hospital Hradec Kralove: Current Employment; AbbVie: Consultancy, Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Merck: Current equity holder in publicly-traded company; Eli Lilly: Current equity holder in publicly-traded company; J&J: Current equity holder in publicly-traded company; Gilead: Other: Travel, Accommodations, Expenses. Špaček: AbbVie, AstraZeneca, Gilead, Janssen, and Roche: Honoraria. Tadmor: Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Visentin: Italfarmaco and Gilead: Speakers Bureau. Vassilakopoulos: AstraZeneca: Honoraria; Amgen: Honoraria, Research Funding; Pfizer: Research Funding; Dr. Reddy's: Research Funding; Novartis: Consultancy, Honoraria; GlaxoSmithKline: Honoraria, Other: Travel; Merck: Honoraria, Research Funding; Integris: Honoraria; Roche: Consultancy, Honoraria, Other: Travel; Genesis Pharma: Consultancy, Honoraria, Other: Travel; Takeda: Consultancy, Honoraria, Other: Travel, Research Funding; AbbVie: Consultancy, Honoraria; Karyopharm: Research Funding. Vitale: Janssen: Honoraria. Yáñez: Gilead-Kite, Janssen, AbbVie, AstraZeneca, Beigene, Roche, Pfizer, Jazz, BMS, and Merck: Other: Advisory board participation fees ; Janssen, AbbVie, AstraZeneca, Gilead-Kite, Roche, Pfizer, and Merck: Speakers Bureau. Antic: AbbVie, Janssen, and Roche: Honoraria. Coscia: Janssen: Honoraria, Other, Research Funding; Gilead: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria, Other. Cuneo: AstraZeneca: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau. Gaidano: Beigene: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astrazeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Guièze: Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Astrazeneca: Consultancy, Honoraria. Laurenti: AstraZeneca: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Roche: Honoraria, Research Funding; Gilead: Honoraria; Janssen: Consultancy, Honoraria; BeiGene: Honoraria. Murru: Abbvie: Consultancy, Honoraria, Other: travel and accommodation; Janssen: Consultancy, Honoraria. Sportoletti: AstraZeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Tam: Beigene: Research Funding; Janssen: Research Funding; Abbvie: Research Funding; Loxo: Honoraria; Beigene: Honoraria; Janssen: Honoraria; Abbvie: Honoraria. Trněný: Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Gilead Sciences: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Celgene: Consultancy; 1st Faculty of Medicine, Charles University, General Hospital in Prague: Current Employment; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Portola: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses. Bosch Albareda: Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria; Abbvie: Consultancy; AstraZeneca: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Kite: Honoraria; Sanofi: Honoraria; Lilly: Honoraria. Doubek: Janssen-Cilag, AbbVie, AstraZeneca, Amgen, Gilead, Novartis: Honoraria, Research Funding. Chatzidimitriou: Abbvie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Ghia: AbbVie: Consultancy, Honoraria, Research Funding; Acerta/AstraZeneca: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; ArQule/MSD: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Celgene/Juno/BMS: Consultancy, Honoraria; Gilead: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Sunesis: Research Funding. Stamatopoulos: AstraZeneca: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Janssen: Honoraria, Research Funding.
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- 2021
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25. Throly Score Successfully Classifies Hodgkin Lymphoma Patients at Risk of Thromboembolic Complication
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Antic, Darko, Otasevic, Vladimir, Borchmann, Sven, Muller, Horst, Vukovic, Vojin, Djurasinovic, Vladislava, Tomic, Kristina, Mihaljevic, Biljana, Gerotziafas, Grigoris, Engert, Andreas, and Fareed, Jawed
- Abstract
Engert: AstraZeneca: Honoraria; MSD Sharp & Dohme: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Affimed Therapeutics: Research Funding; Sandoz: Honoraria; Takeda: Honoraria, Research Funding.
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- 2020
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26. Throly Score Successfully Classifies Hodgkin Lymphoma Patients at Risk of Thromboembolic Complication
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Antic, Darko, Otasevic, Vladimir, Borchmann, Sven, Muller, Horst, Vukovic, Vojin, Djurasinovic, Vladislava, Tomic, Kristina, Mihaljevic, Biljana, Gerotziafas, Grigoris, Engert, Andreas, and Fareed, Jawed
- Abstract
INTRODUCTION: Thromboembolism (TE) in lymphoma patients is gathering substantial attention due to its impact on morbidity and mortality of those patients. The association between lymphoma and increased risk for TE development, especially venous thromboembolism (VTE), has lately been well established through numerous publications. Thrombosis Lymphoma (ThroLy) score has been initially developed as a simple risk assessment model for the risk of TE development in lymphoma patients. It has been both internally and externally validated in several studies, which dominantly included patients with non-Hodgkin lymphoma (NHL). Therefore, aim of our study is to analyse and validate ThroLy score in an extensive cohort of Hodgkin lymphoma (HL) patients.
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- 2020
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27. Neutrophil to Lymphocyte Ratio (NLR), Platelet to Lymphocyte Ratio (PLR) and Risk of Thromboembolism in Patients with Lymphoma
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Antic, Darko, Milic, Natasa, Otasevic, Vladimir, Virijevic Salak, Tanja, Djurasinovic, Vladislava, Vukovic, Vojin, Tomic, Kristina, Mihaljevic, Biljana, and Fareed, Jawed
- Abstract
No relevant conflicts of interest to declare.
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- 2019
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28. Neutrophil to Lymphocyte Ratio (NLR), Platelet to Lymphocyte Ratio (PLR) and Risk of Thromboembolism in Patients with Lymphoma
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Antic, Darko, Milic, Natasa, Otasevic, Vladimir, Virijevic Salak, Tanja, Djurasinovic, Vladislava, Vukovic, Vojin, Tomic, Kristina, Mihaljevic, Biljana, and Fareed, Jawed
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Background: Thromboembolism (TE) is one of major causes of morbidity and mortality in patients with malignancy. Pathophysiological connection between TE and inflammation has been established and it is being thoroughly studied recently. The neutrophil to lymphocyte ratio (NLR) and the platelet to lymphocyte ratio (PLR) are biomarkers for systemic inflammation and might represent a yet unrecognized risk factor for development of venous thromboembolism in lymphoma patients having in mind chronic inflammatory milieu specific for lymphomas.
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- 2019
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29. Biomarkers of Hemostatic Dysregulation and Inflammation in Lymphoma: Potential Relevance to Thrombogenesis
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Antic, Darko, Milic, Natasa, Bontekoe, Emily, Hoppensteadt, Debra, Djurasinovic, Vladislava, Vukovic, Vojin, Otasevic, Vladimir, Tomic, Kristina, Mihaljevic, Biljana, and Fareed, Jawed
- Abstract
No relevant conflicts of interest to declare.
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- 2019
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30. Biomarkers of Hemostatic Dysregulation and Inflammation in Lymphoma: Potential Relevance to Thrombogenesis
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Antic, Darko, Milic, Natasa, Bontekoe, Emily, Hoppensteadt, Debra, Djurasinovic, Vladislava, Vukovic, Vojin, Otasevic, Vladimir, Tomic, Kristina, Mihaljevic, Biljana, and Fareed, Jawed
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INTRODUCTION:The prevalence of thrombotic complications in lymphoma patients ranges from 1.5% up to 59.5%. Lymphoma patients have a 10-fold higher risk for the development of venous thrombosis than patients with lung and gastrointestinal cancers. The pathogenesis of thromboembolic disease in hematological malignancies is complex and multifactorial and can be due to the underlying disorder or related to therapy. A number of biomarkers are associated with the occurence of VTE in cancer patients. Biomarkers reflect activation of coagulation and increased inflammatory potential. This study aimed to profile hemostatic and inflammatory biomarkers in patients with Hodgkin lymphoma, non-Hodgkin lymphoma, and chronic lymphocytic leukemia/ small lymphocytic lymphoma.
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- 2019
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31. HIF-1α Is Not Essential For The Establishment Of MLL-Leukaemic Stem Cells
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Gezer, Deniz, Guitart, Amelie V, Vukovic, Milica, Subramani, Chithra, Dunn, Karen, Pollard, Patrick, Ratcliffe, Peter J, Holyoake, Tessa L., and Kranc, Kamil
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Ratcliffe: RedOx: Founder Other. Holyoake:Novartis: Membership on an entity’s Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity’s Board of Directors or advisory committees; Ariad: Membership on an entity’s Board of Directors or advisory committees.
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- 2013
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32. HIF-1α Is Not Essential For The Establishment Of MLL-Leukaemic Stem Cells
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Gezer, Deniz, Guitart, Amelie V, Vukovic, Milica, Subramani, Chithra, Dunn, Karen, Pollard, Patrick, Ratcliffe, Peter J, Holyoake, Tessa L., and Kranc, Kamil
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Haematopoietic stem cells (HSCs) reside in hypoxic niches in the bone marrow (BM) and sustain long-life haematopoiesis. HSCs are largely quiescent, self-renew, undergo apoptosis and generate progenitor cells, which differentiate to multiple blood lineages. The strict regulation of the balance between these fate decisions is essential for haematopoiesis and their dysregulation in HSCs and progenitor cells can result in leukaemic transformation. HSCs and leukemic stem cells (LSCs) are suggested to share the same niche and are in need to adapt to hypoxic conditions.
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- 2013
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33. Antileukemic Effects of the Novel Agent Elesclomol.
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Chow, Sue, Nagai, Masazumi, He, Suqin, Blackman, Ronald K, Barsoum, James, Vukovic, Vojislav, and Hedley, David
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Chow: Synta Pharmaceuticals Inc.: Research Funding. Nagai:Synta Pharmaceuticals Inc.: Employment. He:Synta Pharmaceuticals Inc.: Employment. Blackman:Synta Pharmaceuticals Inc.: Employment, Equity Ownership. Barsoum:Synta Pharmaceuticals Inc.: Employment, Equity Ownership. Vukovic:Synta Pharmaceuticals Inc.: Employment, Equity Ownership. Hedley:Synta Pharmaceuticals Inc.: Research Funding.
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- 2009
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34. Antileukemic Effects of the Novel Agent Elesclomol.
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Chow, Sue, Nagai, Masazumi, He, Suqin, Blackman, Ronald K, Barsoum, James, Vukovic, Vojislav, and Hedley, David
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Abstract 2736
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- 2009
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35. Direct Interaction of Ahi-1 with BCR-ABL Modulates BCR-ABL Transforming Activity and Imatinib Response in a BCR-ABL Inducible Cell Line Model
- Author
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Chen, Min, Zhou, Leon, DeGeer, Donna, Vukovic, Ranko, Turhan, Ali G, and Jiang, Xiaoyan
- Abstract
(Abelson helper integration site-1) is a novel oncogene that was initially identified by provirus insertional mutagenesis in v-abl-induced murine pre-B cell lymphoma as a candidate cooperate oncogene. The Ahi-1 protein has a SH3 domain, multiple SH3 binding sites and WD-repeat domains, suggesting novel signaling activities. We have recently demonstrated that AHI-1is highly deregulated in human leukemic cells, particularly in BCR-ABL+leukemic stem cells from patients with chronic myeloid leukemia (CML). Overexpression of Ahi-1in primitive hematopoietic cells confers a growth advantage in vitro and induces leukemia in vivo; these effects can be enhanced by BCR-ABL, a fusion oncogene that plays a major role in the genesis of CML. Conversely, RNAi-mediated suppression of AHI-1in BCR-ABL-transduced lin−CD34+human cord blood cells and leukemic stem/progenitor cells from CML patients reduces their growth autonomy in vitro. Interestingly, a direct physical interaction between AHI-1 and BCR-ABL at endogenous levels has been identified in CML cells and this interaction complex further mediates tyrosine kinase inhibitor response/resistance of CML stem/progenitor cells. To further investigate regulatory roles of Ahi-1 in mediating BCR-ABL transforming activities and altered signaling, we have now evaluated co-operative effects of Ahi-1in a BCR-ABLinducible BaF3 cell line model in which the level of expression of p210BCR-ABLcan be variably down-regulated by exposure to doxycycline (Dox). These experiments showed that reduction in BCR-ABL protein expression in the presence of Dox resulted in a corresponding decrease in growth factor independence both in liquid suspension cultures and in semi-solid cultures and an increase in Annexin V+ apoptotic cells in vitro. Interestingly, stable co-expression of Ahi-1in BCR-ABLinducible BaF3 cells under these stringent conditions enabled them to grow continuously in liquid suspension culture, with fewer Annexin V+ apoptotic cells, and to produce more factor independent CFCs than cells transduced with BCR-ABLalone (10–30 fold). Strikingly, Ahi-1co-transduced cells also displayed greater resistance to imatinib and, in the presence of IL-3, produced as many CFCs as were produced by the same cells without treatment of imatinib. In contrast, BCR-ABL-transduced cells alone showed a significant reduction of CFC output in response to imatinib. Western blot analysis further demonstrated that co-expression of Ahi-1in BCR-ABLinducible cells resulted in sustained phosphorylation of BCR-ABL and enhanced activation of JAK2/STAT5 compared to BCR-ABLinducible cells alone when BCR-ABL expression was downregulated in the presence of Dox. Moreover, physical interaction between Ahi-1 and BCR-ABL was demonstrated by co-IP studies in Ahi-1co-expressed BCR-ABLinducible cells. Taken together, these results provide direct evidence of the regulatory role of Ahi-1in BCR-ABL-mediated transformation and imatinib response that is associated with altered BCR-ABL phosphorylation and JAK2/STAT5 activation.
- Published
- 2008
- Full Text
- View/download PDF
36. Direct Interaction of Ahi-1 with BCR-ABL Modulates BCR-ABL Transforming Activity and Imatinib Response in a BCR-ABL Inducible Cell Line Model
- Author
-
Chen, Min, Zhou, Leon, DeGeer, Donna, Vukovic, Ranko, Turhan, Ali G, and Jiang, Xiaoyan
- Abstract
(Abelson helper integration site-1) is a novel oncogene that was initially identified by provirus insertional mutagenesis in v-abl-induced murine pre-B cell lymphoma as a candidate cooperate oncogene. The Ahi-1 protein has a SH3 domain, multiple SH3 binding sites and WD-repeat domains, suggesting novel signaling activities. We have recently demonstrated that AHI-1 is highly deregulated in human leukemic cells, particularly in BCR-ABL+ leukemic stem cells from patients with chronic myeloid leukemia (CML). Overexpression of Ahi-1 in primitive hematopoietic cells confers a growth advantage in vitro and induces leukemia in vivo; these effects can be enhanced by BCR-ABL, a fusion oncogene that plays a major role in the genesis of CML. Conversely, RNAi-mediated suppression of AHI-1 in BCR-ABL-transduced lin−CD34+ human cord blood cells and leukemic stem/progenitor cells from CML patients reduces their growth autonomy in vitro. Interestingly, a direct physical interaction between AHI-1 and BCR-ABL at endogenous levels has been identified in CML cells and this interaction complex further mediates tyrosine kinase inhibitor response/resistance of CML stem/progenitor cells. To further investigate regulatory roles of Ahi-1 in mediating BCR-ABL transforming activities and altered signaling, we have now evaluated co-operative effects of Ahi-1 in a BCR-ABL inducible BaF3 cell line model in which the level of expression of p210BCR-ABL can be variably down-regulated by exposure to doxycycline (Dox). These experiments showed that reduction in BCR-ABL protein expression in the presence of Dox resulted in a corresponding decrease in growth factor independence both in liquid suspension cultures and in semi-solid cultures and an increase in Annexin V+ apoptotic cells in vitro. Interestingly, stable co-expression of Ahi-1 in BCR-ABL inducible BaF3 cells under these stringent conditions enabled them to grow continuously in liquid suspension culture, with fewer Annexin V+ apoptotic cells, and to produce more factor independent CFCs than cells transduced with BCR-ABL alone (10–30 fold). Strikingly, Ahi-1 co-transduced cells also displayed greater resistance to imatinib and, in the presence of IL-3, produced as many CFCs as were produced by the same cells without treatment of imatinib. In contrast, BCR-ABL-transduced cells alone showed a significant reduction of CFC output in response to imatinib. Western blot analysis further demonstrated that co-expression of Ahi-1 in BCR-ABL inducible cells resulted in sustained phosphorylation of BCR-ABL and enhanced activation of JAK2/STAT5 compared to BCR-ABL inducible cells alone when BCR-ABL expression was downregulated in the presence of Dox. Moreover, physical interaction between Ahi-1 and BCR-ABL was demonstrated by co-IP studies in Ahi-1 co-expressed BCR-ABL inducible cells. Taken together, these results provide direct evidence of the regulatory role of Ahi-1 in BCR-ABL-mediated transformation and imatinib response that is associated with altered BCR-ABL phosphorylation and JAK2/STAT5 activation.
- Published
- 2008
- Full Text
- View/download PDF
37. Revalidation of the Flipi Score in the Era of Immunotherapy.
- Author
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Stemmelin, German, Doti, Carlos, Shanley, Claudia, Ceresetto, Jose, Rabinovich, Oscar, Vicente, Angeles, Vukovic, Matias, Cazap, Nicolas, Preiti, Vereonica, Palmer, Silvina, Vitriu, Adriana, and Bullorsky, Eduardo
- Abstract
The FLIPI prognosis score for follicular lymphoma (FL) was developed based on cases diagnosed between 1985 and 1992, and treated with different schemes that did not include rituximab (R). In the present study, we report the evolution of all FL treated in a single institution through the last decade and analize whether FLIPI mantains its effectiveness to identify different risk groups within patients treated with the new therapeutic alternatives available. Material and Methods: We identified sixty two patients with diagnosis of grade I-II-IIIa FL. Patients characteristics: median age 57.5 yr (r, 30–80); 36 males; 63% stages III–IV, and 37% with bone marrow infiltration at the time of diagnosis. Thirty eight percent had a low risk by FLIPI, 34% had an intermediate risk and 27.4% had a high risk. In 19 pts (30.6%) the initial decision was “watch and wait” but 82% received a form of treatment at some point. R was used in 36 pts (58%) with some of the following regimes: chemotherapy (chemo) + R and/or R as consolidation therapy and/or R as monotherapy and/or R as maintenance therapy. Of all prescribed treatments (excluding R as monotherapy and/or maintenance treatment), 52.8% were chemo alone, 20.2% chemo + R, 21.3% radiotherapy and 5.6% received a bone marrow transplant. Results: we considered the analysis of overall survival (OS) the most appropiate approach, since most treatments were seeking the control of the FL, and not the complete remission or cure. The follow up median time was 53.2 months ± 34.8 1SD. The 5-yr OS for the 62 pts was 81.8% ± 11.3 CI 95%. The 5-yr OS for those with a low, intermediate and high risk FLIPI was 100% −5, 84.2% ± 21 and 52% ±26.2, respectively. The difference in 5-yr OS was statistically significant between low and high risk, intermediate and high risk, but failed to prove a significant difference between low and intermediate risk. Among the different risk factors tested in a univariate analysis only age ≥ < 60 yr old demonstrated a significant difference, 60.7% vs 90%, respectively. Conclusions: The 5-yr OS in our series is higher than the one described in the original FLIPI study (Blood2004; 104:1258–65) which was 81.8% vs 71% for the whole group; 90% vs 78.1% for pts <60 yr old; 60.7% vs 57.7% for ≥ 60 yr old; 100% vs 90.6% for low FLIPI and 84.2% vs 77.6% for intermediate FLIPI. The only group that failed to prove an improvement was the high risk FLIPI with 52% vs 52.5%. The impact of novel therapies was more evident in patients with a low or intermediate FLIPI and was even more evident in patients younger than 60 yr old. According to our results, FLIPI maintains its effectiveness in differentiating two risk groups, i.e., low-intermediate vs high. We believe that the OS curves will probably continue to improve as the treatments that are considered today as the most effective ones, were just included in our series in the last three years.
- Published
- 2007
- Full Text
- View/download PDF
38. Properties of CD34+ CML Cells That Predict Clinical Response to Tyrosine Kinase Inhibitors.
- Author
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Jiang, Xiaoyan, Forrest, Donna, Nicolini, Franck, Lambie, Karen, Saw, Kyi Min, Pang, Emily, Vukovic, Ranko, Smith, Clayton, Eaves, Allen, and Eaves, Connie
- Abstract
Imatinib (IM) treatment causes remission in a majority of patients with chronic myeloid leukemia (CML) but relapses remain a problem. The frequent presence in relapsing cells of BCR-ABL kinase domain mutations suggests that their prior but undetected acquisition by rare CML stem cells may be a major contributor to IM treatment failures. We have recently demonstrated that enriched populations of CML stem cells (lin−CD34+CD38− cells) are relatively insensitive to IM and possess multiple unique features that would be expected to promote both innate and acquired mechanisms of resistance to BCR-ABL-targeted therapeutics. These include elevated BCR-ABL expression and tyrosine kinase activity, increased expression of ABCB1/MDR1 and ABCG2, decreased expression of OCT1, and a high degree of genetic instability, as demonstrated by a rapid accumulation of BCR-ABL mutations in vitro. To determine whether these parameters may be predictive of clinical responses to IM, immunomagnetically selected CD34+ stem/progenitor cells from 18 chronic phase CML patients’ samples obtained prior to IM therapy were evaluated and the results compared with subsequent clinical responses. Direct sequencing of transcripts cloned from extracts of freshly isolated CD34+ cells (10 clones/sample) detected a high frequency of pre-existing BCR-ABL kinase mutations in the CD34+ cells from 12 of 12 patients regardless of their subsequent IM responses (20–80%). Interestingly, a higher incidence of BCR-ABL kinase domain mutations was found in 5 IM-nonresponders (33–80% of transcripts showed ≥1 BCR-ABL kinase domain mutation) as compared to 5 IM-responders (values of 20-30%, P<0.02). A higher frequency of BCR-ABL kinase domain mutations was also detected in extracts of colonies generated from assays of cells harvested from 3-week suspension cultures initiated with the same starting CD34+ CML cells (21–68% vs 10–43%). A high incidence of BCR-ABL kinase domain mutations was also documented in freshly isolated or cultured CD34+ cells from 2 patients who developed sudden blast crisis (50–63% and 17–83%). Overall, 38 different mutations were identified from freshly isolated CD34+ CML cells and >50 additional mutations were identified in the progeny of CD34+ CML cells cultured ± IM. These included 15 point mutations frequently associated with clinical IM resistance (including G250, Q252, E255, T315, M351, F359 and H396) and >40 mutations not previously described. Furthermore, freshly isolated CD34+ cells from IM-nonresponders (including the 2 patients who developed blast crisis, n=10) showed a greater resistance to IM in vitro (∼2 fold, P< 0.001 with 5 μM and P<0.02 with 10 μM IM) as compared to CD34+ cells from IM-responders (n=8) in the presence of 5 and 10 μM IM, as determined by colony-forming cell (CFC) assays. Although more IM-resistant CFCs were obtained in the presence of IM from 3-week cultures initiated with CD34+ cells from the same IM-nonresponders than from IM responders, these latter differences were not significantly different (P= 0.28). These results suggest that the CD34+ leukemic cells from individual chronic phase CML patients harbor differences in their biologic properties that are predictive of how they will respond to IM therapy and that assessment of these differences may form the basis of rapid, practical and quantitative tests to assist in optimized patient management.
- Published
- 2007
- Full Text
- View/download PDF
39. Revalidation of the Flipi Score in the Era of Immunotherapy.
- Author
-
Stemmelin, German, Doti, Carlos, Shanley, Claudia, Ceresetto, Jose, Rabinovich, Oscar, Vicente, Angeles, Vukovic, Matias, Cazap, Nicolas, Preiti, Vereonica, Palmer, Silvina, Vitriu, Adriana, and Bullorsky, Eduardo
- Abstract
The FLIPI prognosis score for follicular lymphoma (FL) was developed based on cases diagnosed between 1985 and 1992, and treated with different schemes that did not include rituximab (R). In the present study, we report the evolution of all FL treated in a single institution through the last decade and analize whether FLIPI mantains its effectiveness to identify different risk groups within patients treated with the new therapeutic alternatives available.
- Published
- 2007
- Full Text
- View/download PDF
40. Properties of CD34+CML Cells That Predict Clinical Response to Tyrosine Kinase Inhibitors.
- Author
-
Jiang, Xiaoyan, Forrest, Donna, Nicolini, Franck, Lambie, Karen, Saw, Kyi Min, Pang, Emily, Vukovic, Ranko, Smith, Clayton, Eaves, Allen, and Eaves, Connie
- Abstract
Imatinib (IM) treatment causes remission in a majority of patients with chronic myeloid leukemia (CML) but relapses remain a problem. The frequent presence in relapsing cells of BCR-ABLkinase domain mutations suggests that their prior but undetected acquisition by rare CML stem cells may be a major contributor to IM treatment failures. We have recently demonstrated that enriched populations of CML stem cells (lin−CD34+CD38−cells) are relatively insensitive to IM and possess multiple unique features that would be expected to promote both innate and acquired mechanisms of resistance to BCR-ABL-targeted therapeutics. These include elevated BCR-ABLexpression and tyrosine kinase activity, increased expression of ABCB1/MDR1and ABCG2, decreased expression of OCT1, and a high degree of genetic instability, as demonstrated by a rapid accumulation of BCR-ABLmutations in vitro. To determine whether these parameters may be predictive of clinical responses to IM, immunomagnetically selected CD34+stem/progenitor cells from 18 chronic phase CML patients' samples obtained prior to IM therapy were evaluated and the results compared with subsequent clinical responses. Direct sequencing of transcripts cloned from extracts of freshly isolated CD34+cells (10 clones/sample) detected a high frequency of pre-existing BCR-ABLkinase mutations in the CD34+cells from 12 of 12 patients regardless of their subsequent IM responses (20–80%). Interestingly, a higher incidence of BCR-ABLkinase domain mutations was found in 5 IM-nonresponders (33–80% of transcripts showed ≥1 BCR-ABLkinase domain mutation) as compared to 5 IM-responders (values of 20-30%, P<0.02). A higher frequency of BCR-ABLkinase domain mutations was also detected in extracts of colonies generated from assays of cells harvested from 3-week suspension cultures initiated with the same starting CD34+CML cells (21–68% vs 10–43%). A high incidence of BCR-ABLkinase domain mutations was also documented in freshly isolated or cultured CD34+cells from 2 patients who developed sudden blast crisis (50–63% and 17–83%). Overall, 38 different mutations were identified from freshly isolated CD34+CML cells and >50 additional mutations were identified in the progeny of CD34+CML cells cultured ± IM. These included 15 point mutations frequently associated with clinical IM resistance (including G250, Q252, E255, T315, M351, F359 and H396) and >40 mutations not previously described. Furthermore, freshly isolated CD34+cells from IM-nonresponders (including the 2 patients who developed blast crisis, n=10) showed a greater resistance to IM in vitro (∼2 fold, P< 0.001 with 5 μM and P<0.02 with 10 μM IM) as compared to CD34+cells from IM-responders (n=8) in the presence of 5 and 10 μM IM, as determined by colony-forming cell (CFC) assays. Although more IM-resistant CFCs were obtained in the presence of IM from 3-week cultures initiated with CD34+cells from the same IM-nonresponders than from IM responders, these latter differences were not significantly different (P= 0.28). These results suggest that the CD34+leukemic cells from individual chronic phase CML patients harbor differences in their biologic properties that are predictive of how they will respond to IM therapy and that assessment of these differences may form the basis of rapid, practical and quantitative tests to assist in optimized patient management.
- Published
- 2007
- Full Text
- View/download PDF
41. Preliminary Safety and Efficacy Report of a Randomized Trial of Alemtuzumab vs Chlorambucil as Front-Line Therapy in 297 Patients with Progressive B-Cell Chronic Lymphocytic Leukemia.
- Author
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Hillmen, Peter, Skotnicki, Aleksander B., Robak, Tadeusz, Mayer, Jiri, Jaksic, Branimir, Vukovic, Vojo, and Weitman, Steven
- Abstract
CAM307, a Phase III, open-label, international, randomized trial comparing the efficacy and safety of alemtuzumab (CAMPATH®, MABCAMPATH®) with chlorambucil in B-CLL. Untreated Rai stage I-IV B-CLL patients with evidence of progressive disease were randomized 1:1 to intravenous alemtuzumab 30 mg three times a week for a maximum of 12 weeks or oral chlorambucil 40 mg/m2 once every 28 days, up to a maximum of 12 cycles. Patients with autoimmune thrombocytopenia, prior bone marrow transplant, active infection, positive CMV by quantitative PCR assay, secondary malignancy or CNS involvement were excluded. All alemtuzumab patients received prophylaxis with cotrimoxazole (trimethoprim/ sulfamethoxazole DS) and famciclovir during treatment and after completion of therapy until CD4+ counts were ≥200 cells/μL. The primary endpoint for the trial is progression free survival; secondary endpoints include safety, overall survival and response rate. Patient recruitment has been completed, and demographic data are available for 297 patients (213 males, 84 females; median age 60 years; 67% Rai I/II; 33% Rai III/IV). AEs occurring in >10% of alemtuzumab patients included pyrexia, rigors, dermatitis, urticaria, headache, hypertension, hypotension (“infusion reactions”), CMV antigen reactivation, nausea and neutropenia. In chlorambucil patients, AEs occurring in >10% of patients included nausea and vomiting. A total of 7 deaths have been reported, 2 in the alemtuzumab arm and 5 in the chlorambucil arm. Two deaths in the chlorambucil arm were related to study drug. Symptomatic CMV reactivations have been tracked by investigator reports. Preliminary analysis indicates that 22 of 149 (15%) patients treated with alemtuzumab developed symptomatic CMV reactivation. In 14 of 22 (64%) cases, mild to moderate fever was the only clinical symptom. All symptomatic CMV reactivations resolved promptly with ganciclovir and most patients were able to complete alemtuzumab therapy per protocol. No symptomatic CMV reactivations have been reported in the chlorambucil arm. No deaths due to CMV have been reported. Preliminary efficacy results on approximately 100 patients that have completed 12 months of follow-up following start of treatment and were reviewed by an independent committee will be presented at the meeting. This randomized Phase III trial demonstrates that alemtuzumab as first line therapy has an acceptable toxicity profile compared to chlorambucil. Therefore, this trial will address whether treatment with alemtuzumab as front line therapy results in greater disease reduction than conventional treatment in B-CLL and whether this strategy confers a survival advantage compared to standard approaches.
- Published
- 2004
- Full Text
- View/download PDF
42. Smoking as a Cause for Mild Chronic Neutrophilia.
- Author
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Stemmelin, German R., Doti, Carlos A., Shanley, Claudia M., Ceresetto, Jose M., Rabinovich, Oscar M., Vicente Reparaz, Maria A., Vukovic, Matias Gonzalez, and Bullorsky, Eduardo O.
- Abstract
Mild chronic neutrofilia is a frequent reason for hematologic consultation and in 70% of the cases there is no identifiable cause.
- Published
- 2004
- Full Text
- View/download PDF
43. Smoking as a Cause for Mild Chronic Neutrophilia.
- Author
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Stemmelin, German R., Doti, Carlos A., Shanley, Claudia M., Ceresetto, Jose M., Rabinovich, Oscar M., Vicente Reparaz, Maria A., Vukovic, Matias Gonzalez, and Bullorsky, Eduardo O.
- Abstract
Mild chronic neutrofilia is a frequent reason for hematologic consultation and in 70% of the cases there is no identifiable cause. Objective: to determine if smoking habit could be the etiology for leucocytosis with neutrophilia in smokers with no other pulmonary associated disease. Materials and Methods: We questioned 300 consecutive blood donors from our institution, elaborating a complete record of smoking habit. Immediately before blood donation an automated complete blood count was performed. Leucocytosis was defined as a white cell count above 11 x 109/L, and neutrophilia as a neutrophil count over 7.7 x 109/L. All data is stated as mean value ± 1 SD. Results: we studied 195 (65%) men and 105 (35%) women (n=300). Mean age was 36.5 y.o. (18–69). Fifty-five percent (165/300) smoke or were previous smokers; 8.4% (14/165) of these, did not smoke at the time of this investigation, and only two have quit smoking a year prior to questioning. Mean time of duration of smoking habit was 16.4 years ± 10.6 and the average amount of cigarettes smoked through life (estimated from data referred along different phases of each subject’s history) was 1.26 x 105 ± 1.21 x 105. In the following table results from smokers (previous or actual) vs. non-smokers are compared. Leucocytosis was present in 37/165 (22.4%) of smokers and in 3/135 (2.2%) of non-smokers (p<0.001) and neutrophilia was noted in 19/165 (11.5%) of smokers and in 2/135 (1.5%) of non-smokers (p<0.001). None of the volunteers had a WBC count over 20 x 109/L. A direct association was established for the number of cigarettes smoked and the WBC count and neutrophil count. Discussion: smoking habit affects ciliar movement, inhibits alveolar macrophage function and produces hyperplasia on mucous glands within bronquial walls. These alterations result in entrapment of mucous secretions that will ultimately lead to bacterial colonization. The neutrophilia observed in smokers would be the result of a normal physiologic response to a potential infectious focus. In conclusion, is our understanding that the smoking habit should be considered as a common etiology for mild leucocytosis and neutrophilia. Smokers (n:165) Non-smokers (n:135) p (t-test) WBC x 109/L 9.6 ± 2.1 6.8 ± 1.3 < 0.001 Neutrophils x 109/L 5.7 ± 1.6 3.9 ± 1.0 < 0.001 Hct % 45.9 ± 3.7 45.2 ± 3.6 NS Platelets 207 ± 48.7 206.4 ± 45.8 NS
- Published
- 2004
- Full Text
- View/download PDF
44. Preliminary Safety and Efficacy Report of a Randomized Trial of Alemtuzumab vs Chlorambucil as Front-Line Therapy in 297 Patients with Progressive B-Cell Chronic Lymphocytic Leukemia.
- Author
-
Hillmen, Peter, Skotnicki, Aleksander B., Robak, Tadeusz, Mayer, Jiri, Jaksic, Branimir, Vukovic, Vojo, and Weitman, Steven
- Abstract
CAM307, a Phase III, open-label, international, randomized trial comparing the efficacy and safety of alemtuzumab (CAMPATH®, MABCAMPATH®) with chlorambucil in B-CLL. Untreated Rai stage I-IV B-CLL patients with evidence of progressive disease were randomized 1:1 to intravenous alemtuzumab 30 mg three times a week for a maximum of 12 weeks or oral chlorambucil 40 mg/m2once every 28 days, up to a maximum of 12 cycles. Patients with autoimmune thrombocytopenia, prior bone marrow transplant, active infection, positive CMV by quantitative PCR assay, secondary malignancy or CNS involvement were excluded. All alemtuzumab patients received prophylaxis with cotrimoxazole (trimethoprim/ sulfamethoxazole DS) and famciclovir during treatment and after completion of therapy until CD4+ counts were ≥200 cells/μL. The primary endpoint for the trial is progression free survival; secondary endpoints include safety, overall survival and response rate. Patient recruitment has been completed, and demographic data are available for 297 patients (213 males, 84 females; median age 60 years; 67% Rai I/II; 33% Rai III/IV). AEs occurring in >10% of alemtuzumab patients included pyrexia, rigors, dermatitis, urticaria, headache, hypertension, hypotension (“infusion reactions”), CMV antigen reactivation, nausea and neutropenia. In chlorambucil patients, AEs occurring in >10% of patients included nausea and vomiting. A total of 7 deaths have been reported, 2 in the alemtuzumab arm and 5 in the chlorambucil arm. Two deaths in the chlorambucil arm were related to study drug. Symptomatic CMV reactivations have been tracked by investigator reports. Preliminary analysis indicates that 22 of 149 (15%) patients treated with alemtuzumab developed symptomatic CMV reactivation. In 14 of 22 (64%) cases, mild to moderate fever was the only clinical symptom. All symptomatic CMV reactivations resolved promptly with ganciclovir and most patients were able to complete alemtuzumab therapy per protocol. No symptomatic CMV reactivations have been reported in the chlorambucil arm. No deaths due to CMV have been reported. Preliminary efficacy results on approximately 100 patients that have completed 12 months of follow-up following start of treatment and were reviewed by an independent committee will be presented at the meeting. This randomized Phase III trial demonstrates that alemtuzumab as first line therapy has an acceptable toxicity profile compared to chlorambucil. Therefore, this trial will address whether treatment with alemtuzumab as front line therapy results in greater disease reduction than conventional treatment in B-CLL and whether this strategy confers a survival advantage compared to standard approaches.
- Published
- 2004
- Full Text
- View/download PDF
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