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1. Preleukemic single-cell landscapes reveal mutation-specific mechanisms and gene programs predictive of AML patient outcomes

Author

Isobe, Tomoya, Kucinski, Iwo, Barile, Melania, Wang, Xiaonan, Hannah, Rebecca, Bastos, Hugo P., Chabra, Shirom, Vijayabaskar, M.S., Sturgess, Katherine H.M., Williams, Matthew J., Giotopoulos, George, Marando, Ludovica, Li, Juan, Rak, Justyna, Gozdecka, Malgorzata, Prins, Daniel, Shepherd, Mairi S., Watcham, Sam, Green, Anthony R., Kent, David G., Vassiliou, George S., Huntly, Brian J.P., Wilson, Nicola K., and Göttgens, Berthold

Published
2023
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2. The role of the Dnmt3aR882H mutation in the evolution of clonal haematopoiesis

Author

Marando, Ludovica and Huntly, Brian

Subjects
Clonal Haematopoiesis, Leukaemia, Haematopoietic stem cells
Abstract

DNMT3A mutations are very frequent events in clonal haematopoiesis of indeter- minate potential (CHIP), and considered one of the earliest genetic events during the development of haematopoietic malignancies. Individuals with CHIP, in spite of having a normal full blood count are at increased risk of cardiovascular and pulmonary diseases as well as haematological neoplasms. Somatic mutations in DNMT3A are drivers of CHIP, but decades may elapse between the acquisition of a mutation and CHIP. Besides, only a minority of these individuals will go onto developing a haematological cancer, this wide interindividual heterogeneity suggests that environmental factors influence clonal expansion. It is in particular emerging, that individuals with CHIP have a proinflamma- tory phenotype, additionally, chronic inflammation is typically considered deleterious to normal haematopoiesis, as it leads to haematopoietic stem cells (HSCs) exhaustion. R882H Using a conditional knock-in mouse model heterozygous for Dnmt3a mon DNMT3A mutation, we have assessed the responses of Long-Term Haematopoietic Stem Cells (LT-HSCs) to inflammatory "stress" in vitro and in vivo. We have also em- ployed bulk LT-HSCs genomics studies to interrogate differences in the transcriptional landscape in response to inflammation. We have demonstrated that Dnmt3a-mutant LT- HSCs have a globally abnormal response to inflammation, characterised by faster exit from quiescence and subsequent hyper-proliferation. Interestingly, as well as a larger differentiated output, Dnmt3aR882H HSCs were also better preserving their progenitor compartment and their self-renewal ability compared to wild-type HSCs exposed to the same stimulus, giving some insight into potential mechanisms that lead to clonal expan- sion within an inflammatory microenvironment. We linked this phenotype to the reduced expression of two TP53 target genes: Niam/Tbrg1, involved in the TP53-mediated activation of the p21 pathway that leads to G1 growth arrest upon exposure to "stress", and Necdin/Ndn a regulator of LT-HSCs quiescence. We then went on to demonstrate that TP53 and DNMT3A might function redundantly within the same functional pathway, and that Dnmt3a loss-of-function can lead to re- duced stem cell quiescence in vivo, and increased genomic instability when Dnmt3aR882H progenitors are challenged with genotoxic "stressors". Interestingly, in spite of accumu- lating more DNA damage, Dnmt3aR882H cells did not lose clonogenic ability and showed similar viability to wild-type cells, suggesting that these cells are more tolerant to the accumulation of DNA damage. Subtle changes of this nature are likely to play an im- portant role in a phenomenon that develops over the lifetime of an individual, and could create a permissive state for the retention and accumulation of subsequent mutations, eventually leading to transformation.

Published
2021
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3. Prevalence and significance of DDX41 gene variants in the general population

Author

Ambrose, J. C., Arumugam, P., Bevers, R., Bleda, M., Boardman-Pretty, F., Boustred, C. R., Brittain, H., Brown, M. A., Caulfield, M. J., Chan, G. C., Giess, A., Griffin, J. N., Hamblin, A., Henderson, S., Hubbard, T. J. P., Jackson, R., Jones, L. J., Kasperaviciute, D., Kayikci, M., Kousathanas, A., Lahnstein, L., Lakey, A., Leigh, S. E. A., Leong, I. U. S., Lopez, F. J., Maleady-Crowe, F., McEntagart, M., Minneci, F., Mitchell, J., Moutsianas, L., Mueller, M., Murugaesu, N., Need, A. C., O‘Donovan, P., Odhams, C. A., Patch, C., Perez-Gil, D., Pereira, M. B., Pullinger, J., Rahim, T., Rendon, A., Rogers, T., Savage, K., Sawant, K., Scott, R. H., Siddiq, A., Sieghart, A., Smith, S. C., Sosinsky, A., Stuckey, A., Tanguy, M., Taylor Tavares, A. L., Thomas, E. R. A., Thompson, S. R., Tucci, A., Welland, M. J., Williams, E., Witkowska, K., Wood, S. M., Zarowiecki, M., Cheloor Kovilakam, Sruthi, Gu, Muxin, Dunn, William G., Marando, Ludovica, Barcena, Clea, Nik-Zainal, Serena, Mohorianu, Irina, Kar, Siddhartha P., Fabre, Margarete A., Quiros, Pedro M., and Vassiliou, George S.

Published
2023
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5. Bone Marrow Mesenchymal Stem Cells Support Acute Myeloid Leukemia Bioenergetics and Enhance Antioxidant Defense and Escape from Chemotherapy

Author

Forte, Dorian, García-Fernández, María, Sánchez-Aguilera, Abel, Stavropoulou, Vaia, Fielding, Claire, Martín-Pérez, Daniel, López, Juan Antonio, Costa, Ana S.H., Tronci, Laura, Nikitopoulou, Efterpi, Barber, Michael, Gallipoli, Paolo, Marando, Ludovica, Fernández de Castillejo, Carlos López, Tzankov, Alexandar, Dietmann, Sabine, Cavo, Michele, Catani, Lucia, Curti, Antonio, Vázquez, Jesús, Frezza, Christian, Huntly, Brian J., Schwaller, Juerg, and Méndez-Ferrer, Simón

Published
2020
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8. S121: MULTIPARAMETER PREDICTION OF MYELOID NEOPLASIA RISK

Author

Gu, Muxin, primary, Cheloor Kovilakam, Sruthi, additional, Dunn, William, additional, Marando, Ludovica, additional, Barcena, Clea, additional, Mohorianu, Irina, additional, Kar, Siddhartha, additional, Fabre, Margarete, additional, Gerstung, Moritz, additional, Quiros, Pedro, additional, and Vassiliou, George S, additional

Published
2023
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9. A Phase I/II Open-Label Study of Molibresib for the Treatment of Relapsed/Refractory Hematologic Malignancies

Author

Dawson, Mark A., primary, Borthakur, Gautam, additional, Huntly, Brian J.P., additional, Karadimitris, Anastasios, additional, Alegre, Adrian, additional, Chaidos, Aristeidis, additional, Vogl, Dan T., additional, Pollyea, Daniel A., additional, Davies, Faith E., additional, Morgan, Gareth J., additional, Glass, Jacob L., additional, Kamdar, Manali, additional, Mateos, Maria-Victoria, additional, Tovar, Natalia, additional, Yeh, Paul, additional, Delgado, Regina García, additional, Basheer, Faisal, additional, Marando, Ludovica, additional, Gallipoli, Paolo, additional, Wyce, Anastasia, additional, Krishnatry, Anu Shilpa, additional, Barbash, Olena, additional, Bakirtzi, Evi, additional, Ferron-Brady, Geraldine, additional, Karpinich, Natalie O., additional, McCabe, Michael T., additional, Foley, Shawn W., additional, Horner, Thierry, additional, Dhar, Arindam, additional, Kremer, Brandon E., additional, and Dickinson, Michael, additional

Published
2022
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10. 2008 – INTEGRATIVE SINGLE-CELL ANALYSIS OF PRELEUKAEMIC MUTANT MOUSE MODELS ILLUSTRATES MUTATION-SPECIFIC HAEMATOPOIETIC PERTURBATIONS

Author

Isobe, Tomoya, primary, Kucinski, Iwo, additional, Wang, Xiaonan, additional, Barile, Melania, additional, Hannah, Rebecca, additional, Giotopoulos, George, additional, Horton, Sarah, additional, Marando, Ludovica, additional, Li, Juan, additional, Rak, Justyna, additional, Gozdecka, Malgorzata, additional, Wang, Meng, additional, Prins, Daniel, additional, Park, Hyun Jung, additional, Watcham, Sam, additional, Patel, Ketan, additional, Green, Anthony, additional, Kent, David, additional, Vassiliou, George, additional, Huntly, Brian, additional, Wilson, Nicola, additional, and Göttgens, Berthold, additional

Published
2022
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11. Complement fraction 3 binding on erythrocytes as additional mechanism of disease in paroxysmal nocturnal hemoglobinuria patients treated by eculizumab

Author

Risitano, Antonio M., Notaro, Rosario, Marando, Ludovica, Serio, Bianca, Ranaldi, Danilo, Seneca, Elisa, Ricci, Patrizia, Alfinito, Fiorella, Camera, Andrea, Gianfaldoni, Giacomo, Amendola, Angela, Boschetti, Carla, Di Bona, Eros, Fratellanza, Giorgio, Barbano, Filippo, Rodeghiero, Francesco, Zanella, Alberto, Iori, Anna Paola, Selleri, Carmine, Luzzatto, Lucio, and Rotoli, Bruno

Published
2009
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14. Contrasting requirements during disease evolution identify EZH2 as a therapeutic target in AML

Author

Basheer, Faisal, Giotopoulos, George, Meduri, Eshwar, Yun, Hayang, Mazan, Milena, Sasca, Daniel, Gallipoli, Paolo, Marando, Ludovica, Asby, Ryan, Sheppard, Olivia, Vassiliou, George, Huntly, Brian, Giotopoulos, George [0000-0003-1390-6592], Gallipoli, Paolo [0000-0001-7254-2253], Sheppard, Olivia [0000-0001-5636-3925], Vassiliou, George [0000-0003-4337-8022], Huntly, Brian [0000-0003-0312-161X], and Apollo - University of Cambridge Repository

Subjects
StemCellInstitute, macromolecular substances
Abstract

This study demonstrates that EZH2 has stage-specific and diametrically opposite roles during the induction and maintenance stages of AML. However, different transcriptional programs are affected at each stage, identifying mutant EZH2 as a prognostic marker and paradoxically wild-type EZH2 as a potential therapeutic target

Published
2019

15. Mutational Synergy Coordinately Remodels Chromatin Accessibility, Enhancer Landscape and 3-Dimensional DNA Topology to Alter Gene Expression during Leukemia Induction

Author

Yun, Haiyang, primary, Vohra, Shabana, primary, Mupo, Annalisa, primary, Giotopoulos, George, primary, Sasca, Daniel, primary, Horton, Sarah J., primary, Agrawal-Singh, Shuchi, primary, Meduri, Eshwar, primary, Basheer, Faisal, primary, Marando, Ludovica, primary, Gozdecka, Malgorzata, primary, Dovey, Oliver M., primary, Wang, Xiaonan, primary, Gallipoli, Paolo, primary, Osborne, Cameron, primary, Vassiliou, George S., primary, and Huntly, Brian J. P., primary

Published
2019
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16. Contrasting requirements during disease evolution identify EZH2 as a therapeutic target in AML

Author

Basheer, Faisal, primary, Giotopoulos, George, additional, Meduri, Eshwar, additional, Yun, Haiyang, additional, Mazan, Milena, additional, Sasca, Daniel, additional, Gallipoli, Paolo, additional, Marando, Ludovica, additional, Gozdecka, Malgorzata, additional, Asby, Ryan, additional, Sheppard, Olivia, additional, Dudek, Monika, additional, Bullinger, Lars, additional, Döhner, Hartmut, additional, Dillon, Richard, additional, Freeman, Sylvie, additional, Ottmann, Oliver, additional, Burnett, Alan, additional, Russell, Nigel, additional, Papaemmanuil, Elli, additional, Hills, Robert, additional, Campbell, Peter, additional, Vassiliou, George S., additional, and Huntly, Brian J.P., additional

Published
2019
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20. From Renal Siderosis Due to Perpetual Hemosiderinuria to Possible Liver Overload Due to Extravascular Hemolysis: Changes in Iron Metabolism in Paroxysmal Nocturnal Hemoglobinuria (PNH) Patients On Eculizumab.

Author

Risitano, Antonio M., primary, Seneca, Elisa, additional, Marando, Ludovica, additional, Imbriaco, Massimo, additional, Soscia, Ernesto, additional, Soscia, Francesca, additional, Pizzuti, Laura Micol, additional, Malcovati, Luca, additional, Fenu, Susanna, additional, Iori, Anna Paola, additional, Notaro, Rosario, additional, Matarazzo, Margherita, additional, and Rotoli, Bruno, additional

Published
2009
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21. Subcutaneous Alemtuzumab Is a Safe and Effective Treatment for Global or Single-Lineage Immune-Mediated Marrow Failures: a Survey from the EBMT-WPSAA

Author

Risitano, Antonio M., primary, Seneca, Elisa, primary, Marando, Ludovica, primary, Serio, Bianca, primary, Selleri, Carmine, primary, Scalia, Giulia, primary, Vecchio, Luigi Del, primary, Iori, Annapaola, primary, Kulagin, Alexander, primary, Maury, Sebastien, primary, Halter, Joerg, primary, Gupta, Vikas, primary, Bacigalupo, Andrea, primary, Socié, Gerard, primary, Tichelli, Andre, primary, Marsh, Judith, primary, Schrezenmeier, Hubert, primary, Passweg, Jakob R., primary, and Rotoli, Bruno, primary

Published
2008
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22. C3-Mediated Extravascular Hemolysis as Additional Mechanism of Disease in Paroxysmal Nocturnal Hemoglobinuria (PNH) Patients Treated by the Complent Inhibitor Eculizumab

Author

Risitano, Antonio M., primary, Marando, Ludovica, primary, Ranaldi, Danilo, primary, Seneca, Elisa, primary, Serio, Bianca, primary, Gianfaldoni, Giacomo, primary, Antonioli, Elisabetta, primary, Milano, Filippo, primary, Amendola, Angela, primary, Boschetti, Carla, primary, Barcellini, Wilma, primary, Di Bona, Eros, primary, Carella, Angelo Michele, primary, Barbano, Filippo, primary, Bonfigli, Silvana, primary, Capalbo, Silvana, primary, Fabbiano, Francesco, primary, Pulini, Stefano, primary, Marino, Antonio, primary, Pietrogrande, Francesco, primary, Iuliano, Franco, primary, Rodeghiero, Francesco, primary, Zanella, Alberto, primary, Iori, Annapaola, primary, Notaro, Rosario, primary, Luzzatto, Lucio, primary, and Rotoli, Bruno, primary

Published
2008
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24. Prevalence and significance of DDX41gene variants in the general population

Author

Kovilakam, Sruthi Cheloor, Gu, Muxin, Dunn, William G., Marando, Ludovica, Barcena, Clea, Ambrose, J. C., Arumugam, P., Bevers, R., Bleda, M., Boardman-Pretty, F., Boustred, C. R., Brittain, H., Brown, M.A., Caulfield, M. J., Chan, G. C., Giess, A., Griffin, J. N., Hamblin, A., Henderson, S., Hubbard, T. J. P., Jackson, R., Jones, L. J., Kasperaviciute, D., Kayikci, M., Kousathanas, A., Lahnstein, L., Lakey, A., Leigh, S. E. A., Leong, I. U. S., Lopez, F. J., Maleady-Crowe, F., McEntagart, M., Minneci, F., Mitchell, J., Moutsianas, L., Mueller, M., Murugaesu, N., Need, A. C., O‘Donovan, P., Odhams, C. A., Patch, C., Perez-Gil, D., Pereira, M. B., Pullinger, J., Rahim, T., Rendon, A., Rogers, T., Savage, K., Sawant, K., Scott, R. H., Siddiq, A., Sieghart, A., Smith, S. C., Sosinsky, A., Stuckey, A., Tanguy, M., Taylor Tavares, A. L., Thomas, E. R. A., Thompson, S. R., Tucci, A., Welland, M. J., Williams, E., Witkowska, K., Wood, S. M., Zarowiecki, M., Zainal, Serena Nik, Mohorianu, Irina, Kar, Siddhartha P., Fabre, Margarete A., Quiros, Pedro M., and Vassiliou, George S.

Abstract

-We map DDX41 germline variation in 454,792 volunteers and define the risk of MDS/AML development associated with different variant types.-DDX41-mutant MDS/AML evolves differently to sporadic disease, but individuals at high risk often have somatic DDX41 mutations or a high MCV.

Published
2023
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25. Chronic myelomonocytic leukemia: molecular pathogenesis and therapeutic innovations.

Author

Marando L, Csizmar CM, and Patnaik MM

Subjects
Humans, Disease Management, Molecular Targeted Therapy, Tumor Microenvironment, Prognosis, Disease Susceptibility, Animals, Leukemia, Myelomonocytic, Chronic genetics, Leukemia, Myelomonocytic, Chronic therapy, Leukemia, Myelomonocytic, Chronic pathology
Abstract

Chronic myelomonocytic leukemia (CMML) is an aggressive clonal stem cell disorder categorized among myelodysplastic/ myeloproliferative overlap neoplasms. While sharing features with both myelodysplastic syndromes and myeloproliferative neoplasms, CMML has distinct molecular and clinical profiles. The presence of CMML-specific prognostic models, response criteria, and dedicated clinical trials underscores a unique and complex biology. Age-related changes affecting the bone marrow microenvironment, immune responses, and the intricate balance between epigenetic deregulation and proinflammatory signaling are characteristic of this disease, collectively posing significant scientific and clinical challenges in its management. CMML is an aging-related, clinically heterogeneous neoplasm with limited approved therapeutic options, representing an area of unmet medical need. This review offers a comprehensive analysis of the current understanding of the molecular mechanisms driving CMML evolution and its clinical manifestations within the ever-evolving landscape of precision medicine. In light of the most recent molecular discoveries, we highlight the shortcomings of existing therapies and underscore promising investigational agents. Many of the biological findings discussed are shared across a spectrum of acute and chronic myeloid neoplasms, as well as clonal hematopoiesis, broadening the scope of this review.

Published
2025
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26. A Phase I/II Open-Label Study of Molibresib for the Treatment of Relapsed/Refractory Hematologic Malignancies.

Author

Dawson MA, Borthakur G, Huntly BJP, Karadimitris A, Alegre A, Chaidos A, Vogl DT, Pollyea DA, Davies FE, Morgan GJ, Glass JL, Kamdar M, Mateos MV, Tovar N, Yeh P, Delgado RG, Basheer F, Marando L, Gallipoli P, Wyce A, Krishnatry AS, Barbash O, Bakirtzi E, Ferron-Brady G, Karpinich NO, McCabe MT, Foley SW, Horner T, Dhar A, Kremer BE, and Dickinson M

Subjects
Humans, Lymphoma, Non-Hodgkin drug therapy, Hematologic Neoplasms drug therapy, Leukemia, Myeloid, Acute drug therapy, Thrombocytopenia
Abstract

Purpose: Molibresib is a selective, small molecule inhibitor of the bromodomain and extra-terminal (BET) protein family. This was an open-label, two-part, Phase I/II study investigating molibresib monotherapy for the treatment of hematological malignancies (NCT01943851)., Patients and Methods: Part 1 (dose escalation) determined the recommended Phase 2 dose (RP2D) of molibresib in patients with acute myeloid leukemia (AML), Non-Hodgkin lymphoma (NHL), or multiple myeloma. Part 2 (dose expansion) investigated the safety and efficacy of molibresib at the RP2D in patients with relapsed/refractory myelodysplastic syndrome (MDS; as well as AML evolved from antecedent MDS) or cutaneous T-cell lymphoma (CTCL). The primary endpoint in Part 1 was safety and the primary endpoint in Part 2 was objective response rate (ORR)., Results: There were 111 patients enrolled (87 in Part 1, 24 in Part 2). Molibresib RP2Ds of 75 mg daily (for MDS) and 60 mg daily (for CTCL) were selected. Most common Grade 3+ adverse events included thrombocytopenia (37%), anemia (15%), and febrile neutropenia (15%). Six patients achieved complete responses [3 in Part 1 (2 AML, 1 NHL), 3 in Part 2 (MDS)], and 7 patients achieved partial responses [6 in Part 1 (4 AML, 2 NHL), 1 in Part 2 (MDS)]. The ORRs for Part 1, Part 2, and the total study population were 10% [95% confidence interval (CI), 4.8-18.7], 25% (95% CI, 7.3-52.4), and 13% (95% CI, 6.9-20.6), respectively., Conclusions: While antitumor activity was observed with molibresib, use was limited by gastrointestinal and thrombocytopenia toxicities. Investigations of molibresib as part of combination regimens may be warranted., (©2022 The Authors; Published by the American Association for Cancer Research.)

Published
2023
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