Research

My research interests focus on mechanisms of disease initiation and maintenance and the identification and validation of novel therapeutic targets in myeloid leukaemia. Sequencing and mechanistic studies have improved our understanding of the biology of several subtypes of myeloid leukaemias. This has in turn resulted in the development of more targeted and scientifically validated therapies. However, the overall treatment outcomes, even with the introduction of novel agents, remain suboptimal for most patients, mainly as a result of disease relapse. Both chronic and acute myeloid leukaemia arises in a haematopoietic stem or progenitor cell, which has the ability to self-renew, following the acquisition of recurrent driver mutations. This cell of origin, usually named the Leukaemia Stem Cell (LSC), represents the reservoir for relapse due to its inherent or acquired resistance to current therapies. Therefore, an improved understanding of the molecular mechanisms causing disease relapse, particularly at the LSC level, is required to improve patient outcome.

My research studies the role of adaptive responses to current therapies, including novel targeted therapies, in several subtypes of myeloid leukaemias and at LSC level, with a specific focus on the role of metabolic adaptations, as a mechanism of resistance not driven by genetic mutations. Using a combination of forward genetic screening and cell barcoding, functional characterisation and mechanistic studies, I aim to characterise the clonal dynamics in leukaemic cell populations under therapeutic stress, characterise the mechanisms leading to therapy resistance and identify novel therapeutic vulnerabilities to be targeted in combination with standard therapies in these conditions.

I am also interested in the role that the bidirectional cross-talk between altered metabolism and aberrant signalling and transcriptional programmes play in the establishment of myeloid leukaemias. I am specifically studying how metabolic intermediates interact with transcriptional programmes in acute myeloid leukaemia and conversely how specific driver mutations impact on cellular metabolism to enable leukaemic transformation.

Methodologies: human cell culture, CRISPR/Cas9, RNA-Seq, Mass Spectrometry, metabolic analysis, in vivo experiment.

COLLABORATORS

Dr Christian Frezza, MRC Cancer Unit, Cambridge

Prof Brian Huntly, Wellcome-MRC Cambridge Stem Cell Institute, Cambridge

Dr George Vassiliou, Wellcome Trust Sanger Institute/ Wellcome-MRC Cambridge Stem Cell Institute, Cambridge

Dr Vignir Helgason, Institute of Cancer Sciences, University of Glasgow

Other Activities

• Member of UK, National Cancer Research Institute (NCRI) CML clinical study group -2015 to present
• Trainee member of the UK, NCRI Haemato-Oncology Clinical Study Group - 2015-2016
• Chair of the Postdoctoral committee at Cambridge Institute for Medical Research – 2015
• Medical Graduate School Student Representative at University of Glasgow - 2010-2013
• Trainee representative in the research subgroup of the West of Scotland post-graduate committee in haematology – 2010-2013
• Member European Hematology Association (EHA) - 2009 to date
• Member of American Society of Hematology (ASH) - 2018 to date

Major Funding

• 2023 - NIHR Academic Clinical Fellowship, "Identification of novel therapies in acute myeloid leukaemia (AML)"
• 2021-2025 - CRUK City of London PhD Scholarship, "Exploring adaptive resistance to targeted therapy in AML," £146,622
• 2019-2024- CRUK Advanced Clinician Scientist Fellowship, "Identification and characterisation of metabolic pathways as determinants of drug resistance in acute myeloid leukaemia," £1,427,558
• 2018-2020- American Society of Hematology Global Research Award, "Preliminary investigation on the role of metabolic pathways as determinants of drug responses in acute myeloid leukemia," $140,000
• 2016-2019- Wellcome Trust Postdoctoral Research Training Fellowship for Clinicians, "The role of aberrant metabolism in the pathogenesis and therapy of Acute Myeloid Leukaemia (AML)," £393,467
• 2014-2015- Lady Tata Memorial Trust International Awards, "Preliminary investigations on the role of aberrant metabolism in the pathogenesis and therapy of Acute Myeloid Leukaemia (AML)," £30,000
• 2014-2016- The Academy of Medical Sciences, Starter Grant for Clinical Lecturers, "Investigation of the role of the CBP and p300 lysine acetyltransferases in the maintenance of acute myeloid leukaemia," £30,000
• 2010-2013- Medical Research Council, UK, Clinical Research Training Fellowship, "The relevance of autocrine growth factors activation to the survival and proliferation of primitive chronic myeloid leukaemia cells," £203,583

Recent Publications

Mutational synergy during leukemia induction remodels chromatin accessibility, histone modifications and three-dimensional DNA topology to alter gene expression Yun H, Narayan N, Vohra S et al. Nature Genetics (2021) 53(7) 1443-1455

The Role of Metabolism in the Development of Personalized Therapies in Acute Myeloid Leukemia Dembitz V, Gallipoli P Frontiers in Oncology (2021) 11(7)

Design, implementation and clinical utility of next generation sequencing in myeloid malignancies: acute myeloid leukaemia and myelodysplastic syndrome Hughes CFM, Gallipoli P, Agarwal R Pathology (2021) (1)

Bone Marrow Mesenchymal Stem Cells Support Acute Myeloid Leukemia Bioenergetics and Enhance Antioxidant Defense and Escape from Chemotherapy Forte D, García-Fernández M, Sánchez-Aguilera A et al. Cell Metabolism (2020) 32(7) 829-843.e9

Does Outcome/Survival of Patients With Myelodysplastic Syndromes Should Be Predicted by Reduced Levels of ADAMTS-13? Results From a Pilot Study Castelli R, Bergamaschini L, Teatini T et al. Clinical Lymphoma, Myeloma and Leukemia (2020) 20(7) e461-e467

A randomised phase II trial of hydroxychloroquine and imatinib versus imatinib alone for patients with chronic myeloid leukaemia in major cytogenetic response with residual disease Horne GA, Stobo J, Kelly C et al. Leukemia (2020) 34(7) 1775-1786

Cohesin-dependent regulation of gene expression during differentiation is lost in cohesin-mutated myeloid malignancies Sasca D, Yun H, Giotopoulos G et al. Blood (2019) 134(7) 2195-2208

Introducing a Predictive Score for Successful Treatment Free Remission in Chronic Myeloid Leukemia (CML) Claudiani S, Metelli S, Kamvar R et al. Blood (2019) 134(7) 26

Mutational Synergy Coordinately Remodels Chromatin Accessibility, Enhancer Landscape and 3-Dimensional DNA Topology to Alter Gene Expression during Leukemia Induction Yun H, Vohra S, Mupo A et al. Blood (2019) 134(10) 278-278

Contrasting requirements during disease evolution identify EZH2 as a therapeutic target in AML Basheer F, Giotopoulos G, Meduri E et al. Journal of Experimental Medicine (2019) 216(7) 966-981

Team

Biography

I am a clinical academic haematologist with an interest in the biology and therapy of myeloid leukaemias. I studied Medicine in Naples, Italy, where I graduated in 2002. I then moved to the UK for my postgraduate medical training including my Haematology specialty training. I obtained my PhD, funded via an MRC Clinical Research Training Fellowship, in Prof Holyoake lab in Glasgow in 2013, studying resistance mechanism of Chronic Myeloid Leukaemia (CML) stem cells to BCR-ABL tyrosine kinase inhibitors. I was awarded the Royal College of Pathologist, UK Haematology Specialty Research Medal Award for this work. I then moved to Cambridge to complete my specialty training and worked as a Wellcome Trust funded Clinical Post-doctoral Fellow within Prof Brian Huntly lab where I have developed an independent research line focusing on the role of altered metabolism in the pathogenesis and therapy of myeloid leukaemias. I am clinically active at Consultant level with a leading role on design and set-up of clinical trials through my membership of the NCRI CML Working Group. I am already a principal investigator/sub-investigator on several clinical trials in myeloid malignancies. I have recently been awarded a CRUK Advanced Clinician Scientist Fellowship to start my independent research programme.

• Certificate of Completion of Training (CCT) in Haematology, December 2014
• Fellowship Royal College of Pathologist in Haematology (FRCPath), UK, May 2014
• PhD in Experimental Haematology, University of Glasgow, UK, April 2013
• Membership Royal College of Physicians (MRCP), UK, July 2005
• Laurea in Medicina&Chirurgia (Degree in Medicine&Surgery) Grade: 110/110 summa cum laude awarded with distinction (top 5% of the class), University of Naples “Federico II”, Italy, July 2002