Research

Myelodysplastic Syndromes (MDS) and Acute myeloid leukaemia (AML) are both clonal diseases that harbour MDS stem cells (MDS-SC) and pre-leukemic cells, respectively. Various studies have demonstrated that acquired mutations in haematopoietic cells' genes can lead to clonal fitness and eventually to propagation of the disease. Understanding the switch between clonal haematopoiesis and clonal disease is one of the major challenges of the scientific community, which highlights the need to unravel how epigenetic/spliceosome stresses are integrated by stem cells and dictate their clonal fate.

In the lab we develop in-vitro and in-vivo modelling of MDS and AML diseases. Using primary human samples and multi-omics approaches including RNAseq (Bulk & single cell), Proteomics, Phosphoproteomics, Metabolomics and drug screening, we challenge normal and malignant haematopoiesis to unveil new therapeutic targets in myeloid malignancies.

Key words: Stem cells, patient samples, AML, MDS, splicing, RNA biology, metabolism and translation regulation.

Poster and Oral communications from the group, including prizes:

• September 2021: Oral presentation by Doriana Di Bella (PhD student) at the Barts Cancer Institute PhD Day, Won the Prize for the best oral presentation (AML & Microenvironment)
• October 2021: Oral presentation by Celine Philippe (Postdoctoral Fellow) at the annual conference of Hematology and Oncology, France. Won the Prize for the best presentation (Splicing & MDS)
• October 2021: Poster presentation (KRP) at the Endoplasmic Reticulum Symposium, France. Poster Prize.
• December 2021: Oral presentation by Celine Philippe (Postdoctoral Fellow) at the American Society of Hematology, USA
• December 2021: Oral presentation by Hannah Armes (Postdoctoral Fello) at the myeloid workshop of the American Society of Hematology, USA
• December 2021: Oral presentation (KRP) at the myeloid workshop of the American Society of Hematology, USA
• January 2022: Oral communication (KRP) at the RNA UK 2022
• April 2022: oral communication ESH MDS (Celine Philippe Postdoctoral Fellow)
• May 2023: oral communication and Tito Bastianello Young Investigator Award at the 17^th International MDS Foundation conference (Celine Philippe Postdoctoral Fellow)
• May 2023: oral communication CALR meeting (Celine Philippe Postdoctoral Fellow)
• June 2023: oral communication BCI RNA Cancer Symposium (Celine Philippe Postdoc)

Oral communications/seminars (invited speaker/moderator/Chair)

• March 2018: London Stem Cell Network, Francis Crick Institute, UK
• June 2019: Stem Cell Lunch, KCL, UK
• January 2021: Institute COCHIN Paris, France
• January 2021: Cellular and molecular Radiobiology Institute CEA-Saclay, France
• February 2021: Clinical University of Navarra, Spain
• March 2021: Division of Cancer Sciences University of Manchester, UK
• March 2021: The Crick Stem Cell Forum, Francis Crick Institute, UK
• May 2021: Molecular and Cellular Immunology, UCL Institute of Child Health, UK
• November 2021: 24th Molecular Haemopoieis meeting
• December 2021: Myeloid Workshop American Society of Hematology congress, Atlanta, US
• June 2022: Group of Francophone Myelodysplasia, Nantes, France
• October 2022: NCRI MDS subgroup presentation, UK
• March 2023: Moderator at the Acute Myeloid Leukemia XVIII, Munich, Germany
• July 2023: Stem Cell Lunch, KCL, UK

Other Activities

• Member of the British Society of Haematology
• Member of the European Haematology Association
• Member of the Société Française d'Hématologie

Major Funding

• 2024-2025- European Hematology Association Bilateral Collaborative Grant
• 2023-2026- CRUK Early Detection and Diagnosis Project Award
• 2023-2026- HARP programme (Clinical Research Fellow)
• 2022-2025- Barts Charity, Project Grant
• 2022-2023- British Society of Haematology, Early Stage Research grants support
• 2021-2022- Lady Tata Memorial Trust awarded to Celine Philippe (Postdoctoral Fellow)
• 2019-2022- Academy of Medical Sciences Springboard Award
• 2017-2022- Kay Kendall Leukaemia Fund

Recent Publications

The XPO1-FOXC1-HOX Functional Axis Opens New Therapeutic Avenues to Treat DEK-NUP214 AML Patients Kaya F, Bewicke-Copley F, Izquierdo PC et al. Blood (2023) 142(10) 4302

CRISPR/dCas9 DNA methylation editing is heritable during human hematopoiesis and shapes immune progeny Saunderson EA, Encabo HH, Devis J et al. Proceedings of the National Academy of Sciences of the United States of America (2023) 120(10) e2300224120

O20 TARGETING THE DEFECTIVE COA PATHWAY TO IMPROVE ERYTHROPOIESIS IN SF3B1-MUTANT MDS-RS PATIENTS Philippe C, Mian S, Maniati E et al. Leukemia Research (2023) 128(10) 107133

Mannose metabolism inhibition sensitizes acute myeloid leukaemia cells to therapy by driving ferroptotic cell death Woodley K, Dillingh LS, Giotopoulos G et al. Nature Communications 14(10) 2132

Vitamin B5 and succinyl-CoA improve ineffective erythropoiesis in SF3B1-mutated myelodysplasia Mian SA, Philippe C, Maniati E et al. Science Translational Medicine (2023) 15(10) eabn5135-eabn5135

Integrative phosphoproteomics defines two biologically distinct groups of KMT2A rearranged acute myeloid leukaemia with different drug response phenotypes Casado P, Rio-Machin A, Miettinen JJ et al. Signal Transduction and Targeted Therapy 8(10) 80

The transcription factor DDIT3 is a potential driver of dyserythropoiesis in myelodysplastic syndromes Berastegui N, Ainciburu M, Romero JP et al. Nature Communications 13(10) 7619

Deep Multi-Omics Profiling in Cytogenetically Poor-Risk AML Rio-Machin A, Bewicke-Copley F, Zheng J et al. Blood (2022) 140(10) 1030-1032

Inhibition of Stearoyl-CoA Desaturase Has Anti-Leukemic Properties in Acute Myeloid Leukemia Dembitz V, Lawson H, Philippe C et al. Blood (2022) 140(10) 3058-3060

Germline ERCC excision repair 6 like 2 (ERCC6L2) mutations lead to impaired erythropoiesis and reshaping of the bone marrow microenvironment Armes H, Bewicke‐Copley F, Rio‐Machin A et al. British Journal of Haematology (2022) 199(10) 754-764

Team

Current lab
Celine Philippe (Postdoctoral researcher)
Fadimana Kaya (PhD student)
Faika Laz Banti (PhD student)
Shoshi Burke (Clinical research Fellow)
Postdoc to be communicated (EHA funded)
Postdoc to be communicated (CRUK funded)

Alumni
Doriana Di Bella (PhD 2023)
Wei Wei Tang (PhD 2023)
Pantelitsa Protopapa (Technician 2022)
Evens Bousiquot (Technician 2018)

Biography

Since 2018, I have led a team of 3-4 lab members in the Centre for Haemato-Oncology at the Barts Cancer Institute (QMUL). In September 2021, I was made tenured. I have acquired a national and international reputation as an expert in human haematopoietic stem cell biology, clonal evolution and haematological diseases modelling and have published seminal studies in different journals (including, Cell Stem Cell, Leukaemia, Haematologica, Nature Communications, British Journal of Haematology and Science Translational Medicine). My studies on myelodysplastic syndromes and acute myeloid leukaemia have pioneered important, robust methods for assaying clonal dynamic of hematopoietic stem cell function in health and disease, providing reference tools to the scientific community to screen drugs, to challenge putative target genes and study cross-talk between micro-environment and haematopoietic cells. Using cutting edge technologies on human primary cells we aim to reveal novel mechanisms regulating stem cells’ RNA biology and proteostasis.

Keywords: Hematopoietic Stem Cells, Leukemic stem cells, Myelodysplastic Syndromes (MDS), Acute Myeloid Leukemia (AML), Clonal evolution, Splicing, Endoplasmic Reticulum Stress.