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Stem Cell Biology - Georges Lacaud

Georges graduated as a biotechnology engineer from the European Biotechnology School of Strasbourg (ESBS) in Strasbourg, France. He obtained his PhD from the University Louis Pasteur of Strasbourg, France and then did a postdoctoral fellowship at the National Jewish Medical Center in Denver, Colorado, USA studying early lymphoid cell development in Prof. Gordon Keller’s lab. Georges next moved to the Mount Sinai School of Medicine in New York, NY, USA where he worked on early hematopoietic development. In 2003, he joined the CRUK Manchester Institute as a junior group leader. He is a senior group leader and heads the Stem Cell Biology group. Georges was awarded a Professorship in Stem Cell Biology at The University of Manchester in 2018.

Introduction

The genes encoding the AML1/RUNX1 transcription factor and its cofactor CBFβ are frequently rearranged or mutated in human leukaemias such as acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL). Consistent with its implication in leukaemia, RUNX1 has also been shown to be critical for haematopoietic development and adult haematopoiesis. Similarly, the transcriptional co-activator MOZ is involved in independent myeloid chromosomal translocations in human leukaemia. Our group studies the functions of RUNX1 and MOZ in haematopoietic development and maintenance in order to better understand how alterations of their functions might lead to leukaemogenesis.

Along these lines, we previously demonstrated that the first blood cells are generated by endothelial cells during embryogenesis and that AML/RUNX1 as a critical regulator of this process of endothelial to haematopoietic transition (EHT). More recently, we surveyed RUNX1 transcriptional targets and found that AML1/RUNX1 regulate a cell adhesion and migration programme during the development of the

blood system. This novel function of AML1/RUNX1 might be relevant in the proposed role of AML1/RUNX1 in metastasis of solid tumours. We subsequently identified the two GFI1 transcription repressors, and their binding partner LSD1, as absolutely required during the EHT to epigenetically silence the endothelial programme and promote the emergence of the first haematopoietic stem cells. In another study, we examined the relevance of the different isoforms of RUNX1/AML1 in adult haematopoiesis and discovered a critical role for the RUNX1C isoform in megakaryopoiesis. Regarding our work on MOZ, we established the critical requirement for MOZ histone acetyl transferase activity for the development of haematopoietic and neuronal stem cells by protecting them from replicative senescence. Finally, we recently demonstrated that fibroblasts can be reprogrammed to blood cells using a specific set of defined transcription factors. This finding suggests that reprogramming represents a putative approach to generate haematopoietic cells for patient therapies.

Selected Publications

Thambyrajah R, Fadlullah MZH, Proffitt M, Patel R, Cowley SM, Kouskoff V, Lacaud G. (2018)
HDAC1 and HDAC2 Modulate TGF-β Signaling during Endothelial-to-Hematopoietic Transition.
Stem Cell Reports 10(4):1369-1383. PubMed abstract

Lie-A-Ling M, Marinopoulou E, Lilly AJ, Challinor M, Patel R, Lancrin C, Kouskoff V, Lacaud G. (2018)
Regulation of RUNX1 dosage is crucial for efficient blood formation from hemogenic endothelium.
Development 145(5). PubMed abstract

Draper JE, Sroczynska P, Fadlullah MZH, Patel R, Newton G, Breitwieser W, Kouskoff V, Lacaud G. (2018)
A novel prospective isolation of murine fetal liver progenitors to study in utero hematopoietic defects.
PLoS Genetics 14(1):e1007127. PubMed abstract

Stefanska M, Batta K, Patel R, Florkowska M, Kouskoff V, Lacaud G. (2017)
Primitive erythrocytes are generated from hemogenic endothelial cells.
Scientific Reports 7(1):6401. PubMed abstract

Draper JE, Sroczynska P, Leong HS, Fadlullah MZH, Miller C, Kouskoff V, Lacaud G. (2017)
Mouse RUNX1C regulates premegakaryocytic/erythroid output and maintains survival of megakaryocyte progenitors.
Blood 130(3):271-284. PubMed abstract

Thambyrajah R, Mazan M, Patel R, Moignard V, Stefanska M., Marinopoulou E, Li Y, Lancrin C, Clapes T, Möröy T, Robin C, Miller C, Cowley S, Göttgens B, Kouskoff V, Lacaud G. (2016)
GFI1 proteins orchestrate the emergence of Haematopoietic Stem Cells in the AGM through recruitment of LSD1.
Nature Cell Biology 18(1):21-32. PubMed abstract

Draper J, Sroczynska P, Tsoulaki O, Leong HS, Fadlullah MZH, Miller C, Kouskoff V, Lacaud G. (2016)
RUNX1B expression is highly heterogeneous and distinguishes megakaryocytic and erythroid lineage fate in adult mouse hematopoiesis.
Plos Genetics 12(1):e1005814. PubMed abstract

Batta K, Florkowska M, Kouskoff V, Lacaud G. (2014)
Direct reprogramming of murine fibroblasts to hematopoietic progenitor cells.
Cell Reports 9(5) 1871–1884. PubMed abstract

Lie-A-Ling M, Marinopoulou E, Li Y, Patel R, Stefanska M, Bonifer C, Miller C, Kouskoff V, Lacaud G. (2014)
RUNX1 positively regulates a cell adhesion and migration program in murine hemogenic endothelium prior to blood emergence.
Blood 124(11):e11-20. PubMed abstract

Lancrin C, Sroczynska P, Stephenson C, Allen T, Kouskoff V, Lacaud G. (2009)
The haemangioblast generates haematopoietic cells through a haemogenic endothelium stage.
Nature 457(7231):892-5. PubMed abstract

Team

Postdoctoral Fellows
Michael Lie-A-Ling
Divya Malik
Muhammad Maqbool
Neo Wenhao

Scientific Officer
Rahima Patel

Graduate Students
Renaud Mevel
Muhammad Fadlullah Wilmot
Ewan Selkirk

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