Leukaemia is the 8th most common cause of cancer death in Europe. Treatments of Acute Myeloid Leukaemia (AML) have not dramatically changed, or improved, for the last 30 years and mainly consist of a first step of induction chemotherapy, followed by a consolidation treatment which can be another chemotherapy or a bone marrow transplant. The therapeutic potential of BMT relies on the presence of long-term repopulating haematopoietic stem cells (HSCs) which are able to engraft the recipient and reconstitute all blood cell lineages. In addition to blood stem cell transplantation, mature blood cells such as red blood cells, platelets, and engineered T cells are also increasingly used to treat various diseases. However, the scarcity of allogeneic donor cells is a major hurdle in treating patients. An attractive approach to solving this issue is to produce HSCs and blood derivatives in vitro either from limitless sources such as embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs) or through the reprogramming of somatic cells. However, whilst great progresses have been made toward this goal, we are still far away from the use of in vitro derived blood products in the clinic due to the difficulty to generate the right cells in vitro.
There is therefore a considerable therapeutic interest in understanding better how blood cells are generated during development in order to faithfully reproduce this process in vitro. Additionally, as most key transcription factors (TFs) regulating early haematopoietic development have also been implicated in various types of leukaemia, elucidating their function during normal development should result in a better understanding of their roles during abnormal haematopoiesis in leukaemia.
My laboratory has a long term interest in the study of the early events of blood emergence. In collaboration with the laboratory of Dr Kouskoff, we developed and used the ES cell differentiation system to define the mechanisms underlying the development of blood cells. We demonstrated that the first haematopoietic progenitors are generated by a subset of endothelial cells, a haemogenic endothelium (HE), and that the TF RUNX1 is critical for this endothelial to haematopoietic transition (EHT). We discovered that the transcriptional repressors GFI1 and GFI1B are critical targets of RUNX1 that control the down-regulation of the endothelial programme during the EHT and generation of HSCs. We also uncovered an unexpected early role for RUNX1 in the positive regulation of a cell adhesion and migration programme in HE. This new attribute of RUNX1 could be relevant to its recently described role in solid tumour formation, progression and metastasis.
Transdifferentiation or direct reprogramming has recently emerged a novel promising approach to generate cells for regenerative medicine. We established for the first time that fibroblasts can be robustly reprogrammed to a multi-lineage haematopoietic progenitor cell fate by the concomitant ectopic expression of a limited set of TFs. Despite many remaining questions, our approach holds huge promises.
The monocytic leukemia zinc ﬁnger (MOZ) protein, displaying a histone acetyl transferase (HAT) activity, is recurrently found translocated in leukaemia. It has been proposed that the translocations create fusion proteins with super HAT activity responsible for the deregulation of key pathways leading to leukaemogenesis. Thus a deeper understanding of the HAT activity of MOZ is critical. We generated a mouse line with a specific mutation in its HAT domain supressing its enzymatic activity (MOZΔΗΑΤ). We demonstrated that haematopoietic progenitors undergo premature entry into replicative senescence in these mice due to the impairment of the repression of p16INK4a expression. This repressive activity of MOZ over p16INK4a transcription could be exacerbated in MOZ fusion proteins facilitating the development of leukaemia. We are currently further exploring the role of the epigenetic factor MOZ in normal haematopoiesis and leukaemia.