Stem Cell Biology Group led by Dr Georges Lacaud
Transcription factors bind to specific sequences in DNA and control how genes are transcribed into RNA and, as a consequence, indirectly control the translation of RNA into functional proteins. 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 leukaemias, RUNX1 has also been shown to be critical for haematopoietic development. Similarly, the transcriptional co-activator MOZ is involved in three independent myeloid chromosomal translocations fusing MOZ to the partner genes CBP, P300 or TIF2 in human leukaemia. The group studies the function of RUNX1 and MOZ in haematopoietic development and maintenance in order to better understand how alterations of these functions lead to leukaemogenesis. For this, complementary approaches such as in vitro differentiation of mouse embryonic stem (ES) cells and in vivo mouse models are used.
Previous studies have indicated a critical requirement for RUNX1 at the onset of haematopoietic development and that RUNX1/AML1 is expressed as multiple, naturally occurring spliced isoforms that generate proteins with distinct activities on target promoters. To further define the role of RUNX1 at the onset of haematopoietic commitment, the group has analysed the pattern of expression of the different isoforms of RUNX1 and the developmental potential of cell populations defined by their expression. This research provided evidence that RUNX1 functions at the earliest stage of haematopoietic development. Further experiments identified transcriptional targets of RUNX1, which are likely to be critical for development of the haematopoietic system. Current work aims to evaluate the specific function of some of these target genes in the onset of haematopoiesis. One of the translocation of AML1 observed in human leukaemia results in the generation of the AML-ETO fusion protein. An alternatively spliced variant of AML-ETO has been shown to rapidly cause the development of leukaemia in mice following retroviral transfer. The group has developed a new mouse model to further study the molecular events caused by this form of AML-ETO leading to leukaemia development.
Work of the Stem Cell Biology Group has also established a new model of haematopoietic development. Their data demonstrated that the haemangioblast (the first blood precursor) generates haematopoietic cells through the formation of a haemogenic endothelium intermediate, providing the first direct link between these two precursor populations. This haemogenic endothelial cell population is transiently generated during blast development and is also detected in gastrulating embryos. Further experiments showed that the transcription factor SCL/TAL1 is indispensable for the establishment of this haemogenic endothelium cell population from the haemangioblast, whereas RUNX1/AML1 is critical for generation of haematopoietic cells from this haemogenic endothelium.
All three MOZ fusion genes known in human leukaemia encode enzymes containing a histone acetyl transferase domain (HAT), suggesting that aberrant modification of histones or other factors could provide the first step in the development of malignancies. To specifically address the role of HAT activity of MOZ during haematopoiesis, a mouse strain carrying MOZ with an inactive HAT domain has been generated. Analysis of these mice demonstrated a critical role of MOZ-driven acetylation in the balance between proliferation and differentiation during haematopoiesis. Current work investigates the precise molecular and cellular mechanisms affected in the absence of the HAT activity of MOZ.
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The Stem Cell Biology Group is part of the Paterson Institute for Cancer Research at The University of Manchester. Find out more about the work of the Stem Cell Biology Group.