1013 - CHROMATIN PROTEINS IN HAEMATOPOIETIC STEM CELLS AND HAEMATOLOGICAL MALIGNANCIES

Abstract

A major focus of our work is the role of chromatin modifying complexes in normal haematopoiesis and in leukaemia. For example, somatically acquired mutations in the plant homeodomain finger 6 gene (PHF6) frequently occur in haematopoietic malignancies and often coincide with ectopic expression of TLX3. However, there is no functional evidence to demonstrate whether these mutations contribute to tumourigenesis. Similarly, the role of PHF6 in haematopoiesis is unknown. We found that Phf6 deletion in mice resulted in a reduced number of haematopoietic stem cells (HSCs), an increased number of haematopoietic progenitor cells, and an increased proportion of cycling stem and progenitor cells. Loss of PHF6 caused increased and sustained haematopoietic reconstitution in serial transplantation experiments. Interferon-stimulated gene expression was upregulated in the absence of PHF6 in haematopoietic stem and progenitor cells. The numbers of haematopoietic progenitor cells and cycling haematopoietic stem and progenitor cells were restored to normal by combined loss of PHF6 and the interferon α and β receptor subunit 1. Ectopic expression of TLX3 alone caused partially penetrant leukaemia. TLX3 expression and loss of PHF6 combined caused fully penetrant early-onset leukaemia. Our data suggest that PHF6 is a haematopoietic tumour suppressor and is important for fine-tuning haematopoietic stem and progenitor cell homeostasis.