Roles of Hox and Hox-cofactors in normal and malignant hematopoiesis
Section:
Section of Haemato-Oncology
Mammalian Hox genes consist of 39 highly conserved homeobox containing genes clustered in four different chromosomes. In Drosophila, mutations of Hox genes result in renowned homeotic transformation, indicating their critical roles in normal development. These functions are also highly conserved during evolution although homeotic transformation usually can only be detected in compound knockout mice due to functional compensation from the additional Hox members (e.g., Hox-code). Hox proteins are transcription factors that cooperatively work with Hox-cofactors such as Pbx and Meis-1 to bind and regulate downstream target genes including Hox genes themselves. Individual Hox gene and Hox-cofactor have been implicated in normal and malignant haematopoiesis (So et al., 2004). Members of Hox and Pbx genes form chimeric oncogenic fusion proteins as results of chromosomal translocations in human leukaemia. Forced expression of certain Hox genes such as Hoxb3, a9 leads to myeloid proliferative syndromes; and their coexpression with Meis-1 can rapidly induced acute myeloid leukaemia in mice. Conversely ecotopic expression of Hoxb4 leads to haematopoietic stem cell expression without induction of leukaemia. Thus Hox and Hox-cofactors are critical components for normal haematopoiesis and their dis-regulation may be the underlying mechanisms for different hematological disorders.
Our primary focuses:
- Define the Hox-code for self-renewal of both normal haematopoietic stem cells and leukaemic stem cells
- Examine the roles of Hox-cofactors in MLL and other leukaemia
This work is supported by Association of International Cancer Research (AICR) and the Institute of Cancer Research (ICR).
In the Section of Haemato-Oncology
