We make billions of blood cells every day. In the adult, haematopoiesis (the ongoing formation of blood cells from haematopoietic stem cells (HSCs)) occurs via self-renewal vs differentiation decisions of the HSC. Deregulation of HSCs can result in blood cell diseases (including cancers).
By altering the expression of the two different protein forms of HOXA1 in mouse bone marrow cells, we have developed two mouse models of a blood cell disease called myelodysplastic syndromes (MDS). MDS is a malignant blood cell disease that predominantly results in bone marrow failure in the patients, who die of complications of low blood cell counts. It is a very heterogeneous disease and approximately 30% of patients spontaneously progress to acute myeloid leukaemia. Aside from stem cell transplants (which the majority of patients are ineligible for due to their older age) there is no cure.
The mechanisms underlying MDS are largely unknown, although recent studies have suggested that altered splicing of a gene (i.e. differences in the production of protein forms of the same gene) are causative of MDS. We have confirmed that the expression of the two HOXA1 transcripts are significantly deregulated in 50% of human MDS patients, making our mouse models very clinically relevant for the study of this disease.
We will identify what changes occur in the HSCs to cause MDS. We will also determine if we can target HOXA1-expressing cells to find better therapies for MDS.
The studies will incorporate a range of different techniques used in HSC biology, including isolation of bone marrow cells from mice, fluorescence-based immunostaining accompanied by fluorescence activated cell sorting (FACS), HSC transplants molecular biology techniques, culture studies. We do not expect the student to have much (if any) background knowledge of HSC biology or stem cells.