The role of MYBL2 in the age-related development of blood disorders

Our ability to maintain a supply of healthy functional blood cells throughout our lives is absolutely dependent on the presence in our bone marrow of specialized stem cells. Like other stem cells in the body, these blood stem cells serve to provide a supply of mature cells as required and at the same time are able to make copies of themselves so that they do not become depleted throughout life. As we age, the blood stem cells can gradually acquire mutations in their genetic material sometimes leading to the appearance either of blood disorders in which either the normal number of type of blood cells produced is disrupted or a leukaemia arises. A protein that we know to be critical to limit genetic damage as cells divide is known as MYBL2, and loss of the gene coding for this appears to be linked to certain age-related blood disorders and leukaemia. I have generated a mouse model mimicking the way in which MYBL2 is altered in some patients with blood disorders and I wish to use this to study the precise way in which changes in this protein in stem cells can cause blood diseases as we get older. The outcomes of the project should provide new information to aid diagnosis and prognosis, and may lead to novel treatments for leukaemia and age-related decline in stem cell function.

The haemopoietic system is prone to age-related disorders ranging from deficits in functional blood cells to the development of a variety of neoplastic states. Haemopoietic neoplasms often involve defining cytogenetic abnormalities, frequent amongst which is a deletion in the long arm of chromosome 20 (del20q). MYBL2, a key protein involved in the maintenance of genome integrity, is encoded within the minimum del20q region, suggesting a causative role for the factor in disease onset or progression.

I have demonstrated that mice expressing half the normal level of MYBL2 are susceptible to the development of myeloid disorders with age. Moreover, analysis of global expression studies conducted with cells from patients with myelodysplastic syndrome (MDS) confirmed that down regulation of MYBL2 expression levels correlates with poor prognosis (in refractory anaemia with excess blasts (RAEB)), regardless of the cytogenetic abnormality. The importance of MYBL2 in myeloid neoplasms is supported by a strong correlation between MYBL2 RNA levels and expression of a subset of genes related to cell cycle checkpoint control in cells from patients with MDS.

This project will utilize the mouse model of MYBL2 haploinsufficiency as a tool to study the molecular mechanisms of initiation and progression of haematological malignancies during ageing. The project will also investigate the molecular mechanisms leading to down-regulation of MYBL2 observed in MDS patients that do not exhibit del20q.

If it can be validated that down-regulation of MYBL2 is related to MDS with bad prognosis, then MYBL2 could potentially serve as prognostic biomarker of disease progression and have an impact in prospective therapeutic strategies for MDS patients.

Impact on Knowledge - New information on the the molecular mechanisms that govern blood disorders during ageing will be generated by this project. This will be disseminated through publication in international journals and as well through channels such as the annual Molecular Haematology meeting (held in London), stem cell centre, BUSCC, and the regional stem cell network, MSCA.

Impact on Communication and Engagement - This will be achieved through the auspices of BUSCC and as part of the University of Birmingham Heroes campaign. Events will be held locally in the University or the city of Birmingham at which the public can engage in informed debate about a variety of issues related to stem cell science.

Impact on health and quality of life - The research in this project will not be only fundamental research, but will also study blood disorders using human samples. There will be opportunities to communicate the output to the local clinical haematology community as a part of this type of collaborative projects that are more translational. Long-term, the findings from this project should impact on health issues ranging from prognosis, the treatment of MDS and alleviation of age-related declines in stem cell function.

Impact on International Collaboration - This project will help to mantain an already established international collaboration with the group of Robert Kralovics in Vienna.

Impact on People - The project will lead to training of a postdoctoral staff, and will impact on the training of others in the laboratory, including PhD students, undergraduate students and master students. The expertise of the principal applicant and collaborators, and the new knowledge gained will be of use to several other research groups in the local research environment, as well as the wider community in Birmingham.

Impact on the Economy - We will continue to contribute to development of the local science infrastructure and in providing skilled researchers needed for academia and industry, and this is of particular relevance given the Science City status held by Birmingham and what this means in terms of linking academic output to local industries.