What turns healthy blood stem cells into leukaemic stem cells?

Lead researcher - Professors Constanze Bonifer and Peter Cockerill, University of Birmingham
Mechanistic insights into aberrant transcriptional programming in acute myeloid leukaemia
Amount awarded: £1,543,859
Award duration: 5 years

Stem cells in the bone marrow generate billions of different blood cells each day. This process involves many sequential steps which are each controlled by genes acting as regulators. Leukaemia arises when the DNA of a stem cell is changed by mutations, which often occur in important regulator genes, disrupting the finely balanced sequence of blood cell production. The mutated cells then develop into leukemic cells that multiply and take over the body. We used state of the art technology that looks at the activity of all genes within a cell to show that aberrant regulators switch hundreds of other genes on or off, many of them regulators themselves, and thereby cause acute myeloid leukaemia (AML). We also demonstrated that regulator genes are deregulated in a different way in every patient. For one type of AML, we found that removing the aberrant regulator sends cells back on the path to a normal state. We now wish to identify (i) the most important aberrant regulators that keep cells in a leukaemic state and target them, (ii) how they differ in different types of AML, and (iii) how patients respond to the treatment with drugs that aim at restoring normal gene function.