1) What is the problem/issue being addressed?
Hematopoietic stem cells (HSC) are blood cells responsible for generating all types of blood cells. In acute myeloid leukemia (AML), HSC are transformed into malignant or leukemia stem cells (LSC), responsible for the onset of the disease. HSC are found in a tightly regulated microenvironment inside the bone marrow cavity, which has shown to be essential in AML progression. Growing amount of data, including work from the lab of the Supervisor, links chronic inflammation, metabolism and intercellular communication to the onset of myeloid malignancies. In this context, the main question that we wanted to address in SuccHSC was the mechanisms of transformation of HSC into LSC, focussing on the potential role of succinylation, as a major effector event involved in the epigenetic remodeling of HSC into LSC.
2) Why is it important for society?
Finding new treatment options for an aggressive blood cancer like AML requires acquisition of new knowledge on the pathogenic mechanisms. The current best treatment option is chemotherapy and stem cell transplant, which offer 5-year survival to 20% of patients above the age of 60 and 40% to the younger patients. Stem cell transplantation is not performed in older patients due to their frailty. However, the incidence of AML increases with age with a median age at diagnosis of 67 years of age, with 55% of cases occurring in people over the age of 65.
3) What are the overall objectives?
The goal was to identify and compare the DNA sequences which have succinate bound to histones, between HSC obtained from healthy donors and LSC obtained from AML patients. Using an experimental mouse model, we would demonstrate the causal association between succinylation and leukemic transformation.
The questions we wanted to address were:
1. What is the amount of succinate metabolite inside human bone marrow cells?
2. How much succinate is bound to histones at specific genes?
3. Does gene succinylation influence expression and cell function?
4. How does that correlate with inflammatory parameters?
5. How does succinylation impact AML origin and progression?
6. Can we capitalize this knowledge to design a treatment strategy?
Conclusions
These objectives could only be partially accomplished due to delays, technical challenges and early termination of the grant.
