SuccHSC · Succinate-induced leukemic stem cell formation via epigenetic remodeling of hematopoietic stem cell
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2022-03-11 → 2024-03-10
- EU contribution
- €202,159
- Participants
- 1
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
Succinate-induced leukemic stem cell formation via epigenetic remodeling of hematopoietic stem cell
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.
Data: CORDIS, © European Union
Project objective
In life, no matter how small, changes can have huge impact on its quality. For hematopoietic stem cells (HSC), similar can happen. Through minor shifts, from normal to pre-leukemic and finally leukemic phenotype, generation of leukemic stem cells (LSC) results in overt malignancy, such is acute myeloid leukemia (AML). Life quality of AML patients is severely impaired, even in “disease-free” state after the treatment. AML chemotherapy and stem cell transplant offers 5-year survival to only 20% of patients above age of sixty, 40% to the rest. Currently, a major clinical factor in AML onset and relapse are ever-present LSC. Mechanisms by which HSC turn into LSC, in their highly regulated environment, are still largely unknown, which is why new knowledge is needed to unveil this troubling issue. With the growing amount of data correlating chronic inflammation and onset of various types of malignancies, the SuccHSC project will explore the role of succinate, one of the major inflammation-induced effector molecules, in LSC formation by epigenetic remodeling of HSC. Chronic inflammation generates various molecules, which can be picked-up by bone marrow HSC. Chronic HSC activation leads to peripheral blood entering, myeloid skewing, self-renewal exaustion and even perhaps leukemia. On mechanistic side, HSC react to inflammatory mediators by elevated glycolysis, reduced oxygen and increased succinate. New succinate molecules can reach nucleus through mito-nuclear communication. Among other modifications, histones were shown to be modified with succinate, but yet with no known role. SuccHSC will explore histone succinylation and its effect on gene expression comparing leukemic and normal human samples biochemically, by ChIP-seq and by RNA-seq. Transgene succinate-dehydrogenase KO mice model, which accumulates succinate, will be used to confirm succinylation role in gene expression regulation and HSC transformation into pre-leukemic cell stage.
Original text from CORDIS.
Participants
- UNIVERSITETET I TROMSOE - NORGES ARKTISKE UNIVERSITET · TromsoCoordinatorNorway
Links
Data: CORDIS, © European Union