Succinate-induced leukemic stem cell formation via epigenetic remodeling of hematopoietic stem cell
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.