AGATHOCLEOUS LAB

Research Focus

Metabolites, the small molecules involved in cellular metabolism, regulate cell function. Traditionally, these molecules have been difficult to study, especially within rare cell populations, but new techniques developed in our laboratory now make this possible. Discovering how metabolites regulate stem cell function is essential in order to understand the mechanisms by which diet and the environment can influence tissue regeneration and cancer formation.

We are particularly interested in how metabolites impact the stem cell genome during the life of an organism, and how the metabolism of cancer cells, and normal stem cells that give rise to cancers, compare. We use a combination of cell biology, metabolomics and mouse genetics to tackle these questions. Our fundamental objectives are to discover new roles for metabolites that affect stem cell function, and to discover metabolic vulnerabilities of cancer cells that can be targets for therapy.

Research Projects

Stem Cell Metabolomics

Control of Hematopoietic Stem Cells and Leukemia By Ascorbate

Metabolism of Lymphoid and Myeloid Leukemia

Stem Cell Metabolomics

Are intracellular metabolites limiting for stem cell function and cancer initiation in an organism? This simple question has not been answered because metabolite levels are difficult to measure in purified populations of rare cells in vivo. We developed tools that allow routine metabolomics analysis of rare cells from tissues, including stem cells. We used these tools to show that cell differentiation in the hematopoietic system is accompanied by metabolic differentiation, even for lineally related cells that reside in a similar environment. Almost all metabolites we could detect show cell type-specific patterns of enrichment, and conversely all cell types we analyzed have distinct metabolic signatures. We do not know the reason for almost any of the metabolite patterns we identified, and we are currently investigating some of them in hematopoietic stem cells and other cell types.

Control of Hematopoietic Stem Cells and Leukemia By Ascorbate

We have shown that hematopoietic stem cells (HSCs) in vivo accumulate high levels of ascorbate (Vitamin C), and that ascorbate is limiting for the activity of the alpha-ketoglutarate dependent dioxygenase enzyme Tet2 (Agathocleous et al., 2017). Tet2 modifies methylated cytosines on DNA, and Tet2 loss promotes HSC function and causes myeloid leukemia in mice and humans. We found that systemic or cell autonomous ascorbate depletion augments HSC function. Ascorbate is critical in restraining the expansion of hematopoietic cells that have acquired pre-leukemic mutations, and ascorbate depletion accelerates the progression of myeloid leukemia. Our observations suggest that a diet-derived metabolite alters epigenetic regulation and tumor suppression in stem cells. We are currently investigating how ascorbate depletion impacts the epigenome and genome of HSCs and leukemic cells.

Metabolism of Lymphoid and Myeloid Leukemia 

Cancer metabolism is determined by driver mutations, the environment, and the tissue of origin. Cancers arise from particular cell types within a tissue, and we hypothesize that cancer metabolism is also determined by the metabolism of the stem or progenitor cell of origin. Our previous observations on the cell type specificity of metabolism raise the question of whether leukemias that arise from different cell types are metabolically distinct from each other. We have identified a metabolic pathway that is required in only one hematopoietic cell type, but not others, and in the leukemia that arises from that cell type. We are pursuing these findings to understand the mechanistic connection between cell type and metabolism and to target this pathway therapeutically in leukemia.

About Dr. Agathocleous

Michalis Agathocleous earned his B.A. and Ph.D. degrees from Cambridge University, where he studied embryonic retinal development with Professor Bill Harris. He performed postdoctoral work at Cambridge as a Research Fellow at Gonville and Caius College. He continued his postdoctoral work at CRI with Professor Sean Morrison as a Royal Commission for the Exhibition of 1851 Research Fellow. The postdoctoral work of Dr. Agathocleous led to important discoveries about the relationship between metabolism, stem cells and cancer and how metabolites regulate hematopoietic stem cell function and leukemia.

In 2017, Dr. Agathocleous became a Cancer Prevention and Research Institute of Texas (CPRIT) Scholar and joined the faculty of the Children’s Medical Center Research Institute at UT Southwestern as an assistant professor.

Contact Dr. Agathocleous

Selected Publications

Agathocleous, M., Meecham, C.E., Burgess, R.J., Piskounova, E., Zhao, Z., Crane, G.M., Cowin, B.L., Bruner, E., Murphy, M.M., Chen, W., Spangrude, G.J., Hu, Z., DeBerardinis, R.J., and Morrison, S.J. (2017). Ascorbate regulates haematopoietic stem cell function and leukaemogenesis. Nature 549, 476-481. (PubMed)

Piskounova, E., Agathocleous, M., Murphy, M.M., Hu, Z., Mann, S., Zhao, Z., Leitch, A.M., Johnson, T.M., DeBerardinis, R.J., and Morrison, S.J. (2015). Oxidative stress inhibits distant metastasis by human melanoma cells. Nature 527, 186-191. (PubMed)

Love, N.K., Keshavan, N., Lewis, R., Harris, W.A., and Agathocleous, M. (2014). A nutrient-sensitive restriction point is active during retinal progenitor cell differentiation. Development 141, 697-706. (Pubmed)

Agathocleous, M., Love, N.K., Randlett, O., Harris, J.J., Liu, J., Murray, A.J., and Harris, W.A. (2012). Metabolic differentiation in the embryonic retina. Nat Cell Biol 14, 859-864. (Pubmed)


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Lab News

  • NBC: Can Vitamin C Prevent Leukemia?

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  • The Scientist: Vitamin C Depletion Accelerates Leukemia in Mice

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  • CRI scientists discover vitamin C regulates stem cell function and suppresses leukemia development

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  • CRI Scientists Find Antioxidant Use May Promote Spread of Cancer

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  • See more news articles

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Lab Members

Sojeong Jun

Ph.D. Student

Swetha Mahesula, M.S.

Lab Manager/Research Associate