MICHALIS AGATHOCLEOUS LABORATORY

Research Focus

We are interested in the relationship between metabolism and cell type. We focus on the metabolism of hematopoietic stem cells (HSCs) and their progeny including cells of the myeloid and T cell lineages. To assess cell-type specific metabolism, we have developed techniques to measure metabolites in stem cells and other rare cells isolated from tissues (Nature 549:476, Cell Metab. 33:1777). We aim to understand how metabolism affects hematopoiesis, leukemia development, and the host’s response to infection.

Image: Ascorbate crystals | Credit: Gwyneth Thurgood, Wellcome Trust Collection

Research Projects

Stem Cell Metabolism

Metabolism and infection

Metabolism of Leukemia Cells

Stem Cell Metabolism

How do metabolic pathways operate in stem cells? We have shown that in the hematopoietic system cell differentiation is accompanied by metabolic differentiation. Each hematopoietic cell type has a distinct metabolic signature. Almost all metabolites show cell type-specific enrichment patterns, mostly for unknown reasons. We are interested in understanding why different cell types have different kinds of metabolism and in uncovering novel roles for metabolites in hematopoietic stem cells and other hematopoietic cell types.

Metabolism and infection

We are interested in understanding the metabolism of myelopoiesis. In infections, myeloid cells produced from HSCs and myeloid progenitors can fight pathogens but may also damage host tissues. We are investigating the impact of hematopoietic and myeloid cell metabolism on the host response to infection.

Metabolism of Leukemia Cells

Cancer cell metabolism is determined by driver mutations, the environment, and the tissue of origin. We have shown that the requirement of leukemia cells for pyruvate oxidation is determined by the metabolism of the progenitor cell of origin. Pyruvate oxidation is required in double positive thymocytes and in T cell acute lymphoblastic leukemia cells, but not in HSCs, myeloid progenitors, other hematopoietic cells, or myeloid leukemia cells. We are working to understand the cell type specificity of central carbon metabolism. More broadly, we aim to uncover leukemia-specific metabolic requirements.

About Dr. Agathocleous

Michalis Agathocleous , stem cell metabolomics

Contact Dr. Agathocleous

Dr. Michalis Agathocleous earned his B.A. and Ph.D. degrees at the University of Cambridge, where he studied embryonic retinal development with Dr. Bill Harris. He was a Research Fellow at Gonville and Caius College, University of Cambridge where he worked on the metabolism of embryonic retinal stem and progenitor cells. He was then an 1851 Research Fellow with Dr. Sean Morrison at CRI, where he worked on the metabolism of hematopoietic stem cells and leukemia cells.

He joined the Children’s Medical Center Research Institute at UT Southwestern as an assistant professor in 2017. Dr. Agathocleous is a Cancer Prevention and Research Institute of Texas Scholar (2017), a recipient of the Alex’s Lemonade Stand Foundation ‘A’ Award (2018) and an American Society of Hematology Scholar (2020).

Selected Publications

Jun, S., Mahesula, S., Mathews, T.P., Martin-Sandoval, M.S., Zhao, Z., Piskounova, E., and Agathocleous, M. (2021). The requirement for pyruvate dehydrogenase in leukemogenesis depends on cell lineage. Cell Metab. 33, 1777-1792. (PubMed)

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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