Stephen M. Sykes, Ph.D.

Associate Professor
Pediatrics
Hematology

Cancer Biology Program
Molecular Cell Biology Program
Biochemistry, Biophysics, and Structural Biology Program

  • 314-454-6018

  • s.m.sykes@wustl.edu

  • Identify and define those molecular features that drive leukemogenesis and then use that information to develop rational therapeutic strategies for improving outcomes in acute leukemia

Research Abstract:

The Role and Regulation of Metabolic Processes in Hematopoiesis and Leukemia

The principal objective of my laboratory is to identify and define those molecular features that drive leukemogenesis and then use that information to develop rational therapeutic strategies for improving outcomes in acute leukemia.

The lab is most interested in molecular pathways that: 1) are differentially regulated between malignant cells and their healthy counterparts; 2) promote resistance to conventional chemotherapies; and 3) support leukemia stem cell biology. Based on these criteria, lab projects fall within one or more of the following three themes:

1. Intracellular Metabolism: Due to the distinct metabolic dependencies of many human cancers, cellular metabolism has emerged as both a major point of investigation and therapeutic targeting in cancer biology. Based our recently published studies, we are currently investigating the following metabolic processes in acute leukemia: Amino acid and nucleotide metabolism, cellular energetics and polyunsaturated fatty acid metabolism.

2. Unfolded Protein Response: The unfolded protein response or UPR is a signal transduction network that helps cells negotiate multiple cellular stresses such as endoplasmic reticulum (ER) stress, metabolic stress, responses to chemotherapy and more. We and others have shown that certain sub-types of acute leukemia are highly dependent upon UPR signaling. To extend these findings, we are currently focused on determining the upstream and downstream UPR components that support acute leukemia as well as assessing the therapeutic efficacy of targeting these pathways in leukemia.

3. Regulation of Mitochondrial Biology: Mitochondria represent the engines of the cell and are often commandeered for the purpose of maximal energy output in many forms of human cancer, including acute leukemia. While these organelles are often strictly thought of as energy generators, mitochondria are increasingly being recognized as multi-faceted systems that require an ensemble of regulators to maintain proper function. Our aim is to elucidate these regulators and in particular those that are hijacked in human cancer.

Importantly, because leukemia arises from mutated hematopoietic stem and progenitor cells (HSPCs) I am also very interested in assessing how these pathways influence healthy HSPC biology.

Selected Publications:

Maifrede S, Le BV, Nieborowska-Skorska M, Golovine K, Sullivan-Reed K, Dunuwille WMB, Nacson J, Hulse M, Keith K, Madzo J, Caruso LB, Gazze Z, Lian Z, Padella A, Chitrala KN, Bartholdy BA, Matlawska-Wasowska K, Di Marcantonio D, Simonetti G, Greiner G, Sykes SM, Valent P, Paietta EM, Tallman MS, Fernandez HF, Litzow MR, Minden MD, Huang J, Martinelli G, Vassiliou GS, Tempera I, Piwocka K, Johnson N, Challen GA, Skorski T. TET2 and DNMT3A Mutations Exert Divergent Effects on DNA Repair and Sensitivity of Leukemia Cells to PARP Inhibitors. Cancer Res. 2021. PMID:34215619

Di Marcantonio D, Martinez E, Kanefsky JS, Huhn JM, Gabbasov R, Gupta A, Krais JJ, Peri S, Tan Y, Skorski T, Dorrance A, Garzon R, Goldman AR, Tang HY, Johnson N, Sykes SM. ATF3 coordinates serine and nucleotide metabolism to drive cell cycle progression in acute myeloid leukemia. Mol Cell. 2021;81(13):2752-2764.e6. PMID:34081901

Stanek TJ, Gennaro VJ, Tracewell MA, Di Marcantonio D, Pauley KL, Butt S, McNair C, Wang F, Kossenkov AV, Knudsen KE, Butt T, Sykes SM, McMahon SB. The SAGA complex regulates early steps in transcription via its deubiquitylase module subunit USP22. EMBO J. 2021;e102509. PMID:34155658

Nacson J, Di Marcantonio D, Wang Y, Bernhardy AJ, Clausen E, Hua X, Cai KQ, Martinez E, Feng W, Callén E, Wu W, Gupta GP, Testa JR, Nussenzweig A, Sykes SM, Johnson N. BRCA1 Mutational Complementation Induces Synthetic Viability. Mol Cell. 2020;78(5):951-959.e6. PMCID:PMC7418109 PMID:32359443

Peshkova IO, Aghayev T, Fatkhullina AR, Makhov P, Titerina EK, Eguchi S, Tan YF, Kossenkov AV, Khoreva MV, Gankovskaya LV, Sykes SM, Koltsova EK. IL-27 receptor-regulated stress myelopoiesis drives abdominal aortic aneurysm development. Nat Commun. 2019;10(1):5046. PMCID:PMC6834661 PMID:31695038

Di Marcantonio D, Sykes SM. Flow Cytometric Analysis of Mitochondrial Reactive Oxygen Species in Murine Hematopoietic Stem and Progenitor Cells and MLL-AF9 Driven Leukemia. J Vis Exp. 2019;(151). PMCID:PMC7239511 PMID:31545325

Sykes SM. NCAM1 supports therapy resistance and LSC function in AML. Blood. 2019;133(21):2247-2248. PMID:31122937

Last Updated: 10/18/2021 5:41:28 PM

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