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College of Medicine: Department of Biochemistry and Molecular Biology

Brian Koss student highlight

Brian is a Ph.D. student starting his fifth year in the Biochemistry and Molecular Biology Department in the laboratory of Dr. Alan Tackett.

He has a B.A. in Biochemistry and Molecular Biology from Hendrix College.

Research Interest Statement

My doctoral work focuses on the dynamic interplay between the epigenetic and metabolic pathways used by T cells to sense and respond to environmental pressures. Specifically, I focused on the loss of the histone methyltransferase EZH2 (H3K27me3) in CD8+ T cells, which occurs during solid tumor infiltration and renders T cells dysfunctional. My work revealed loss of H3K27me3 leads to mitochondrial dysfunction and metabolic exhaustion, through a Cdkn2a.ARF-mediated, p53-independent mechanism. Reprogramming T cells to express a gain-of-function EZH2 mutant enhanced inhibition of tumor growth in a model of adoptive T cell therapy. My data suggest manipulation of EZH2 in T cells represents a potential strategy to protect tumor-specific T cells, which is currently unaccounted for in the clinical development of EZH2 inhibitors.

Career Goals

Once I am finished with my PhD, I plan to continue my current work and pursue early independence opportunities.

Experiment or Technique You Would Most Like to Do

This changes from time to time. However, I currently enjoy using proteomic approaches to interrogate protein turnover rates at a proteome level. I believe this approach will give us novel insights into how a cell prepares its proteome for rapid adaptation to environmental conditions.

Fun fact

My wife, Cary, and I have two boys, Bennett (5 years) and Parker (3 years).

Publications

  1. Koss, B.; Shields, B. D; Taylor, E. M.; Storey, A. J.; Byrum, S. D.; et. al. Epigenetic control of Cdkn2a.Arf protects tumor-infiltrating lymphocytes from metabolic-exhaustion. Cancer Research, (accepted).
  2. Trentzsch, M.; Nyamugenda, E.; Miles, T. K.; Griffin, H.; Russell, S.; Koss, B.; Cooney, K. A.; Phelan, K. D.; Tackett A. J., Iyer, S.; Boysen, G.; Baldini, G. Delivery of phosphatidylethanolamine blunts stress in hepatoma cells exposed to elevated palmitate by targeting the endoplasmic reticulum. Cell Death Discovery 6:8 (2020).
  3. Taylor, E.; Koss, B.; Davis L. E.; Tackett, A. J. Histone Modifications as Biomarkers for Immunotherapy. Methods in Molecular Biology 2055:213-228 (2019).
  4. Chiang, T.; Koss, B.; Su, L. J.; Washam, C. L.; Byrum, S. D.; Storey, A.; Tackett, A. J. Effect of sulforaphane and 5-aza-2’-deoxycytidine on melanoma cell growth. Medicines 6, 71 (2019).
  5. Lee, T.; Christov, P. P.; Shaw, S.; Tarr, J. C.; Zhao, B.; Veerasamy, N.; Jeon, K. O.; Mills, J. J.; Bian, Z.; Sensintaffar, J. L.; al. Discovery of Potent Myeloid Cell Leukemia-1 (Mcl-1) Inhibitors That Demonstrate in Vivo Activity in Mouse Xenograft Models of Human Cancer. Journal of medicinal chemistry 62, 3971–3988 (2019).
  6. Shields, B. D.; Koss, B.; Taylor, E. M.; Storey, A. J.; West, K. L.; Byrum, S. D.; Mackintosh, S. G.; Edmondson, R.; Mahmoud, F.; Shalin, S. C.; Tackett, A. J. Loss of E-Cadherin Inhibits CD103 Antitumor Activity and Reduces Checkpoint Blockade Responsiveness in Melanoma. Cancer Research 79, 1113–1123 (2019).
  7. Ren, Z.; Ahn, J. H.; Liu, H.; Tsai, Y.-H.; Bhanu, N. V; Koss, B.; Allison, D. F.; Ma, A.; Storey, A. J.; Wang, P. PHF19 promotes multiple myeloma tumorigenicity through PRC2 activation. Blood blood-2019000578 (2019).
  8. Shields, B. D.; Mahmoud, F.; Taylor, E. M.; Byrum, S. D.; Sengupta, D.; Koss, B.; Baldini, G.; Ransom, S.; Cline, K.; Mackintosh, S. G. Indicators of responsiveness to immune checkpoint inhibitors. Scientific Reports 7, 807 (2017).
  9. Lee, T.; Bian, Z.; Zhao, B.; Hogdal, L. J.; Sensintaffar, J. L.; Goodwin, C. M.; Belmar, J.; Shaw, S.; Tarr, J. C.; Veerasamy, N.; Matulis, S. M.; Koss, B.; Fischer, M. A.; Arnold, A. L.; Camper, D. V.; Browning, C. F.; Rossanese, O. W.; Budhraja, A.; Opferman, J.; Boise, L. H.; Savona, M. R.; Letai, A.; Olejniczak, E. T.; Fesik, S. W. Discovery and biological characterization of potent myeloid cell leukemia-1 inhibitors. FEBS Letters 591, 240–251 (2017). 
  10. Koss, B.; Ryan, J.; Budhraja, A.; Szarama, K.; Yang, X.; Bathina, M.; Cardone, M. H.; Nikolovska-Coleska, Z.; Letai, A.; Opferman, J. T. Defining specificity and on-target activity of BH3-mimetics using engineered B-ALL cell lines. Oncotarget 7, (2016).
  11. Haverkamp, J. M.; Smith, A. M.; Weinlich, R.; Dillon, C. P.; Qualls, J. E.; Neale, G.; Koss, B.; Kim, Y.; Bronte, V.; Herold, M. J.; Green, D. R.; Opferman, J. T.; Murray, P. J. Myeloid-derived suppressor activity is mediated by monocytic lineages maintained by continuous inhibition of extrinsic and intrinsic death pathways. Immunity 41, 947–959 (2014).
  12. Koss, B.; Morrison, J.; Perciavalle, R. M.; Singh, H.; Rehg, J. E.; Williams, R. T.; Opferman, J. T. Requirement for antiapoptotic MCL-1 in the survival of BCR-ABL B-lineage acute lymphoblastic leukemia. Blood 122, 1587–1598 (2013).
  13. Tripathi, P.; Koss, B.; Opferman, J. T.; Hildeman, D. A. Mcl-1 antagonizes Bax/Bak to promote effector CD4(+) and CD8(+) T-cell responses. Cell death and differentiation 20, 998–1007 (2013).
  14. Wang, X.; Bathina, M.; Lynch, J.; Koss, B.; Calabrese, C.; Frase, S.; Schuetz, J. D.; Rehg, J. E.; Opferman, J. T. Deletion of MCL-1 causes lethal cardiac failure and mitochondrial dysfunction. Genes and Development 27, 1351–1364 (2013).
  15. Cohen, N. A.; Stewart, M. L.; Gavathiotis, E.; Tepper, J. L.; Bruekner, S. R.; Koss, B.; Opferman, J. T.; Walensky, L. D. A competitive stapled peptide screen identifies a selective small molecule that overcomes MCL-1-dependent leukemia cell survival. Chemistry and Biology 19, 1175–1186 (2012).
  16. Perciavalle, R. M.; Stewart, D. P.; Koss, B.; Lynch, J.; Milasta, S.; Bathina, M.; Temirov, J.; Cleland, M. M.; Pelletier, S.; Schuetz, J. D.; Youle, R. J.; Green, D. R.; Opferman, J. T. Anti-apoptotic MCL-1 localizes to the mitochondrial matrix and couples mitochondrial fusion to respiration. Nature Cell Biology 14, 575–583 (2012).
  17. Stewart, D. P.; Koss, B.; Bathina, M.; Perciavalle, R. M.; Bisanz, K.; Opferman, J. T. Ubiquitin-independent degradation of antiapoptotic MCL-1. Molecular and cellular biology 30, 3099–3110 (2010).

Complete List of Published Work:

https://www.ncbi.nlm.nih.gov/myncbi/1pihpxbtPQJQh/bibliography/public/

Grants

  • 2019-present NIH/NCI F31 predoctoral fellowship. Epigenetic regulation of metabolic stress pathways in melanoma infiltrating lymphocytes (F31CA232464). 7th percentile. $124,851
  • 2019 Department of Defense Horizon Award. Epigenetic regulation of metabolic stress pathways in melanoma infiltrating lymphocytes. Recommended for funding as alternate.
  • 2017-2018 Systems Pharmacology and Toxicology Graduate Fellowship, a T32 program; University of Arkansas for Medical Sciences.

Awards

  • 2020 Sanofi Scholar-in-Training Award. American Association for Cancer Research (AACR), San Diego, CA
  • 2020 Keystone Symposia Scholarship. Emerging Cellular Therapies: Cancer and Beyond. Banff, AB Canada
  • 2019 Cancer Institute Member Spotlight. University of Arkansas for Medical Sciences, Little Rock AR.
  • 2019 Graduate School Outstanding Achievement Award. University of Arkansas for Medical Sciences, Little Rock AR.
  • 2018 Immuno-Oncology Innovation Award, Miltenyi Biotec. Fully paid travel to AACR 2018 and $2500 for research.