Congratulations to Dr. Grover Miller, Professor of Biochemistry and Molecular Biology, on his appointment to the Xenobiotic and Nutrient Disposition and Action (XNDA) Study Section in the National Institutes of Health’s Center for Scientific Review. Dr. Miller will serve a four-year term on the panel, whose members are selected for their excellence and achievement in their scientific discipline. At UAMS, Dr. Miller and his team develop and apply new and powerful strategies to better assess drug liabilities that cause significant adverse drug events including cardio- and hepato-toxicity.
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
- 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).
- 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).
- Taylor, E.; Koss, B.; Davis L. E.; Tackett, A. J. Histone Modifications as Biomarkers for Immunotherapy. Methods in Molecular Biology 2055:213-228 (2019).
- 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).
- 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).
- 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).
- 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).
- 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).
- 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).
- 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).
- 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).
- 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).
- 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).
- 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).
- 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).
- 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).
- 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.
Alumnus Highlight: Michael Guderyon
Michael Guderyon graduated from UAMS in may 2015 with an M.S. in Biochemistry and Molecular Biology. His advisor was Dr. Kevin Raney. After graduating, Mike went to UT Health San Antonio where he received a Ph.D. in Integrated Biomedical Sciences/ Biology of Aging Track. Mike is currently a Process Development Scientist I at SanBio. In addition, he’s in the Airforce Reserves and is an entrepreneur.
Description of Current Job
Combines extensive knowledge of biotechnology and bio-manufacturing to manufacture mesenchymal stem cell products and monitor existing processes and products for quality and efficiency. Problem-solves and conceptualizes solutions for producing large scale stem cell products and standardizes protocols.
- Works hand and hand with Quality Control to develop and qualify potency assays for cell-based products
- Design and execute experiments in support of process optimization of cell-based products and process improvement
- Leads statistical analyses of completed projects in collaboration with assay development and manufacturing teams
- Develops and implements processes to scale up manufacturing and automation of cell-based products
- Draft and author study protocols, feasibility, comparability, and qualification reports as source documents for regulatory filing support
Important Aspect of the Biochemistry and Molecular Biology Program
I was surrounded by excellent mentors at all levels which prepared me for the road ahead.
Something Notable about Time as a Graduate Student
Once during my studies, I was purifying a protein for future use and while formulating the final protein product, I accidentally threw away the entire protein. I am sure my colleagues and mentors sensed my embarrassment and were very supportive moving forward. I distinctly remember my mentor cracking a smile and saying, “always secure the ‘gold’ first”.
Fun Fact
I plan to earn an MBA in the future.
On the cover
Congratulations to postdoctoral fellow Maroof Zafar and his co-authors, Lindsey Hazeslip, Zain Chauhan, and Alicia Byrd. Cover art by Lindsey Hazeslip for their recent article on regulation of expression by non-canonical G-quadruplexes was selected for the cover of the July 2020 issue of Biochemistry.
June publications
Wongsurawat T, Jenjaroenpun P, De Loose A, Alkam D, Ussery DW, Nookaew I, Leung YK, Ho SM, Day JD, Rodriguez A.
Acta Neuropathol Commun. 2020
The Expression of Human DNA Helicase B Is Affected by G-Quadruplexes in the Promoter.
Zafar MK, Hazeslip L, Chauhan MZ, Byrd AK.
Biochemistry. 2020
Findings on DNA Damage Repair Published by UAMS Cancer Researcher
LITTLE ROCK — A research team led by cancer researcher Justin Leung, Ph.D., at the University of Arkansas for Medical Sciences (UAMS) has uncovered the role of the protein RNF168 in DNA damage repair and shown how mutations of the protein affect people with a rare genetic condition.
The study titled “Histone H2A variants alpha1-extension helix directs RNF168-mediated ubiquitination” was published in the May 18 issue of the open-access journal Nature Communications.
“Every day our cells are subjected to environmental sources of DNA damage, such as ultraviolet radiation and toxic chemical exposure. If left unrepaired, these damages can accumulate, leaving mutations in our DNA and ultimately cause cells to become cancerous,” said Leung, assistant professor in the UAMS College of Medicine Department of Radiation Oncology.
In most cases, this damage is detected and repaired by a tightly regulated method involving many proteins. To develop better cancer therapies, researchers such as Leung strive to understand the regulation of DNA damage and repair by sensitizing cells to radiation therapy and chemotherapy drugs that target DNA.
“Our lab studies the repair of double stranded breaks, where both strands of DNA are broken apart completely. When a double strand break occurs, a cascade of protein activity is set off to try to resolve the damage,” Leung said.
Mutations in one of these proteins, RNF168, have been found in patients with RIDDLE syndrome, a rare genetic disorder that increases a person’s predisposition to blood cancer and is characterized by several attributes:
- Susceptibility to DNA damaging agents
- Immunodeficiency, or failure of the immune system to protect the body from infection
- Developmental abnormalities
- Learning disabilities
RNF168 adds a small signaling molecule called ubiquitin onto a subunit of chromatin, where we store our genetic information. The ubiquitin signal brings repair proteins to DNA double strand breaks. However, exactly how RNF168 recognizes the specific target remains unclear.
Using molecular and structural analysis methods, Leung’s team uncovered crucial components of RNF168 and chromatin required for the implementation of repair pathways in response to DNA damage. Their findings suggest that a recognition between RNF168 and chromatin is required to activate the downstream DNA repair processes.
“RNF168 is a central DNA damage response protein. Understanding the precise mechanisms by which it activates its targets is essential for understanding how the DNA damage response goes awry. Our results help demystify the role of RNF168 in proper DNA damage repair and understand the implications of RNF168 mutations such as those seen in RIDDLE syndrome,” Leung said.
UAMS authors for this study included Jessica Kelliher, B.S., research assistant, and Kirk West, Ph.D., postdoctoral fellow.
Alan Diekman receives Master Teacher Award from the College of Medicine
Alan Diekman, Ph.D., was honored as the 2020 Master Teacher in recognition of his work with first-year medical students. When College of Medicine students are asked about their best teachers, Diekman’s name comes up often. As director of the Molecules to Cells course, Diekman teaches first-year students and works with other faculty to ensure the students gain a firm grasp of biochemistry, cell biology and genetics – including complex concepts that many medical students nationwide struggle to grasp.
“Most importantly, he has convinced students that understanding molecular and cellular mechanisms is an important part of their medical training,” Department of Physiology and Biophysics Chair Michael Jennings, Ph.D., wrote in a letter of support for Diekman, who has served on the faculty since 2002.
“The word ‘outstanding’ may underestimate the quality of Dr. Diekman’s teaching effort, ability and outcomes,” Biochemistry and Molecular Biology Chair Kevin Raney, Ph.D., wrote in his nomination letter. “He is a superb communicator who treats students respectfully, while maintaining high expectations. Dr. Diekman also sets high standards for his colleagues, thereby improving the quality of teaching of those around him.”
James Graham, M.D., executive associate dean for academic affairs in the college, also wrote in support, noting strong performance by UAMS students in areas of the notoriously difficult United States Medical Licensing Exam Step 1 that are covered in Diekman’s course, as well as improved overall performance on the exam in recent years. Diekman has been instrumental in major curriculum revisions that change how first- and second-year medical students prepare for their clinically focused training.
“I am very honored by this recognition from my colleagues, and I thank them for their past support,” said Diekman. “The privilege of educating our medical students in the complex disciplines of biochemistry, cell biology and genetics is both challenging and fulfilling. My goal is to provide our students with a firm foundation in these disciplines, not just for their sake, but also for that of their future patients.”
May publications
Genome Maintenance by DNA Helicase B.
Hazeslip L, Zafar MK, Chauhan MZ, Byrd AK.
Genes (Basel). 2020
Selective Survival of Sim1/MC4R Neurons in Diet-Induced Obesity.
Nyamugenda E, Griffin H, Russell S, Cooney KA, Kowalczyk NS, Islam I, Phelan KD, Baldini G.
iScience. 2020
Dual mechanisms suppress meloxicam bioactivation relative to sudoxicam.
Barnette DA, Schleiff MA, Osborn LR, Flynn N, Matlock M, Swamidass SJ, Miller GP.
Toxicology. 2020
Drug Metab Rev. 2020
2020 Graduates
The UAMS Graduate School held a virtual hooding ceremony which you can read more about here. The Biochemistry and Molecular Biology Department graduated three students last year. Tresor Mukiza, Ph.D. is now a postdoctoral fellow in Joseph Opferman’s lab at St. Jude Children’s Research Hospital. Tresor’s mentor at UAMS was Wayne Wahls. Eugene Nyamugenda, Ph.D. is now a postdoctoral fellow in Ravi Allada’s lab at Northwestern University in the Department of Neurobiology. Eugene’s mentor at UAMS was Giulia Baldini. Bradley Shields, M.D., Ph.D. is beginning a residence in dermatology at Intermountain Medical Center and the University of Pittsburgh Medical Center. Bradley’s mentor at UAMS was Alan Tackett.
Recognize this researcher?
Alan Tackett, a professor in the Department of Biochemistry and Molecular Biology, was featured in a story on KARK this morning about clinical trials at UAMS.