Mark Irvin Manzano, PhD

Research Program: Cancer Biology Faculty Rank: Assistant Professor Campus: University of Arkansas for Medical Sciences College: College of Medicine Department: Microbiology & Immunology

Cancer Research Interest

• Research Keywords: B cell lymphoma, primary effusion lymphoma, tumor virus, genomics
• Research Interest Statement: My lab uses functional genomics to study host-pathogen interactions and biological processes. Functional genomics (in our case, using CRISPR screens) allows for the simultaneous interrogation of the contribution of each gene in the human genome to a particular phenotype. Simply put, this bridges genotype to phenotype on a genome-wide scale in one experiment. We are interested in studying primary effusion lymphoma (PEL), an aggressive B cell cancer caused by the Kaposi’s sarcoma-associated herpesvirus or human herpesvirus 8 (KSHV/HHV8). PEL tumor cells rely on the constitutive expression of virally encoded genes that globally reprogram host gene expression to create a conducive environment optimal for tumor cell proliferation and survival. We previously performed genome-wide CRISPR/Cas9 screens and identified 210 host genes that are required for tumor cell proliferation and survival. Our over-all goal is to understand the functions of these host genes in B cell lymphoma. Using CRISPR/Cas9, CRISPRi and CRISPRa-based synthetic lethality and rescue screens, we aim to identify functional genetic interactions of these host genes. We anticipate that this unbiased approach will uncover novel and underappreciated insights into the biology of these host genes. We will furthermore leverage these host genetic dependencies by testing the efficacy of small molecule inhibitors against PEL in vitro and in vivo. Lastly, we are developing a CRISPR-Cas13 system to screen for coding and non-coding transcripts from KSHV that are essential for tumor cell proliferation and survival. Together, our research program will provide a better understanding of the oncogenic processes driven by the tumor virus KSHV, uncover new biology of host genes, and develop new therapeutics for this aggressive malignancy.

Contact Information

• Email Address: MMANZANO@UAMS.EDU
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Active Grants

• NIH/Nat. Cancer Institute – 1K22CA241355
  “Oncogenic Roles and Therapeutic Potential of MCL1 Addiction in Primary Effusion Lymphoma”
  Principal Investigator
  09/04/20 – 08/31/23

Publications

• Kuehnle N, Osborne SM, Liang Z, [et al., including Manzano M]. CRISPR screens identify novel regulators of cFLIP dependency and ligand-independent, TRAIL-R1-mediated cell death. Cell death and differentiation. 2023. PMID: 36801923. PMCID: PMC10154404.
• Dunham D, Viswanathan P, Gill J, Manzano M. Expression Ratios of the Antiapoptotic BCL2 Family Members Dictate the Selective Addiction of Kaposi's Sarcoma-Associated Herpesvirus-Transformed Primary Effusion Lymphoma Cell Lines to MCL1. Journal of virology. 2022 96(23):e0136022. PMID: 36416587. PMCID: PMC9749474.
• Manzano M, Günther T, Ju H, [et al.]. Kaposi's Sarcoma-Associated Herpesvirus Drives a Super-Enhancer-Mediated Survival Gene Expression Program in Primary Effusion Lymphoma. mBio. 2020 11(4). PMID: 32843547. PMCID: PMC7448273.
• Morrison K, Manzano M, Chung K, [et al.]. The Oncogenic Kaposi's Sarcoma-Associated Herpesvirus Encodes a Mimic of the Tumor-Suppressive miR-15/16 miRNA Family. Cell reports. 2019 29(10):2961-2969.e6. PMID: 31801064. PMCID: PMC6939447.
• Patil A, Manzano M, Gottwein E. Genome-wide CRISPR screens reveal genetic mediators of cereblon modulator toxicity in primary effusion lymphoma. Blood advances. 2019 3(14):2105-2117. PMID: 31300418. PMCID: PMC6650732.
• Manzano M, Patil A, Waldrop A, [et al.]. Gene essentiality landscape and druggable oncogenic dependencies in herpesviral primary effusion lymphoma. Nature communications. 2018 9(1):3263. PMID: 30111820. PMCID: PMC6093911.
• Patil A, Manzano M, Gottwein E. CK1? and IRF4 are essential and independent effectors of immunomodulatory drugs in primary effusion lymphoma. Blood. 2018 132(6):577-586. PMID: 29954751. PMCID: PMC6085990.
• Balasubramanian A, Manzano M, Teramoto T, [et al.]. High-throughput screening for the identification of small-molecule inhibitors of the flaviviral protease. Antiviral research. 2016 134:6-16. PMID: 27539384. PMCID: PMC5065773.