In the era of personalized medicine, we are developing targeted drug combinations for acute myeloid leukemia patients harboring mutations in the H3K4 methyltransferase, MLL (myeloid/lymphoid or mixed lineage leukemia) and the receptor tyrosine kinase FLT3 (FMS-like tyrosine kinase 3).  Preclinical studies utilize a mouse model of acute myeloid leukemia that harbors these two genetic mutations.  We are targeting the downstream effects of both mutations by testing the efficacy of epigenetic modifiers as well as tyrosine kinase inhibitors in drug trials.  We hope to find a combinatorial effect that gives MLL-PTD; FLT3-ITD pts a potentially better therapeutic outcome. Future experiments will address epigenetic changes that occur in response to the drugs with the goal of finding yet more therapeutic targets to help these patients survive longer and eventually be cured of cancer.

Additional areas of research in AML include study of the role of the Axl/Gas6 pathway in the pathogenesis of acute myeloid leukemia (AML).  The Axl/Gas6 pathway is a receptor tyrosine kinase (RTK) known to be involved in a variety of biological functions.  As it was previously published, the Axl/Gas6 pathway is crucial for signaling of another RTK c-Kit, which is highly homologous to RTK FLT3.  As FLT3 is the most well-known prognostic marker for AML, my work has been to test the hypothesis that the Axl/Gas6 pathway may contribute to AML through regulating FLT3 and its biological functions.  Current data has demonstrated that the Axl/Gas6 pathway promotes the growth and survival of leukemic cells and blocks myeloid differentiation.  Furthermore, the Axl/Gas6 pathway is crucial for FLT3 signaling.  Ongoing and future study is to test whether inhibiting the Axl/Gas6 pathway can suppress the occurrence of AML in vivo in mouse leukemia model.

NK Cell Biology:

Research efforts are directed to define the molecular mechanisms regulating the immunoregulatory and cytotoxicity functions of Natural Killer cells and their subsets.  To achieve this goal we are currently dissecting the activatory and inhibitory pathways that regulate Natural killer (NK) cell activity.  In particular, we’ve discovered that the inositol-phosphatase SHIP-1 and the PP2A inhibitor SET are, respectively, a negative and a positive regulator of Interferon gamma production which is induced in NK cells by different monokines. We also have evidences that SET regulates NK cell cytotoxicity by effecting expression of granules components like the Granzyme B. In addition, we also investigated the role of anti-inflammatory cytokines TGF-β in regulating Fc Receptor Functions. We reported that the anti-inflammatory cytokine TGF-β utilizes SMAD3 to inhibit CD16-mediated IFN-γ production, antibody dependent cytotoxicity, Granzyme B and Perforin expression in NK cells. Based on these findings we are also investigating the role of microRNAs (miRs) in the regulation of NK cell activation and/or development.  The final goal of my studies is the identification of activatory and inhibitory molecules which can be used to enhance NK cell anti-tumor activity.

EBV associated disease:

EBV associated post-transplant lymphoproliferative disorder (PTLD) is a common and often fatal malignancy in organ transplant patients.  The incidence of PTLD has been shown to be directly related to a low frequency of EBV-specific cytotoxic T lymphocytes (CTLs) in patients receiving immunosuppressive therapy to prevent organ rejection.  Using a chimeric mouse-human model of human PTLD and subsequently in PTLD patients, we have identified that the expression an EBV lytic gene, BZLF1, plays an important role in controlling the development of PTLD.  We hypothesize that at least one component of the increased incidence of PTLD in this patient population is a cellular immune deficiency against EBV lytic and latent antigens.  A corollary to this hypothesis is that vaccine-enhanced, EBV-specific immunity will restore the protection from this malignancy.  We recently reported a novel strategy for vaccination against the EBV-associated PTLD using a chimeric rAdF35/BZLF1 viral vector or a highly purified EBV BZLF1 protein.  Approximately 75% of normal human donor cells show a moderate to strong immune responses to rAdF35/BZLF1 viral vector stimulation assayed by an IFN- ELISpot. Moreover, rAdF35BZLF1 viral vector transduced dendritic cell vaccination greatly improve survival rate in a Hu-PBL-SCID animal model. We have cloned the lytic EBV BZLF1 protein into a prokaryotic vector expression cassette name pET26b+ system, expressed in E. Coli BL26 cells. From this system, large quantities of highly purified and endotoxin-free BZLF1 protein (>95% by SDS-PAGE) have been obtained by ion exchange and subsequent size column chromatography.  We’ve shown that the highly purified BZLF1-loaded human antigen presenting cells (APCs) can promote the expansion of the EBV BZLF1 specific memory CD8+ CTLs in vitro.  We are currently evaluating the efficacy of highly purified BZLF1 protein-mediated vaccination in a chimeric mouse-human model of human PTLD. 

The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) 460 W. 10th Avenue, Columbus, OH 43210 Phone: 1-800-293-5066 | Email: