Xianzheng Zhou, Ph.D., M.D.
Associate Professor of Pediatrics, Microbiology and Immunology, and Cell Biology and Anatomy
Director, Translational Tumor Immunology Research
Division of Hematology, Oncology and Stem Cell Transplantation
Department of Pediatrics
Vosburgh Pavilion, room 318a
Valhalla, NY 10595
My research interest is focused on human cancer immunotherapy in the context of hematopoietic stem cell transplantation. My translational research is to develop novel cell therapy strategies that will be used to enhance anti-tumor immunity after transplant. My basic research is to explore the role of microRNAs in hematopoiesis.
1) Sleeping Beauty-mediated T-cell therapy for human cancer. My laboratory was the first to demonstrate that the non-viral Sleeping Beauty (SB) transposon system was able to mediate stable gene transfer and expression in human primary peripheral blood lymphocytes (PBL). We also showed that the SB system can redirect both CD4 and CD8 T-cells derived from PBL and umbilical cord blood (UCB) to kill CD19+ leukemia and lymphoma via anti-CD19 single chain chimeric antigen receptors (CARs). In addition, CAR+ T cells with both 4-1BB and CD28 signaling domains were more potent effectors than CAR+ T cells with 4-1BB or CD28 signaling alone. My laboratory also demonstrated that piggyBac and Tol2 transposons preferred integrations near the transcription start sites, CpG islands and DNase I hypersensitive sites, whereas SB integrations were fairly random across the human T-cell genome. We also found unanticipated high copy numbers of SB transposase random integration in human T cells, although stable integration of functional transposase was a rare event and had no apparent genotoxicity.
Currently, we are interested in moving SB engineered T cells into a Phase I clinical trial in patients with relapsed leukemia, lymphoma, sarcoma, brain tumor or other types of cancer. We are also interested in developing new CARs to target sarcoma and brain tumor in pediatric patients.
2) Sleeping Beauty-mediated genetic modification of hematopoietic stem/progenitor cells (HSPCs). My laboratory was one of the first two groups to demonstrate the superiority of hyperactive SB transposase (SB100X) to piggyBac and the first generation SB transposase (SB11) in mediating stable gene transfer and expression in cord blood-derived CD34+ HSPCs. In vitro differentiation assays further demonstrated that SB100X-transfected CD34+ HSPCs can develop into DsRed+ human T, B, natural killer (NK) cells and myeloid cells. Transplantation of SB100X-transfected HSPCs in NOD-scid IL2cnull (NSG) mice demonstrated high levels of DsRed+ human cell engraftment, and multi lineage development. Our results support the continuing development of SB100X-based gene transfer into human HSPCs as a modality for gene therapy.
Currently, we are interested in testing our hypothesis that SB100X modified HSPCs can reconstitute long-term anti-tumor specific NK and T cells and prevent leukemia relapse. Both in vitro NK- and T-cell developmental models and humanized mice will be used to test cell differentiation, phenotype, lineage-specific transgene expression, engraftment and reactivity against human leukemia.
My laboratory has recently established humanized mouse models (NSG, NOG and BLT) to test HSPC engraftment, NK- and T-cell development, and primary AML engraftment. These models will have wide applications in studying hematopoiesis, lymphocyte development, iPS cells, and chemotherapeutic drugs on primary human tumors.
3) MicroRNAs in hematopoiesis. Regulation of monocyte differentiation into dendritic cells (DCs) by microRNAs (miRNAs) remains largely unknown. We have identified differential expression of 27 miRNAs during human monocyte differentiation into immature and mature DCs. Among these miRNAs, we found that the altered miR-221 and miR-155 expression correlated with p27kip1 accumulation in DCs. We also found that Kip1 ubiquitination-promoting complex 1 (KPC1), suppressor of cytokine signaling 1 (SOCS-1), and CD115 (M-CSFR) were functional targets of miR-155. Furthermore, we demonstrated that miR-155 indirectly regulated p27kip1 protein levels by targeting KPC1. Thus, our study has uncovered the new regulatory role of miR-221 and miR-155 in human DC apoptosis and IL-12p70 production.
We are currently testing the role of other differentially expressed miRNAs during monocyte differentiation into DCs using silencing or overexpression as well as knockout and humanized mice. We are also interested in identifying novel miRNAs and other non-coding RNAs in human DCs. Our ultimate goal is to identify the targets of these miRNAs in regulating DC differentiation and functions, and to integrate novel regulatory circuits with well-known signaling and transcriptional networks. In addition, we are interested in exploring these miRNAs to modulate DC functions in anti-tumor or transplant tolerance in vivo. We are also interested in uncovering the miRNA regulatory network in human T-cell development to understand how regulatory circuits are wired in immune cells.
Post Graduate Studies:
Massachusetts Institute of Technology (Herman Eisen laboratory), Cambridge, MA,
Johns Hopkins University (Drew Pardoll and Elizabeth Jaffee laboratories), Baltimore, MD
Graduate Degree: Ph.D., M.D.
Graduate Degree Institution: Karolinska Institute (Mikael Jondal and Hans-Gustaf Ljunggren laboratories), Stockholm, Sweden
Undergraduate Institution: Jiangxi Medical College of Nanchang University, Nanchang, China, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
Huang X, Wilber A, Bao L, Dong T, Tolar J, Orchard P, Levine BL, June CH, McIvor S, Blazar
BR, and Zhou X. Stable gene transfer and expression in human primary T cells by the
Sleeping Beauty transposon system. Blood. 107:483-491, 2006.
Huang X, Guo H, Kang JT, Choi S, Zhou TC, Tammana S, Milone MC, Levine BL, Tolar J, June CH, McIvor RS, Wagner JE, Blazar BR, and Zhou X. Sleeping Beauty transposon mediated engineering of human primary T cells for therapy of CD19+ lymphoid malignancies. Mol. Ther. 16:580-589, 2008.
Huang X, Wilber AC, McIvor RS, and Zhou X. DNA transposons for modification of human primary T lymphocytes. Meth. Mol. Biol. 506:115-126, 2009.
Bao H, Guo H, Huang X, Tammana S, Wong M, McIvor RS, and Zhou X. High titer lentiviral vectors stimulate fetal calf serum specific human CD4 T-cell responses: implications and solutions in human gene therapy. Gene Ther. 16:788-795, 2009.
Xue X, Huang X, Johnson SE, Mates L, Ma L, Zsuzsanna I, Ivics Z, LeBien T, Wagner JE, and
Zhou X. Stable gene transfer and expression in cord blood-derived CD34 hematopoietic
stem and progenitor cells by a hyperactive Sleeping Beauty transposon system. Blood. 114:1319-1330, 2009.
Tammana S, Huang X, Wong M, Milone MC, Ma L, Levine BL, June CH, Wagner JE, Blazar BR, and Zhou X. 4-1BB and CD28 signaling plays a synergistic role in redirecting umbilical cord blood T cells against B-cell malignancies. Hum. Gene Ther. 21:75-86, 2010.
Huang X, Guo H, Tammana S, Jung YC, Mellgren E, Bassi P, Cao Q, Tu ZJ, Kim YC, Ekker SC, Wu X, Wang SM and Zhou X. Gene transfer efficiency and genome-wide integration profiling of Sleeping Beauty, Tol2 and piggyBac transposons in human primary T cells. Mol. Ther. 18:1803-1813, 2010.
Huang X, Haley K, Wong M, Guo H, Lu C, Wilber AW, and Zhou X. Unexpectedly high copy number of random integration but low frequency of persistent expression of the Sleeping Beauty transposase following trans deliver in primary human T cells. Hum. Gene Ther. 21:1577-1590, 2010.
Chen S, Bohrer LR, Rai AN, Pan Y, Gan L, Zhou X, Bagchi A, Simon JA, and Huang H. Cyclin-dependent kinases regulate epigenetic gene silencing via phosphorylation of EZH2. Nat. Cell Biol. 12:1108-1114, 2010.
Lu C, Huang X, Zhang X, Roensch K, Cao Q, Nakayama K, Blazar BR, Zeng Y, and Zhou X. MiR-221 and miR-155 regulate human dendritic cell development, apoptosis and IL-12 production through targeting of p27kip1, KPC1 and SOCS-1. Blood. 117:4293-4303, 2011.
Flyan RP, Zacharias J, Zhou X, Cannon ML, and Philpott NJ. Non-integrating lentiviral vectors for specific killing of Epstein Barr virus nuclear antigen 1-positive B cell lymphoma cells. J. Gene Med. 13:487-96, 2011.
Page updated: September 21, 2012