Department of Medical Sciences
Titles and Education
- VMD-University of Pennsylvania, Philadelphia, PA
PhD-University of Pennsylvania, Philadelphia, PA
Rotating Intership-Michigan State University, East Lasing, MI
Medical Oncology Residency-University of Wisconsin-Madison, Madison, WI
It is of critical importance that the rates of hematopoietic stem cell (HSC) differentiation and self-renewal are carefully regulated and kept in balance, because severe disease states arise when this balance is disrupted. Unfortunately, the mechanisms that maintain this balance are poorly understood, and this lack of understanding represents a major roadblock to research progress, while also severely restricting the clinical potential of HSC-based therapeutic interventions. Our group identified PcG protein YY1 as an essential regulator of HSC self-renewal and differentiation in mice. Hematopoietic Stem Cell (HSC) quiescence is regulated by both intrinsic and extrinsic signals. Cell-cycle regulators, transcription factors, as well as epigenetic modifications, have been identified as intrinsic regulators of HSC cell-cycle progression. However, correlations of epigenetic signatures are often not highly instructive, and the mechanistic implication of epigenetic signatures in HSC self-renewal is incompletely understood. We have generated a conditional mouse knockout of YY1 in HSCs and showed that YY1 knockout decreases HSC long-term repopulating activity and ectopic YY1 expression expands HSCs. YY1-deficiency deregulates the genetic network that regulates HSC proliferation and impaired stem cell factor/c-Kit signaling, and interferes with establishment of quiescence in HSCs. These results reveal how a ubiquitously-expressed epigenetic repressor regulates lineage-specific functions and plays a critical role during hematopoiesis in adult mice. Our group currently is focusing on assessing the structure-function relationships in YY1 and dissecting the underlying mechanisms that control chromosome structural change at the Kit locus.
Novel targeted therapy for treating diffuse large B cell lymphoma
My clinical research focused on identifying novel targeted therapy for canine diffuse large B cell lymphoma (DLBCL). Naturally-occurring cancers in pet dogs share many similarities to human cancers including histological appearance, molecular target, tumor genetics, biological behavior and response to therapeutics. Compared to experimental rodents, pet dogs with naturally-occurring cancers provide a more powerful preclinical model for assessing anti-cancer treatment due to larger body weight, more diverse genetic background and are genetically closer to humans than rodents. The lack of conventional therapies with sustainable efficacy for DLBCL in humans and dogs is strong motivation for additional research on novel therapeutic approaches for DLBCL. My studies showed that the STAT3 pathway is upregulated in canine DLBCL and JAK1/2 inhibitors suppress canine lymphoma cell growth. I designed and conducted a phase I clinical trial in canine cancer patients, and defined the maximum tolerated dose and dose-limiting toxicity of a novel targeted drug combination-therapy using a receptor tyrosine kinase inhibitor plus cytotoxic chemotherapy. My findings justify further clinical investigation of the safety and efficacy of JAK1/2 inhibitors in canine DLBCL and suggest new opportunities for novel anticancer therapies in dogs and humans.
Cell & Molecular Biology
Veterinary Medical Oncology
- Lu Z, Hong CC, Kong G, Assumpção ALFV, Ong IM, Bresnick EH, Zhang J, Pan X. Polycomb Group Protein YY1 Is an Essential Regulator of Hematopoietic Stem Cell Quiescence. Cell Rep. 2018 Feb 6;22(6):1545-1559. PubMed PMID: 29425509.
Lu Z, Hong CC, Jark PC, Assumpção ALFV, Bollig N, Kong G, Pan X. JAK1/2 Inhibitors AZD1480 and CYT387 Inhibit Canine B-Cell Lymphoma Growth by Increasing Apoptosis and Disrupting Cell Proliferation. J Vet Intern Med. 2017 Nov;31(6):1804-1815. PubMed PMID: 28960447; PubMed Central PMCID: PMC5697192.
Assumpção ALFV, Jark PC, Hong CC, Lu Z, Ruetten HM, Heaton CM, Pinkerton ME, Pan X. STAT3 Expression and Activity are Up-Regulated in Diffuse Large B Cell Lymphoma of Dogs. J Vet Intern Med. 2018 Jan;32(1):361-369. PubMed PMID: 29119628; PubMed Central PMCID: PMC5787155.
- Assumpção, A., Lu, Z., Marlowe, K., Shaffer, K. and Pan, X., Targeting NEDD8-activating enzyme is a new approach to treat canine diffuse large B cell lymphoma. Vet Comp Oncol, 2018 July DOI: 10.1111/vco.12428
- Pan, X., Papsani, M., Hao, Y., Calamito, M., Wei, F., Quinn, W., Wang, JW., Shi, Y., Allman, D., Cancro, M. and Atchison, M.L., YY1 controls Igk repertoire and B-cell development, and localizes with condensin on the Igk Locus. EMBO J., doi: 10.1038/emboj.2013.66 (2013).
- Pan X, Tsimbas K, Kurzman ID, Vail DM. Safety evaluation of combination CCNU and continuous toceranib phosphate (Palladia(®) ) in tumour-bearing dogs: a phase I dose-finding study. Vet Comp Oncol. 2016 Jun;14(2):202-9. PubMed PMID: 24735385.
- Pan, X., Jones, M., Jiang, J., Yu, D.N., Pear, W., Maillard, I. and Atchison, M.L., Increased Expression of PcG Protein YY1 Negatively Regulates B Cell Development While Allowing Accumulation of Myeloid Cells and LT-HSC Cells. PLoS One. 7(1):e30656 (2012)
- Basu, A., Hodawadekar, S., Andrews, O., Knox, A., Pan, X., Wilkinson, F. and Atchison, M.L., YY1 PcG Function as a Potential Cancer Therapeutic Target. Forum Immunopath. Dis. Ther. 1: 31-50 (2010).
- Srinivasan, L., Pan, X. and Atchison, M.L., Transient requirements of YY1 expression for PcG transcriptional rescue and phenotypic rescue. J. Cell. Biochem. 96:689-699 (2005).