Immunology Faculty Member - Leonard Zon, MD

Leonard Zon, MD

Boston Children's Hospital / HHMI
Karp Research Building, 5th Floor, Room 5211
1 Blackfan Circle
Boston, MA 02115
Tel: 617-919-2069
Fax: 617-730-0222

The Zon Lab has had a long-standing interest in hematopoiesis and cancer biology and uses the zebrafish as a model system for our research. We have examined how stem cells are born during embryogenesis, how they migrate, and how the niche supports blood stem cells in adulthood. Our work has defined signaling pathways and transcriptional mechanisms that operate in hematopoietic cells to drive self-renewal, differentiation, or migration. We also study melanoma, particularly focusing on transcriptional mechanisms that either initiate tumors or cause them to spread. We have examined cell fate decisions that are driving melanoma formation, including reprogramming events that re-initiate the neural crest program. More recently, we have found that T cells and myeloid cells infiltrate the zebrafish melanomas, and this allows us to use confocal microscopy to examine the process of cell migration, live in the tumors. Using ATAC seq as a method to find open chromatin, we have defined enhancers that are operative in CD8 positive T cells, and have developed transgenic fish with these enhancers. We can watch live the CD8-positive T cells arrive at the border of the tumor and exhaust. Remarkably, there are subsets of these T cells that appear to move slowly in the tumors, apparently interacting with dendritic cells. We have transgenic lines to visualize the macrophages and dendritic populations. Given that we have developed tissue-specific CRISPR technology for the zebrafish, it will be possible to undertake genetic screens to better understand the process of CD8 cell migration, myeloid engagement, and tumor-specific responses. Based on some recent work, we will inactivate epigenetic regulators in the tumor and examine responses of T cell migration. We are attempting to make mammalian PD-1 and PD-L1 transgenic fish to examine responses to checkpoint blockade. We have undertaken a chemical genetic approach to attempt to drive CD8 cells into tumors, done by directly injecting small molecules into the tumor and watching the T cells enter without exhaustion. As many of the mechanisms we have found in the zebrafish are also conserved in the mammal, we will extend our observations and test if these migratory processes are present in human tumor primagrafts and xenografts.

Last Update: 2/3/2020


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