Jill de Jong, M.D., Ph.D.
My laboratory studies the genes that regulate normal hematopoietic stem cell (HSC) function in the bone marrow and after hematopoietic transplantation, and the mechanisms by which those genes contribute to the development of leukemia or lymphoma when their expression is dysregulated.
Currently the lab is focused on three main research projects:
1.) Genetic Screen for Regulators of Hematopoietic Stem Cell Engraftment
We are using the zebrafish as a unique animal model system to perform an unbiased in vivo genetic screen for regulators of HSC function in the hopes of identifying new pathways important for HSC engraftment. The zebrafish provides a number of advantages, including small size, high fecundity, rapid maturation and external fertilization, making the zebrafish amenable to genetic screens and other studies that would be prohibitively expensive or impossible in the mouse. Capitalizing on these advantages of the zebrafish, our goal is to characterize the genes identified in the screen, validate their function in mammalian cells, and ultimately apply what we discover to the treatment of human blood diseases.
2.) Characterization of Major Histocompatibility Complex (MHC) Genes in the Zebrafish
Major Histocompatibility Complex (MHC) genes play a central role in the host animal recognizing a transplanted tissue as either foreign or self. Immunologic matching of the Class I and Class II MHC genes in mammals involves typing donors and recipients at a single chromosomal locus, but in the zebrafish the MHC genes appear to be scattered across several chromosomal loci. Functionally, very little is known about the zebrafish MHC genes, and this lack of knowledge has hindered transplantation experiments.
We have cloned most of the putative zebrafish MHC genes into expression vectors and are developing transgenic zebrafish lines for tumor transplantation experiments to test which genes are important for the rejection of transplanted tissues. A related project also studies graft vs. host disease in zebrafish after transplantation of immunologically mismatched hematopoietic stem cells.
3.) Examining the Function of Histone Deacetylase 1 (HDAC1) in Hematopoietic Stem Cells
Gene regulation by chromatin modification is critical for normal cellular differentiation, while dysregulation of these mechanisms can lead to cancer. Histone deactelylases (HDACs) modify the structure of chromatin by removing acetyl groups, thereby inhibiting the transcription of adjacent genes. When HDAC activity is aberrantly increased, as observed in many types of cancer including leukemia and lymphoma, the gene expression profile of a cell is altered, resulting in malignant transformation. This project focuses on HDAC1 and its role in the function of HSCs and leukemia cells. Preliminary work has identified HDAC1 as playing a role in the emergence of HSCs during early zebrafish development and in their marrow during recovery from radiation injury. We are employing chromatin immunoprecipitation assays to identify genetic targets of HDAC1 in zebrafish leukemias, and hematopoietic transplantation assays to verify the effects of HDAC1 on HSC function. By characterizing HDAC1 in normal HSCs, insight will be gained into the mechanism by which HDACs contribute to leukemia development.
de Jong JL, Burns CE, Chen AT, Pugach E, Mayhall EA, Smith AC, Feldman HA, Zhou Y, Zon LI. Characterization of immune-matched hematopoietic transplantation in zebrafish. Blood. 2011 Apr 21;117(16):4234-42. Epub 2011 Feb 23. PMID: 21346254
de Jong JL, Davidson AJ, Wang Y, Palis J, Opara P, Pugach E, Daley GQ, Zon LI. Interaction of retinoic acid and scl controls primitive blood development. Blood. 2010 Jul 15;116(2):201-9. Epub 2010 Apr 21. PMID: 20410509
Paik EJ, de Jong JL, Pugach E, Opara P, Zon LI. A chemical genetic screen in zebrafish for pathways interacting with cdx4 in primitive hematopoiesis. Zebrafish. 2010 Mar;7(1):61-8. PMID: 20415644.
Smith AC, Raimondi AR, Salthouse CD, Ignatius MS, Blackburn JS, Mizgirev IV, Storer NY, de Jong JL, Chen AT, Zhou Y, Revskoy S, Zon LI, Langenau DM. High-throughput cell transplantation establishes that tumor-initiating cells are abundant in zebrafish T-cell acute lymphoblastic leukemia. Blood. 2010 Apr 22;115(16):3296-303. Epub 2010 Jan 7. PMID: 20056790
de Jong JL, Zon LI. Use of the zebrafish system to study primitive and definitive hematopoiesis. Annu Rev Genet. 2005;39:481-501. PMID: 16285869