Innovative research in the laboratory of Jaebok Choi, PhD, focuses on optimizing allogeneic hematopoietic stem cell transplantation (allo-HSCT) for the treatment of hematopoietic malignancies. Specifically, researchers are working to prevent and/or treat graft-versus-host disease (GvHD) while enhancing beneficial graft-versus-leukemia effect (GvL).
Allo-HSCT remains the most effective treatment for patients with hematologic malignancies, as the therapeutic benefit of allo-HSCT is primarily derived from donor T cell-mediated GvL. However, allo-HSCT also carries the risk that the donor T cells in the donor graft will become overzealous and begin attacking not only the leukemia but also the patient’s skin, intestines and liver, resulting in GvHD, the most significant barrier to success for allo-HSCT.
Because of a strong association between the two donor T cell-mediated immune responses, specifically limiting GvHD while enhancing GvL remains the goal of allo-HSCT. Several groups, including ours, have proposed therapeutic strategies to reduce GvHD while enhancing GvL in animal models and human patients. However, the mechanisms by which allogeneic donor T cells differentially modulate GvHD and GvL remain largely unknown. This gap in our mechanistic understanding hinders our ability to specifically prevent and treat GvHD while enhancing GvL.
We hypothesize that the genes we identify as being differentially associated with donor T cells that infiltrate tumors versus GvHD organs will be critical targets for the prevention of GvHD while enhancing GvL. To this end, we performed an unbiased genome-wide CRISPR/Cas9 library screen as seen above.
As a result, we have, for the first time, identified 487 novel GvHD-associated genes that could potentially serve as molecular targets in GvHD and GvL, as the guide RNAs for these genes were enriched only in tumor nodules but not in any GvHD target organs. We found five sets of genes that are involved in known pathways are most significantly enriched in these 487 genes. All of these five pathways are closely linked to the RELN-RAP1-FGFR3 axis. Thus, we currently are investigating if genetic/pharmacologic inhibition of the RELN-RAP1-FGFR3 axis results in the prevention of GvHD and enhancement of GvL in our mouse models of GvHD/GvL.
Additional research in the lab involves interferon gamma receptor (IFNGR), interleukin-6 receptor (IL6R) and downstream JAK-STAT. The goals of this project are to elucidate the mechanisms by which IFNGR/IL6R-JAK-STAT signaling in both donor and recipient cells influences GvHD/GvL and then develop novel therapeutic strategies to optimally modulate GvHD and GvL. Managing the threat of GvHD while maintaining or enhancing GvL would broaden the scope and benefit of allo-HSCT.