TY - JOUR
T1 - Selective targeting of histone modification fails to prevent graft versus host disease after hematopoietic cell transplantation
AU - Choi, Jaebok
AU - Alahmari, Bader
AU - Cooper, Matthew
AU - Ziga, Edward
AU - Ritchey, Julie
AU - DiPersio, John F.
N1 - Publisher Copyright:
© 2018 Alahmari et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2018/11
Y1 - 2018/11
N2 - Allogeneic hematopoietic cell transplantation is often complicated by graft versus host disease (GvHD), primarily mediated through allo-reactive donor T cells in the donor stem cell graft. Enhancer of Zeste Homolog 2 (EZH2), a histone-lysine N-methyltransferase and a component of the Polycomb Repressive Complex 2, has been shown to play a role in GvHD pathology. Although not yet clear, one proposed mechanism is through selective tri-methylation of lysine 27 in histone 3 (H3K27me3) that marks the promoter region of multiple pro-apoptotic genes, leading to repression of these genes in allo-reactive T cells. We found that selective pharmacologic inhibition of H3K27me3 with EPZ6438 or GSK126 did not prevent murine GvHD. This suggests the GvHD mitigating properties of DZNep are independent from H3K27me3 inhibition. Furthermore, while pharmacologic inhibition of EZH2 by DZNep has been shown to be effective in abrogating mouse GvHD, we found that DZNep was not effective in preventing GvHD in a human T cell xenograft mouse model. Although EZH2 is an attractive target to harness donor allo-reactive T cells in the post-transplant setting to modulate GvHD and the anti-leukemia effect, our results suggest that more selective and effective ways to inhibit EZH2 in human T cells are required.
AB - Allogeneic hematopoietic cell transplantation is often complicated by graft versus host disease (GvHD), primarily mediated through allo-reactive donor T cells in the donor stem cell graft. Enhancer of Zeste Homolog 2 (EZH2), a histone-lysine N-methyltransferase and a component of the Polycomb Repressive Complex 2, has been shown to play a role in GvHD pathology. Although not yet clear, one proposed mechanism is through selective tri-methylation of lysine 27 in histone 3 (H3K27me3) that marks the promoter region of multiple pro-apoptotic genes, leading to repression of these genes in allo-reactive T cells. We found that selective pharmacologic inhibition of H3K27me3 with EPZ6438 or GSK126 did not prevent murine GvHD. This suggests the GvHD mitigating properties of DZNep are independent from H3K27me3 inhibition. Furthermore, while pharmacologic inhibition of EZH2 by DZNep has been shown to be effective in abrogating mouse GvHD, we found that DZNep was not effective in preventing GvHD in a human T cell xenograft mouse model. Although EZH2 is an attractive target to harness donor allo-reactive T cells in the post-transplant setting to modulate GvHD and the anti-leukemia effect, our results suggest that more selective and effective ways to inhibit EZH2 in human T cells are required.
UR - http://www.scopus.com/inward/record.url?scp=85056740222&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0207609
DO - 10.1371/journal.pone.0207609
M3 - Article
C2 - 30452487
AN - SCOPUS:85056740222
SN - 1932-6203
VL - 13
JO - PloS one
JF - PloS one
IS - 11
M1 - e0207609
ER -