Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment for patients with relapsed/refractory leukemia. The therapeutic benefits of allo-HSCT for hematologic malignancies are primarily derived from a graft-versus-leukemia (GvL) effect that is mediated by mature donor T cells present in the bone marrow graft. Unfortunately, the same donor T cells that mediate the beneficial GvL effect can also cause graft-versus-host disease (GvHD), the major life-threatening complication of allo-HSCT. Managing the threat of GvHD while maximizing the beneficial GvL effect would broaden the scope and usefulness of allo-HSCT procedures, CD4+CD25+FOXP3+ regulatory t cells (Tregs) have been shown to prevent GvHD in preclinical studies by suppressing alloreactive donor T cells without sacrificing GvL, thereby providing a promising treatment option. Unfortunately, several limitations have prevented the routine clinical use of Tregs: 1) the low circulating numbers of Tregs in peripheral blood, 2) loss of suppressor activity following in vitro expansion and 3) the lack of Treg-specific surface markers necessary to purify in vitro expanded Tregs. We previously reported that the DNA methyltransferase inhibitor azacitidine (AzaC)-induced Foxp3 expression and increased donor Tregs in vivo, thereby mitigating GvHD without abrogating GvL in a murine allo-HSCT model. Surprisingly, we found that AzaC-mediated suppression of GvHD was independent of Foxp3, the master regulator of Treg function. We identified three candidate genes that are highly upregulated by AzaC in anti-CD3/CD28 bead- and APC-activated CD4+/CD25- T cells and which might be responsible for the suppressor function of AzaC-induced Tregs based on genome-wide RNA profiling analyses. We hypothesize that AzaC will induce similar immunomodulatory effects in human T cells. In this SPORE project we will assess the safety and efficacy of AzaC in patients with AML and MDS undergoing allogeneic stem cell transplant (Aim 1) and will perform mechanistic studies to determine how AzaC and other DNMT1 inhibitors exert their immunomodulatory effects on GvHD and GvL in vitro and in vivo.
(Aim 2).

Public Health Relevance

Although modern therapy for AML and MDS is evolving as our understanding of leukemia genomics and signaling pathways expands, allogeneic stem cell transplant still remains the only curative therapy. The outcomes are limited by morbitity and mortality associated with GvHD and leukemic relpase. Identifying simple, cost effective and non-toxic methods of overcoming these obstacles for success would be transformative resulting in improved patient outcomes.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA171963-02
Application #
8764900
Study Section
Special Emphasis Panel (ZCA1-RPRB-0)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
2
Fiscal Year
2014
Total Cost
$218,262
Indirect Cost
$51,269
Name
Washington University
Department
Type
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Xia, Jun; Miller, Christopher A; Baty, Jack et al. (2018) Somatic mutations and clonal hematopoiesis in congenital neutropenia. Blood 131:408-416
Duncavage, Eric J; Jacoby, Meagan A; Chang, Gue Su et al. (2018) Mutation Clearance after Transplantation for Myelodysplastic Syndrome. N Engl J Med 379:1028-1041
Khoury, Hanna Jean; Langston, Amelia A; Kota, Vamsi K et al. (2018) Ruxolitinib: a steroid sparing agent in chronic graft-versus-host disease. Bone Marrow Transplant 53:826-831
Schroeder, Mark A; Choi, Jaebok; Staser, Karl et al. (2018) The Role of Janus Kinase Signaling in Graft-Versus-Host Disease and Graft Versus Leukemia. Biol Blood Marrow Transplant 24:1125-1134
Perry, Justin S A; Russler-Germain, Emilie V; Zhou, You W et al. (2018) CD36 Mediates Cell-Surface Antigens to Promote Thymic Development of the Regulatory T Cell Receptor Repertoire and Allo-tolerance. Immunity 48:923-936.e4
Wong, Terrence N; Miller, Christopher A; Jotte, Matthew R M et al. (2018) Cellular stressors contribute to the expansion of hematopoietic clones of varying leukemic potential. Nat Commun 9:455
Christopher, Matthew J; Petti, Allegra A; Rettig, Michael P et al. (2018) Immune Escape of Relapsed AML Cells after Allogeneic Transplantation. N Engl J Med 379:2330-2341
Trissal, Maria C; Wong, Terrence N; Yao, Juo-Chin et al. (2018) MIR142 Loss-of-Function Mutations Derepress ASH1L to Increase HOXA Gene Expression and Promote Leukemogenesis. Cancer Res 78:3510-3521
Jacoby, Meagan A; Duncavage, Eric J; Chang, Gue Su et al. (2018) Subclones dominate at MDS progression following allogeneic hematopoietic cell transplant. JCI Insight 3:
Monlish, Darlene A; Bhatt, Sima T; Duncavage, Eric J et al. (2018) Loss of Toll-like receptor 2 results in accelerated leukemogenesis in the NUP98-HOXD13 mouse model of MDS. Blood 131:1032-1035

Showing the most recent 10 out of 64 publications