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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-0)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Saint Louis
United States
Zip Code
Ghobadi, Armin; Choi, Jaebok; Fiala, Mark A et al. (2016) Phase I study of azacitidine following donor lymphocyte infusion for relapsed acute myeloid leukemia post allogeneic stem cell transplantation. Leuk Res 49:1-6
Al-Hussaini, Muneera; Rettig, Michael P; Ritchey, Julie K et al. (2016) Targeting CD123 in acute myeloid leukemia using a T-cell-directed dual-affinity retargeting platform. Blood 127:122-31
Welch, John S; Petti, Allegra A; Miller, Christopher A et al. (2016) TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes. N Engl J Med 375:2023-2036
Rashidi, Armin; Ebadi, Maryam; Colditz, Graham A et al. (2016) Outcomes of Allogeneic Stem Cell Transplantation in Elderly Patients with Acute Myeloid Leukemia: A Systematic Review and Meta-analysis. Biol Blood Marrow Transplant 22:651-7
Fehniger, Todd A; Cooper, Megan A (2016) Harnessing NK Cell Memory for Cancer Immunotherapy. Trends Immunol 37:877-888
Wong, Terrence N; Miller, Christopher A; Klco, Jeffery M et al. (2016) Rapid expansion of preexisting nonleukemic hematopoietic clones frequently follows induction therapy for de novo AML. Blood 127:893-7
Rashidi, Armin; Walter, Roland B; Tallman, Martin S et al. (2016) Maintenance therapy in acute myeloid leukemia: an evidence-based review of randomized trials. Blood 128:763-73
Shirai, Cara Lunn; Ley, James N; White, Brian S et al. (2015) Mutant U2AF1 Expression Alters Hematopoiesis and Pre-mRNA Splicing In Vivo. Cancer Cell 27:631-43
Wong, Terrence N; Ramsingh, Giridharan; Young, Andrew L et al. (2015) Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia. Nature 518:552-5
Uy, Geoffrey L; Hsu, Yen-Michael S; Schmidt, Amy P et al. (2015) Targeting bone marrow lymphoid niches in acute lymphoblastic leukemia. Leuk Res 39:1437-42

Showing the most recent 10 out of 32 publications