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)
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Special Emphasis Panel (ZCA1-RPRB-0 (M1))
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Washington University
Saint Louis
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White, Brian S; DiPersio, John F (2014) Genomic tools in acute myeloid leukemia: From the bench to the bedside. Cancer 120:1134-44
Mesa, Ruben A; Kiladjian, Jean-Jacques; Verstovsek, Srdan et al. (2014) Comparison of placebo and best available therapy for the treatment of myelofibrosis in the phase 3 COMFORT studies. Haematologica 99:292-8
Hopman, Rusudan K; DiPersio, John F (2014) Advances in stem cell mobilization. Blood Rev 28:31-40
Welch, John S (2014) Mutation position within evolutionary subclonal architecture in AML. Semin Hematol 51:273-81
Ramsingh, Giridharan; Westervelt, Peter; McBride, Ali et al. (2014) Phase I study of cladribine, cytarabine, granulocyte colony stimulating factor (CLAG regimen) and midostaurin and all-trans retinoic acid in relapsed/refractory AML. Int J Hematol 99:272-8
Giralt, Sergio; Costa, Luciano; Schriber, Jeffrey et al. (2014) Optimizing Autologous Stem Cell Mobilization Strategies to Improve Patient Outcomes: Consensus Guidelines and Recommendations. Biol Blood Marrow Transplant 20:295-308
Anthony, Bryan A; Link, Daniel C (2014) Regulation of hematopoietic stem cells by bone marrow stromal cells. Trends Immunol 35:32-7
Welch, John S; Niu, Haixia; Uy, Geoffrey L et al. (2014) A phase I dose escalation study of oral bexarotene in combination with intravenous decitabine in patients with AML. Am J Hematol 89:E103-8
Calvi, Laura M; Link, Daniel C (2014) Cellular complexity of the bone marrow hematopoietic stem cell niche. Calcif Tissue Int 94:112-24
Jacoby, Meagan A; Martin, Michael G; Uy, Geoffrey L et al. (2014) Phase I study of oral clofarabine consolidation in adults aged 60 and older with acute myeloid leukemia. Am J Hematol 89:487-92

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