The long term goal of this project is to identify the patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) who are the most likely to respond to decitabine therapy. Decitabine is a hypomethylating agent that has efficacy in both MDS and AML. It can be given as an outpatient, and it is well tolerated in most patients. However, response rates are modest;even with modern aggressive schedules, only 4 5 % of patients achieve a complete response. The molecular basis of decitabine sensitivity and/or resistance is not yet clear.
Specific Aims :
Aim1. Wewilldefinethemolecularsignatureofdecitabineresponders.Wewillprospectivelybank125 properly consented patients treated with the current state-of-the-art decitabine protocol. We will comprehensively define patient-specific molecular signatures through exome sequencing and expression profiling, using both mRNA and miRNA based arrays. We will correlate genotyping and expression results with clinical features, including responsiveness to decitabine therapy. These studies will correlate genomic signatures of DNMT3A, I D H I , IDH2, and TET2 with outcomes. In addition, comprehensive, unbiased analysis will determine whether specific molecular signatures are associated with decitabine responses.
Aim 2. We will determine whether the rate of AML clearance and persistence of AML-associated subclones corresponds tddrug metabolism, molecular, and/or clinical features of AML in each case. We will assess the velocity of patient-specific mutation clearance on day 0, 10, and 28, and the persistence of AML-associated subclones despite blast clearance. W e will correlate this with steiady-state decitabine drug levels, the reduction of methylcytosine in the total marrow sample (a biomarker of effective dosing), and with clinical response rates and event-free survival.

Public Health Relevance

Many patients do not respond to decitabine therapy for AML or MDS. The causes of sensitivity and resistance are unknown. In this study we will optimize a pipeline for comprehensive molecular characterization of patient-specific mutations, expression profiles, and pharmacologic outcomes. We will determine whether molecular signatures predict response or resistance to decitabine.

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
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
Choi, Jaebok; Cooper, Matthew L; Staser, Karl et al. (2018) Baricitinib-induced blockade of interferon gamma receptor and interleukin-6 receptor for the prevention and treatment of graft-versus-host disease. Leukemia 32:2483-2494

Showing the most recent 10 out of 64 publications