Abstract

The Washington University SPORE in Leukemia is a highly dynamic translational cancer research program that focuses specifically on leukemias and myelodysplastic syndromes (MDS). We have assembled an outstanding group of investigators with complementary expertise in basic and clinical leukemia research. In this SPORE, we leverage expertise in cancer genomics, immunology, and hematopoiesis to develop innovative translational research in leukemia. Our long term goal is to develop novel biomarkers and treatments for leukemias and MDS and to recruit and promote innovative translational leukemia research. To achieve these goals, the following specific aims are proposed.
Aim 1. To exploit recent advances in cancer genomics to develop novel biomarkers and treatments for leukemias and MDS. Washington University has been at the forefront of genomic studies in AML and MDS. Through sequencing of primary acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) genomes, we identified several novel recurring mutations of genes involved in DNA methylation (DNMT3A and IDH1) and RNA splicing (U2AF1). This basic research has led to the development of the following two translational SPORE projects. Project 1. Molecular determinants of decitabine responsiveness Project 3. Development of RNA splicing modulators for myelodysplastic syndromes and AML.
Aim 2. To leverage local expertise in immunology and hematopoiesis to develop novel treatments for leukemias and myelodvsplastic syndromes. Institutional expertise in basic immunology and hematopoiesis research has led to the development of two innovative translational projects in leukemia. Project 2. Targeting the bone marrow microenvironment in acute lymphocytic leukemia. Project 4. Epigenetic modulation of graft versus host disease and graft versus leukemia.
Aim 3. To enhance the infrastructure that supports translational leukemia research. This SPORE will support the following Shared Research Resources: 1) Core A. Biospecimen Processing;2) Core B. Biostatistics;and 3) Core C. Administration.
Aim 4. To recruit and train new investigators in translational research.
Aim 5. To facilitate inter-SPORE collaboration.

Public Health Relevance

This SPORE will promote translational research in leukemia and myelodysplastic syndromes. The proposed studies will test novel approaches to treat patients with acute myeloid leukemia, acute lymphoid leukemia, and myelodysplastic syndromes.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
1P50CA171963-01A1
Application #
8548461
Study Section
Special Emphasis Panel (ZCA1-RPRB-0 (M1))
Program Officer
Nothwehr, Steven F
Project Start
2013-09-03
Project End
2018-06-30
Budget Start
2013-09-03
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$2,151,000
Indirect Cost
$719,220

  Institution

Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130

  Publications

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
Staser, Karl W; Eades, William; Choi, Jaebok et al. (2018) OMIP-042: 21-color flow cytometry to comprehensively immunophenotype major lymphocyte and myeloid subsets in human peripheral blood. Cytometry A 93:186-189
Warner, Wayne A; Spencer, David H; Trissal, Maria et al. (2018) Expression profiling of snoRNAs in normal hematopoiesis and AML. Blood Adv 2:151-163
Nguyen, Hai Dang; Leong, Wan Yee; Li, Weiling et al. (2018) Spliceosome Mutations Induce R Loop-Associated Sensitivity to ATR Inhibition in Myelodysplastic Syndromes. Cancer Res 78:5363-5374
Cooper, Matthew L; Choi, Jaebok; Staser, Karl et al. (2018) An ""off-the-shelf"" fratricide-resistant CAR-T for the treatment of T cell hematologic malignancies. Leukemia 32:1970-1983
Wang, Tianjiao; Jacoby, Meagan A; Duncavage, Eric J et al. (2018) Exome analysis of treatment-related AML after APL suggests secondary evolution. Br J Haematol :
Bansal, Dhruv; Vij, Kiran; Chang, Gue Su et al. (2018) Lenalidomide results in a durable complete remission in acute myeloid leukemia accompanied by persistence of somatic mutations and a T-cell infiltrate in the bone marrow. Haematologica 103:e270-e273

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