The long term goal of the """"""""Genomics of AML"""""""" PPG is to define the genetic and epigenetic changes responsible for the development of acute myeloid leukemia. We intend to identify somatic mutations that are responsible for the initiation and progression of disease (Projects 1, 2, and 4), and the genetic and epigenetic changes associated with relapse and chemotherapeutic resistance (Project 3). We also intend to identify mechanisms leading to increased AML susceptibility in patients with bone marrow failure syndromes (Project 5), and in patients who have received alkylator therapy (Project 6). To accomplish these aims, we have developed an infrastructure that utilizes array-based whole genome screens to identify genes for resequencing. Pathologic material and clinical data from AML patients is collected in Core A, and patient samples are banked and subjected to genomic screens in Core B. A set of 94 fully annotated """"""""discovery set"""""""" AML samples will be assessed with array-based expression profiling, and will be tested for deletions, amplifications, and uniparental disomy with high-resolution, array-based comparative genomic hybridization and SNP genotyping. Similar studies will be performed with samples obtained at relapse, and compared with samples collected at presentation (Project 3). The output of these genomic screens will be analyzed using a variety of novel approaches (Project 2 and Core C) to identify good candidate genes for resequencing in Core D. When genetic changes that are predicted to alter gene function are identified, germline samples derived from the same patients will be resequenced to determine whether the change is somatic. The frequency of mutations will be further assessed in an additional 94 carefully annotated samples obtained from CALGB. All potentially relevant mutations will be assessed for impact on clinical outcomes and gene expression patterns (Project 2 and Core C). To discover mutations that are 'invisible'to these genomic screens, we will also sequence the entire genomes of the AML cells and skin cells from at least five individuals with FAB M1 AML (Project 1). Mutations defined by this discovery pipeline will be selected for biologic validation in the laboratories of the investigators heading Projects 2-6. Using the information gained from these studies, we intend to create molecular diagnostic tools for disease stratification, and we will identify candidate genes for targeted therapeutic approaches.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA101937-06
Application #
7617677
Study Section
Special Emphasis Panel (ZCA1-GRB-S (J1))
Program Officer
Li, Jerry
Project Start
2003-09-19
Project End
2013-03-31
Budget Start
2009-04-01
Budget End
2010-03-31
Support Year
6
Fiscal Year
2009
Total Cost
$2,775,922
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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
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
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:
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
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
Xia, Jun; Miller, Christopher A; Baty, Jack et al. (2018) Somatic mutations and clonal hematopoiesis in congenital neutropenia. Blood 131:408-416
Fisher, D A C; Malkova, O; Engle, E K et al. (2017) Mass cytometry analysis reveals hyperactive NF Kappa B signaling in myelofibrosis and secondary acute myeloid leukemia. Leukemia 31:1962-1974
Shirai, Cara Lunn; White, Brian S; Tripathi, Manorama et al. (2017) Mutant U2AF1-expressing cells are sensitive to pharmacological modulation of the spliceosome. Nat Commun 8:14060

Showing the most recent 10 out of 122 publications