The goal of Core C is to provide high-throughput production and analysis of AML genomic and epigenomic sequence data for all four projects in this PPG. This includes sequencing, somatic and germline variant detection and validation, and integration of many data types. This will be achieved by generating high-quality DNA and RNA sequencing data and analyzing it using cutting-edge algorithms and techniques.
Specific Aim /Core Service 1: (Sequence Production) Sequencing of samples in Core C will take place using the Illumina HiSeqX, 4000, and NovaSeq platforms. The data produced in Core C will be comprehensive: whole genome, exome, and capture validation for DNA, as well as error-corrected sequencing, single-cell RNA-seq, total and small RNA-seq, whole genome bisulfite sequencing, and other custom epigenetic analyses. These data will be processed through state-of-the-art genomic pipelines to produce primary results like sequence alignments and variant calls.
Specific Aim /Core Service 2: (Bioinformatic Analysis) These pipelines provide a starting point for the detailed, novel, and iterative analyses which will take place in Core C and are foundational for each project. Project 1 will require integrative analysis of genomic and epigenomic (transcriptome, scRNA-Seq, WGBS) data to better define the events that drive initiation, progression, and relapse in samples with and without DNMT3A mutations. In Project 2, we will leverage our experience in immunogenomics to define minor histocompatibility antigens that mediate allo-transplant response, and characterize the genetic and epigenetic changes that drive relapse in a mouse model of transplantation. In Projects 3 and 4, we will utilize enhanced WGS, error-corrected sequencing, bulk RNA-seq, scRNA-seq, and phased-read data to define the mechanisms that drive subclonal expansion and progression from MDS to sAML (Project 3), or the specific effects of TP53 mutations on the development of aneuploid AML (Project 4). Answering the questions outlined in these projects requires deep integrative analysis that goes far beyond the simple mutation counting that was a hallmark of previous genomic studies. This requires common infrastructure, comprehensive databases, and extensive expertise that will be provided by tight integration between project leadership and the scientists in Core C.

Public Health Relevance

The Genomics of AML PPG is focused on sequencing the DNA and RNA of AML samples, so that we can find all of the changes that contribute to its development and progression. Core C is responsible for generating and analyzing that sequence data for all projects. The core will use a variety of computer programs and statistical approaches to define key mutations and their consequences, and generate new hypotheses about this deadly disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA101937-17
Application #
10067521
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Jhappan, Chamelli
Project Start
Project End
Budget Start
2020-12-01
Budget End
2021-11-30
Support Year
17
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Washington University
Department
Type
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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
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
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

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