The long-term goal of Project 2 is to define the genomic and transcriptional alterations that contribute to acute myeloid leukemia (AML) relapse after chemotherapy and/or allogeneic hematopoietic stem cell transplantation (alloHSCT). Although standard induction chemotherapy (cytarabine with an anthracycline) is curative for some AML patients, approximately 60-80% will either relapse after achieving a first complete remission, or have disease that is refractory to initial induction chemotherapy. The curative potential of alloHSCT is based on the ability of donor lymphocytes to immunologically control the outgrowth of host residual malignant cells (graft-versus-leukemia [GvL]). However, disease relapse in medullary and/or extramedullary sites remains the most common cause of treatment failure in patients with AML who have had an alloHSCT. The fundamental hypothesis of Project 2 is that events which contribute to relapse and resistance in AML after chemotherapy and allogeneic HSCT are caused by genetic events that can be identified using the discovery platforms established in the Genomics of AML (GAML) PPG.
Specific Aim 1 : We will define the genetic changes that contribute to AML relapse after chemotherapy. We will perform whole genome, whole exome, and RNA sequencing (Core C) on 50 linked trios of normal skin, cfe novo AML and relapsed AML.
Specific Aim 2 : We will define the genetic changes that contribute to AML relapse after alloHSCT. Since relapse of AML following alloHSCT can occur at extramedullary (EM) sites with or without bone marrow (BM) involvement, we will investigate 10 patients with BM relapse only, 10 patients with EM relapse only, and 10 patients with both BM and EM relapse. We will purify AML blasts by sorting CD45''/SSC'"""""""" AML cells from the de novo sample and post-alloHSCT (BM and/or EM) relapsed samples, and perform whole genome, whole exome, and RNA sequencing to identify all relapse-specific mutations.
Specific Aim 3 : We will define the genetic changes that contribute to AML relapse after chemotherapy or alloHSCT in a mouse model of AML. We will use a mouse model of acute promyelocytic leukemia (APL) to generate chemotherapy (cytarabine and daunorubicin) and allogeneic T cell resistant tumor cells in vivo . These chemotherapy and allo-resistant APL cells will then be analyzed by whole exome sequencing (Core C), and mRNA and miRNA expression profiling (Core B) to identify genomic and transcriptional alterations that contribute to relapse after chemotherapy vs. alloHSCT.

Public Health Relevance

Most patients with acute myeloid leukemia (AML) die from progressive disease after relapse. In Project 2 we will use next-generation sequencing approaches (whole genome, exome, and transcriptome sequencing) to define the genetic changes that contribute to AML relapse after chemotherapy and allogeneic hematopoietic stem cell transplantation in both humans and mice.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA101937-11
Application #
8696960
Study Section
Special Emphasis Panel (ZCA1-RPRB-J)
Project Start
Project End
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
11
Fiscal Year
2014
Total Cost
$321,797
Indirect Cost
$101,871
Name
Washington University
Department
Type
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Al-Hussaini, Muneera; Rettig, Michael P; Ritchey, Julie K et al. (2016) Targeting CD123 in acute myeloid leukemia using a T-cell-directed dual-affinity retargeting platform. Blood 127:122-31
Welch, John S; Petti, Allegra A; Miller, Christopher A et al. (2016) TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes. N Engl J Med 375:2023-2036
Wong, Terrence N; Miller, Christopher A; Klco, Jeffery M et al. (2016) Rapid expansion of preexisting nonleukemic hematopoietic clones frequently follows induction therapy for de novo AML. Blood 127:893-7
Griffith, Malachi; Griffith, Obi L; Krysiak, Kilannin et al. (2016) Comprehensive genomic analysis reveals FLT3 activation and a therapeutic strategy for a patient with relapsed adult B-lymphoblastic leukemia. Exp Hematol 44:603-13
Cole, Christopher B; Verdoni, Angela M; Ketkar, Shamika et al. (2016) PML-RARA requires DNA methyltransferase 3A to initiate acute promyelocytic leukemia. J Clin Invest 126:85-98
Churpek, Jane E; Pyrtel, Khateriaa; Kanchi, Krishna-Latha et al. (2015) Genomic analysis of germ line and somatic variants in familial myelodysplasia/acute myeloid leukemia. Blood 126:2484-90
Wong, Terrence N; Ramsingh, Giridharan; Young, Andrew L et al. (2015) Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia. Nature 518:552-5
Engle, E K; Fisher, D A C; Miller, C A et al. (2015) Clonal evolution revealed by whole genome sequencing in a case of primary myelofibrosis transformed to secondary acute myeloid leukemia. Leukemia 29:869-76
Griffith, Malachi; Miller, Christopher A; Griffith, Obi L et al. (2015) Optimizing cancer genome sequencing and analysis. Cell Syst 1:210-223
Lu, Charles; Xie, Mingchao; Wendl, Michael C et al. (2015) Patterns and functional implications of rare germline variants across 12 cancer types. Nat Commun 6:10086

Showing the most recent 10 out of 98 publications