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Comprehensive deciphering of the genetic, epigenetic and immunogenetic mechanisms of post-allogeneic transplant relapse in acute myeloid leukemia
Project Title: Comprehensive deciphering of the genetic, epigenetic and immunogenetic mechanisms of post-allogeneic transplant relapse in acute myeloid leukemia
Project Duration: 2023-2025
MOHCCN Consortium: Princess Margaret Cancer Consortium
Investigators: Dr. Igor Novitzky Basso, Dr. Dennis Kim; Dr. Zhaolei Zhang
Partners:
- Princess Margaret Cancer Centre
- OICR
Aim/goals:
Whole genome sequencing (WGS) to provide a full mutational landscape, chromosomal structural variants and clonal evolution in relapsed AML patients after HCT
Use of single cell sequencing to define the clonal architecture of post-HCT relapsed AML at single cell resolution and reveal clonal relationships of AML driver mutations at relapse post-HCT.
Whole transcriptomics and genome wide methylation array to evaluate epigenetic and gene expression profiles in immune regulatory genes and other potential biological pathways as targets
Summary:
It has become apparent that myeloid disorders may undergo changes in clonal structure with acquisition or loss of specific mutations, which may occur in response to pre-transplant chemotherapy (i.e. post-diagnosis) or due to immune pressures from the graft-versus-leukemia effect. A clone may be selected out that has a competitive advantage vs. the normal bone marrow cells which then grows unimpeded and ultimately leads to a full blown clinical relapse. In order to dissect clonal evolution in the post transplant setting it is necessary to study the genetic and epigenetic changes in the leukemic clone. Whole genome sequencing (WGS) allows the full assessment of shifts in the genetic landscape of the relapsing clone, and is advantageous over targeted sequencing which may miss potentially important regulatory regions which are not part of the targeted panel. Whole transcriptome (WT) analysis can provide more detailed information on the genes being expressed, by analyzing both coding and multiple forms of noncoding RNA for a comprehensive view of the transcriptome. WT analysis is complementary to WGS and will reveal potential transcriptome changes in leukemic cells which promote immune evasion, which is a common pathway for relapse post allogeneic stem cell transplant. Thus, this study will capture both known and novel features of the genomic and transcriptomic landscape in patients relapsed post allogeneic stem cell transplant.