Epigenetic and regulatory evolution in re-lapsed acute myeloid leukemia
Abstract/Contents
- Abstract
- In patients with acute myeloid leukemia ("AML"), ≥50% of cases patients who achieve a remission following initial therapy will experience disease relapse. Relapsed AML is a poorly understood entity with dismal outcomes and few treatment options. As mechanisms of AML relapse remain poorly understood, we sought to clarify the clonal dynamics of AML relapse using a cohort of previously published genotyped relapse pairs. We analyzed AML relapse cohorts and found that 40% of relapses occur without any change in driver mutations, suggesting that non-genetic mechanisms drive relapse in a large proportion of cases. To explore such mechanisms, we characterized epigenetic pat-terns of disease relapse in matched diagnosis-relapse samples using ATAC-seq. Chromatin accessibility data revealed a relapse-specific chromatin accessibility signature for mutationally stable AML, marked by activation of gene regulatory programs such as DNA damage response and cell cycle pathways, and associated with trans-regulatory factors including FOX and GATA. Analysis of cell subpopulations, including populations enriched for leukemia stem cells ("LSCs"), further revealed LSCs display epigenetic evolutionary patterns at relapse which were distinct from epigenetic evolutionary pat-terns occurring in associated blast populations, highlighting epigenetic heterogeneity during disease evolution. Single-cell ATAC-seq identified a subset of cells present at diagnosis that harbor the relapse-specific chromatin signature, suggesting that AML epigenetic evolution occurs in part by selection of pre-existing cells present at diagnosis. Finally, we used mitochondrial single-cell ATAC-seq (mtscATAC) to map clones from diagnosis into relapse along with their epigenetic features and found that distinct mitochondrially-defined clones exhibit similar chromatin accessibility at relapse, thereby demonstrating convergent epigenetic evolution in relapsed AML. Overall, our findings highlight patterns of non-genetic mechanisms of disease evolution in AML and indicate epigenetic mechanisms of AML relapse in the absence of genetic evolution.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2022; ©2022 |
| Publication date | 2022; 2022 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Nuno, Kevin Andrew |
|---|---|
| Degree supervisor | Majeti, Ravindra, 1972- |
| Thesis advisor | Majeti, Ravindra, 1972- |
| Thesis advisor | Chang, Howard Y. (Howard Yuan-Hao), 1972- |
| Thesis advisor | Gentles, Andrew J |
| Thesis advisor | Mitchell, Beverly S |
| Thesis advisor | Winslow, Monte |
| Degree committee member | Chang, Howard Y. (Howard Yuan-Hao), 1972- |
| Degree committee member | Gentles, Andrew J |
| Degree committee member | Mitchell, Beverly S |
| Degree committee member | Winslow, Monte |
| Associated with | Stanford University, Cancer Biology Program |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Kevin Andrew Nuno. |
|---|---|
| Note | Submitted to the Cancer Biology Program. |
| Thesis | Thesis Ph.D. Stanford University 2022. |
| Location | https://purl.stanford.edu/rj568yd7300 |
Access conditions
- Copyright
- © 2022 by Kevin Andrew Nuno
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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