Convergent epigenetic evolution drives relapse in acute myeloid leukemia

  1. Kevin Nuno
  2. Armon Azizi
  3. Thomas Koehnke
  4. Caleb Lareau
  5. Asiri Ediriwickrema
  6. M Ryan Corces
  7. Ansuman T Satpathy
  8. Ravindra Majeti

  • Curated by eLife

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    eLife assessment

    This important work substantially advances our understanding of how resistant leukemia can arise without changes in mutational patterns by displaying epigenetic changes. The evidence supporting the conclusions is compelling, with rigorous genomic assays done on primary samples. and state-of-the-art microscopy. The work will be of broad interest to hematologists and cancer biologists.

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Abstract

Relapse of acute myeloid leukemia (AML) is highly aggressive and often treatment refractory. We analyzed previously published AML relapse cohorts and found that 40% of relapses occur without changes in driver mutations, suggesting that non-genetic mechanisms drive relapse in a large proportion of cases. We therefore characterized epigenetic patterns of AML relapse using 26 matched diagnosis-relapse samples with ATAC-seq. This analysis identified a relapse-specific chromatin accessibility signature for mutationally stable AML, suggesting that AML undergoes epigenetic evolution at relapse independent of mutational changes. Analysis of leukemia stem cell (LSC) chromatin changes at relapse indicated that this leukemic compartment underwent significantly less epigenetic evolution than non-LSCs, while epigenetic changes in non-LSCs reflected overall evolution of the bulk leukemia. Finally, we used single-cell ATAC-seq paired with mitochondrial sequencing (mtscATAC) to map clones from diagnosis into relapse along with their epigenetic features. We found that distinct mitochondrially-defined clones exhibit more similar chromatin accessibility at relapse relative to diagnosis, demonstrating convergent epigenetic evolution in relapsed AML. These results demonstrate that epigenetic evolution is a feature of relapsed AML and that convergent epigenetic evolution can occur following treatment with induction chemotherapy.

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  1. Version published to 10.7554/elife.93019 on eLife
  2. eLife

    eLife assessment

    This important work substantially advances our understanding of how resistant leukemia can arise without changes in mutational patterns by displaying epigenetic changes. The evidence supporting the conclusions is compelling, with rigorous genomic assays done on primary samples. and state-of-the-art microscopy. The work will be of broad interest to hematologists and cancer biologists.

  3. eLife

    Reviewer #1 (Public Review):

    Analysis of a sizable number of matched primary AML samples from diagnosis and relapse was done with ATAC-seq and showed that epigenetic changes are seen at relapse. Meta-analysis of multiple studies showed that relapse is not associated generally with changes in mutational burden. The authors also performed clonal tracking with mitochondrial clones and show that heterogeneity in clonal expansions is seen in various cases. Overall, these are novel findings with translational relevance.

  4. eLife

    Reviewer #2 (Public Review):

    In the manuscript entitled, "Convergent Epigenetic Evolution Drives Relapse in Acute Myeloid Leukemia", Majeti and colleagues describe patterns of chromatin accessibility alterations at relapse in AML. Through an analysis of publicly available datasets as well as their samples, they show that a subset of AML cases show significant changes in chromatin accessibility despite showing little to no change in clonal composition. Evaluation of predicted changes in gene expression based on chromatin accessibility identifies common differentially expressed pathways at relapse and indicates that blasts are more immature at relapse. Using mitochondrial single-cell ATAC-seq, the authors identify "mitoclones' and observe that mitochondrially-defined clones exhibit more similar chromatin accessibility at relapse relative to diagnosis. Based on these data, the authors conclude that epigenetic evolution is a feature of relapsed AML and that convergent epigenetic evolution can occur following induction chemotherapy.

    The strengths of this study are its novelty in AML and its rigorous use of single-cell ATAC-seq and mitochondrial single-cell ATAC-seq to identify chromatin accessibility patterns in AML blasts at diagnosis and relapse, including in clonally related blasts determined by mitochondrial DNA sequencing. That epigenetic changes contribute to relapse and therapy resistance, or that blasts at relapse are less differentiated are not new ideas, but these studies rigorously demonstrate these concepts in AML patient samples. These insights are important since they have the potential to identify novel targets that can be targeted in combination with induction chemotherapy.

    While these findings advance our understanding of potential mechanisms or disease relapse/therapy resistance in AML, some of the conclusions are less supported due to the lack of more information on clonally unstable cases. Given that 60-70% of AML cases are not clonally stable following chemotherapy, this raises questions regarding the broad applicability of the authors' proposed model. Indeed, it remains unclear why only a subset of AML cases shows stable clonal patterns.

  5. eLife

    Reviewer #3 (Public Review):

    This manuscript reports a detailed genetic and epigenomic analysis of diagnostic and relapsed AML. The study is mostly correlative and some of the initial findings, such as the stability of mutations in epigenetic regulators at diagnosis and relapse and in signaling pathway modulators such as FLT3 and NRAS being lost - not novel.

    The authors show that in a large fraction (approximately half) of the relapsed AMLs they study, there are no alterations in the AML driver mutations. The authors conclude that this indicates that these patients show non-genetic mechanisms of relapse, for which the authors embark on a series of epigenomic experiments to try and pin down the correlative or causative epigenetic mechanisms. In 9 (out of 25) patient samples with stable driver mutations ( i.e. no change in clonality or novel AML driver mutation accumulation) the study shows that there is high epigenetic variability as measured by chromatin accessibility changes and that these changes resemble less differentiated state in the relapsed compared to the diagnostic sample. The manuscript makes some key observations: 1) non-genetic mechanisms are likely to account for relapse in a substantial proportion of patients. 2) some of the clones that emerge following relapse are likely present in prior diagnosis samples indicating that chemotherapy selects for them, 3) Of note, the authors also look at the LSC and non-LSC compartments and show that the LSC compartment is more rigid in terms of epigenetic evolution towards relapse than the non-LSC cells. 4) Using a small number of patients (but justifiable since the assays used are rigorous and demanding) - the authors present the most interesting finding of the study - that epigenetic evolution of relapse in several different AML patients seems to be convergent.
    This is based on the epigenetic similarities in clones (as defined by mitochondrial Atac-seq) between different epigenetic relapsed clones, even though they were distinct at diagnosis. Thus, this study has several important observations. Some of these observations are incremental - it has been shown that epigenetic mechanisms drive relapse in AML but several are not. I think this study - although descriptive and not showing causal relationships - is an important study for advancing our understanding of AML relapse.

  6. Version published to 10.1101/2023.10.10.561642v1 on bioRxiv