Cancer Biology Graduate Program, Stanford University School of Medicine, Stanford, United States; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, United States; Cancer Institute, Stanford University School of Medicine, Stanford, United States; Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, United States
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, United States; Cancer Institute, Stanford University School of Medicine, Stanford, United States; Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, United States; University of California Irvine School of Medicine, Irvine, United States
Thomas Koehnke
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, United States; Cancer Institute, Stanford University School of Medicine, Stanford, United States; Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, United States
Department of Pathology, Stanford University, Stanford, United States; Program in Immunology, Stanford University, Stanford, United States
Asiri Ediriwickrema
Cancer Biology Graduate Program, Stanford University School of Medicine, Stanford, United States; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, United States; Cancer Institute, Stanford University School of Medicine, Stanford, United States; Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, United States
M Ryan Corces
Cancer Biology Graduate Program, Stanford University School of Medicine, Stanford, United States; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, United States; Cancer Institute, Stanford University School of Medicine, Stanford, United States; Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, United States; Gladstone Institute of Neurological Disease, San Francisco, United States; Gladstone Institute of Data Science and Biotechnology, San Francisco, United States; Department of Neurology, University of California, San Francisco, San Francisco, United States
Ansuman T Satpathy
Department of Pathology, Stanford University, Stanford, United States; Program in Immunology, Stanford University, Stanford, United States; Parker Institute for Cancer Immunotherapy, Stanford University, Stanford, United States; Gladstone-UCSF Institute of Genomic Immunology, San Francisco, United States
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, United States; Cancer Institute, Stanford University School of Medicine, Stanford, United States; Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, United States
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.
