Epigenetic Signature of Leukemia Stem Cells Defines Subgroups Associated with Clinical Outcome and Cell of Origin in AML

Abstract

Acute myeloid leukemia (AML) is a hematologic malignancy initiated by leukemia-initiating or leukemia stem cells (LSC) which can differentiate into clonally related leukemic blast cells. This leukemia stem cell model proposes that functional properties of LSC and their blast progeny must be derived by epigenetic differences. Here, we examined genome wide DNA methylation of LSC-enriched populations and blast cells from 15 AML patients, along with 6 well-defined hematopoietic stem and progenitor cell (HSPC) populations from 5 normal controls using Illumina Infinium Human Methylation 450 BeadChip array. Strikingly, LSC-enriched populations exhibited global hypomethylation compared to non-engrafting blast cells, demonstrating that epigenetic change could drive the functional difference of LSC and their blast progeny. We defined an LSC epigenetic signature by integrating DNA methylation and gene expression analysis. The signature independently predicted overall survival of patients in both DNA methylation and gene expression data sets. Finally, we identified that LSC-enriched populations formed two major clusters when compared to normal HSPC: a granulocyte-macrophage progenitor (GMP)-like and a lymphoid-primed multipotential progenitor (L-MPP)-like subgroup that may reflect the cell of origin for these cases. These subgroups showed strong association with cytogenetic abnormalities and molecular mutations associated with the cell of origin. These results provide the first evidence for epigenetic variation between LSC and their blast progeny that are prognostic, and for epigenetically defined cell of origin of AML LSC. DisclosuresNo relevant conflicts of interest to declare.