Preleukemic mutations in human acute myeloid leukemia affect epigenetic regulators and persist in remission

Significance A growing body of evidence has determined that somatic mutations in acute myeloid leukemia (AML) accumulate in self-renewing hematopoietic stem cells (HSCs). Thus, at the time of diagnosis, AML patients harbor preleukemic HSCs containing some, but not all, of the mutations in the downstream leukemia. Despite these findings, common patterns of preleukemic clonal evolution have not been determined, nor has the response of preleukemic HSCs to standard therapy been identified. This report addresses both of these questions determining that there are common patterns of preleukemic clonal evolution in AML, and that these preleukemic HSCs often survive standard induction chemotherapy. This study is of interest to the AML field, and broadly in cancer genomics as the principle that stem cells acquire initial cancer-initiating mutations is likely to extend beyond AML. Cancer is widely characterized by the sequential acquisition of genetic lesions in a single lineage of cells. Our previous studies have shown that, in acute myeloid leukemia (AML), mutation acquisition occurs in functionally normal hematopoietic stem cells (HSCs). These preleukemic HSCs harbor some, but not all, of the mutations found in the leukemic cells. We report here the identification of patterns of mutation acquisition in human AML. Our findings support a model in which mutations in “landscaping” genes, involved in global chromatin changes such as DNA methylation, histone modification, and chromatin looping, occur early in the evolution of AML, whereas mutations in “proliferative” genes occur late. Additionally, we analyze the persistence of preleukemic mutations in patients in remission and find CD34+ progenitor cells and various mature cells that harbor preleukemic mutations. These findings indicate that preleukemic HSCs can survive induction chemotherapy, identifying these cells as a reservoir for the reevolution of relapsed disease. Finally, through the study of several cases of relapsed AML, we demonstrate various evolutionary patterns for the generation of relapsed disease and show that some of these patterns are consistent with involvement of preleukemic HSCs. These findings provide key insights into the monitoring of minimal residual disease and the identification of therapeutic targets in human AML.