title: Clonal evolution of pre-leukemic hematopoietic stem cells precedes human acute myeloid leukemia.
abstract: Massively parallel DNA sequencing has uncovered recurrent mutations in many human cancers. In acute myeloid leukemia (AML), cancer genome/exome resequencing has identified numerous recurrently mutated genes with an average of 5 mutations in each case of de novo AML. In order for these multiple mutations to accumulate in a single lineage of cells, they are serially acquired in clones of self-renewing hematopoietic stem cells (HSC), termed pre-leukemic HSC. Isolation and characterization of pre-leukemic HSC have shown that their mutations are enriched in genes involved in regulating DNA methylation, chromatin modifications, and the cohesin complex. On the other hand, genes involved in regulating activated signaling are generally absent. Pre-leukemic HSC have been found to persist in clinical remission and may ultimately give rise to relapsed disease through the acquisition of novel mutations. Thus, pre-leukemic HSC may constitute a key cellular reservoir that must be eradicated for long-term cures.
authors.affiliation: Department of Internal Medicine, Division of Hematology, Cancer Institute, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, USA. Electronic address: rmajeti@stanford.edu.
authors.forename: Ravindra
authors.initials: R
authors.lastname: Majeti
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D000097722:Cohesins
chemical_list: D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D004273:DNA, Neoplasm; D000097722:Cohesins
keywords: acute myeloid leukemia; clonal evolution; hematopoietic stem cells (HSC); pre-leukemic HSC