Abstract
Given that most bone marrow cells are short-lived, the accumulation of multiple leukemogenic mutations in a single clonal lineage has been difficult to explain. We propose that serial acquisition of mutations occurs in self-renewing hematopoietic stem cells (HSCs). We investigated this model through genomic analysis of HSCs from six patients with de novo acute myeloid leukemia (AML). Using exome sequencing, we identified mutations present in individual AML patients harboring the FLT3-ITD (internal tandem duplication) mutation. We then screened the residual HSCs and detected some of these mutations including mutations in the NPM1, TET2, and SMC1A genes. Finally, through single-cell analysis, we determined that a clonal progression of multiple mutations occurred in the HSCs of some AML patients. These preleukemic HSCs suggest the clonal evolution of AML genomes from founder mutations, revealing a potential mechanism contributing to relapse. Such preleukemic HSCs may constitute a cellular reservoir that should be targeted therapeutically for more durable remissions.
MeSH terms
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Animals
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Cell Cycle Proteins / genetics
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Cell Lineage / genetics
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Cell Proliferation*
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Cell Separation / methods
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Chromosomal Proteins, Non-Histone / genetics
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Clonal Evolution*
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DNA Mutational Analysis
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DNA-Binding Proteins / genetics
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Dioxygenases
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Exome
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Flow Cytometry
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Founder Effect
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Gene Expression Regulation, Leukemic
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Genetic Markers
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Genetic Predisposition to Disease
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Hematopoietic Stem Cell Transplantation
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Hematopoietic Stem Cells / pathology*
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Humans
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Leukemia, Myeloid, Acute / genetics*
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Leukemia, Myeloid, Acute / pathology
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Leukemia, Myeloid, Acute / surgery
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Mice
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Mutation*
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Neoplastic Stem Cells / pathology*
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Neoplastic Stem Cells / transplantation
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Nuclear Proteins / genetics
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Nucleophosmin
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Phenotype
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Preleukemia / genetics*
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Preleukemia / pathology
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Prognosis
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Proto-Oncogene Proteins / genetics
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fms-Like Tyrosine Kinase 3 / genetics
Substances
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Cell Cycle Proteins
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Chromosomal Proteins, Non-Histone
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DNA-Binding Proteins
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Genetic Markers
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NPM1 protein, human
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Npm1 protein, mouse
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Nuclear Proteins
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Proto-Oncogene Proteins
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structural maintenance of chromosome protein 1
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Nucleophosmin
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Dioxygenases
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TET2 protein, human
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FLT3 protein, human
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fms-Like Tyrosine Kinase 3