Mutant H3 histones drive human pre-leukemic hematopoietic stem cell expansion and promote leukemic aggressiveness
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Nature Publishing Group
Abstract
Our ability to manage acute myeloid leukemia (AML) is limited by our incomplete understanding of the epigenetic disruption central to leukemogenesis, including improper histone methylation. Here we examine 16 histone H3 genes in 434 primary AML samples and identify Q69H, A26P, R2Q, R8H and K27M/I mutations (1.6%), with higher incidence in secondary AML (9%). These mutations occur in pre-leukemic hematopoietic stem cells (HSCs) and exist in the major leukemic clones in patients. They increase the frequency of functional HSCs, alter differentiation, and amplify leukemic aggressiveness. These effects are dependent on the specific mutation. H3K27 mutation increases the expression of genes involved in erythrocyte and myeloid differentiation with altered H3K27 tri-methylation and K27 acetylation. The functional impact of histone mutations is independent of RUNX1 mutation, although they at times co-occur. This study establishes that H3 mutations are drivers of human pre-cancerous stem cell expansion and important early events in leukemogenesis. © 2019, The Author(s).
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Animals, Animals, genetically modified, Antineoplastic agents, Base sequence, Bone marrow cells, Cell differentiation, Cell transformation, neoplastic, Dna, Drosophila melanogaster, Epigenomics, Gene expression regulation, leukemic, Hematopoiesis, Hematopoietic stem cells, Histones, Humans, Leukemia, myeloid, acute, Mice, Mutation, Neoplasms, experimental, Cd34 antigen, Cd45ra antigen, Histone h3, Antineoplastic agent, Histone, Cancer, Cell component, Differentiation, Gene, Gene expression, Methylation, Protein, Acute myeloid leukemia, Adolescent, Adult, Aggressiveness, Animal experiment, Animal model, Animal tissue, Article, Cell counting, Cell culture, Cell growth, Cell viability, Child, Chromatin immunoprecipitation, Cohort analysis, Colony formation, Controlled study, Drosophila, Epigenetics, Female, Flow cytometry, Gene frequency, Gene mutation, Genetic transfection, Genetic variability, Hematopoietic stem cell, Human, Human cell, Human tissue, Immunoblotting, Immunofluorescence, Leukemogenesis, Major clinical study, Male, Middle aged, Mouse, Nonhuman, Polymerase chain reaction, Rna sequence, Sanger sequencing, Sequence alignment, Stem cell expansion, Virus load, Whole exome sequencing, Xenotransplantation, Animal, Bone marrow cell, Cell transformation, Drug effect, Experimental neoplasm, Gene expression regulation, Genetics, Metabolism, Nucleotide sequence, Physiology, Transgenic animal