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.
Highlights
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
The well-established role of histone modifications in leukemia led us to examine two cohorts of AML samples in which we identified mutations in histone H3 variants
We observed a higher frequency of H3 mutations in secondary AML (s-AML)
Summary
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. 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. Pre-cancerous expansions of mutated hematopoietic clones occur commonly in myeloid disease, such as AML, secondary AML (s-AML), and myelodysplastic syndrome (MDS), and rarely in healthy individuals These pre-leukemic HSCs represent an intermediate step in leukemogenesis and put individuals at an increased risk for developing de novo or secondary hematological malignancies[3,4,7,8,9,10]. Our results demonstrate a role for oncohistones early in the leukemogenic process and in the expansion of human pre-cancerous stem cells
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