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Mutated H3 Histones Drive Human Pre-Leukemic Hematopoietic Stem Cell Expansion And Promote Leukemic Aggressiveness.

ABSTRACT: Data Access Committee EGAC00001001054

PROVIDER: EGAC00001001054 | EGA |

REPOSITORIES: EGA

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Mutant H3 histones drive human pre-leukemic hematopoietic stem cell expansion and promote leukemic aggressiveness.

Project description: Not available

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Mutated H3 Histones Drive Human Pre-Leukemic Hematopoietic Stem Cell Expansion And Promote Leukemic Aggressiveness

Project description:Leukemogenesis is a stepwise progression from mutated, pre-neoplastic hematopoietic stem cells (HSCs) to full-blown leukemia. Our ability to prevent or treat de novo and secondary acute myeloid leukemia (AML) is limited by our incomplete understanding of the epigenetic disruption that is central to this process, including improper histone methylation. We performed a comprehensive analysis of 16 histone H3 genes in 434 primary acute myeloid leukemia (AML) samples and identified mutations in adult and pediatric cases (1.6%), with a higher incidence in secondary AML (s-AML) (9%). These included four novel amino acid substitutions (Q69H, A26P, R2Q and R8H) as well as K27M and K27I in H3.1 and H3.3 genes. These mutations are important early events in leukemogenesis as they were observed in pre-leukemic HSCs in two cases and were in the major clones in every sample. Consistent with a role in pre-leukemic HSC clonal expansion, the mutant histones increased functional human HSC frequency and altered differentiation along the erythroid and myeloid lineages, with activity dependent on the specific mutation (K27M, K27I and Q69H). In established human leukemia, the K27M/I mutant histones amplified leukemic aggressiveness, with increased proliferation, expansion of leukemic progenitor and blast cells, and superior competitiveness in vivo. This was associated with increased expression in genes involved in erythrocyte and myeloid differentiation, correlated with a corresponding decrease in histone H3 K27 tri-methylation and increase in K27 acetylation. While histone mutations can co-occur with alterations in RUNX1, we observed that the functional impact of histone mutations is independent of RUNX1 mutations. Taken together, these data establish the involvement of H3 mutations as early drivers of pre-leukemic HSC expansion and leukemogenesis.

2019-04-05 | GSE122273 | GEO

Mutated H3 Histones Drive Human Pre-Leukemic Hematopoietic Stem Cell Expansion And Promote Leukemic Aggressiveness

Project description:Leukemogenesis is a stepwise progression from mutated, pre-neoplastic hematopoietic stem cells (HSCs) to full-blown leukemia. Our ability to prevent or treat acute myeloid leukemia (AML) is limited by our incomplete understanding of the epigenetic disruption that is central to this process, including improper histone methylation. Comprehensive analysis of 16 histone H3 genes in 434 primary AML samples identified Q69H, A26P, R2Q, R8H and K27M/I mutations (1.6%), and a higher incidence in secondary AML (s-AML) (9%). We establish that these mutations are important early events in leukemogenesis. They occur in pre-leukemic HSCs, increase the frequency of functional human HSCs, and alter differentiation. The mutations are present in the major leukemic clones in primary samples, and the mutant histones amplify leukemic aggressiveness with increased proliferation, expansion of leukemic progenitor and blast cells, and superior competitiveness in vivo. These effects are dependent on the specific mutation. Genome-wide analysis of K27 mutants revealed increased expression of genes involved in erythrocyte and myeloid differentiation with a corresponding decrease in histone H3 K27 tri-methylation and increase in K27 acetylation. The functional impact of histone mutations is independent of RUNX1 mutations, although they can co-occur. These data establish the involvement of H3 mutations as initial drivers of pre-cancerous stem cell expansion and leukemogenesis.

| EGAS00001003288 | EGA

Mutated H3 Histones Drive Human Pre-Leukemic Hematopoietic Stem Cell Expansion And Promote Leukemic Aggressiveness

Project description:Mutated H3 Histones Drive Human Pre-Leukemic Hematopoietic Stem Cell Expansion And Promote Leukemic Aggressiveness

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