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

ABSTRACT: 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.

PROVIDER: EGAS00001003288 | EGA |

REPOSITORIES: EGA

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Project description:Epigenetic deregulation plays a critical role in the pathogenesis of Acute Myeloid Leukemia. But changes in histone modification patterns at the epigenome level still remain largely unknown. Here, we analyzed alterations of histone H3 acetylation patterns in a large number of patients with AML compared to CD34+ progenitor cells. Using ChIP-Chip assays, we demonstrate that AML blasts exhibit significant changes in Histone H3 acetylation levels at more than 1000 genomic loci. Importantly, at core promoter regions losses of H3 acetlyation levels prevailed which suggested that a large number of genes is epigenetically silenced in AML. The validation of identified genes led to the discovery of Peroxiredoxin 2 (PRDX2) as a potential tumor suppressor gene in AML. Peroxiredoxin-2 (PRDX2) was silenced in most AML patients by decreased Histone H3 acetylation and in almost 20% by promoter DNA hypermethylation. Low protein expression of the antioxidant PRDX2 gene was clinically associated with a poor prognosis in AML patients. Functionally, PRDX2 acted as an inhibitor of myeloid cell growth by reducing levels of reactive oxygen species generated in response to cytokines. A high level of PRDX2 expression inhibited myc-induced murine leukemogenesis whereas loss of PRDX2 increased myeloid cell proliferation and accelerated myc-induced leukemogenesis. Taken together, we identify widespread loss of Histone H3 acetylation at core promoter regions as a signature of AML blasts. Epigenome wide analyses of histone H3 acetylation led to the identification of PRDX2 as an epigenetically silenced growth suppressor that contributed to the malignant phenotype in AML. Blasts from patients with AML (n=72) were obtained at the time of diagnosis (in a few cases at first relapse). CD34+ progenitor cells (n=17) and white blood cells (n=16) were used as control samples. Immunoprecipitations were performed for anti-acetylated Histone H3. Chromatin-IPs were amplified using ligation mediated PCR and labeled using Cy3 coupled to incorporated amino-allyl-UTP. Common reference DNA consisting of a mixture of genomic DNA from AML patients was prepared, amplified and labeled in a similar way with Cy5.

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

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