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Clin Epigenetics. 2019 Oct 12;11(1):141. doi: 10.1186/s13148-019-0738-6.

Epigenetic down-regulation of the HIST1 locus predicts better prognosis in acute myeloid leukemia with NPM1 mutation.

Author information

1
Epigenetic Factors in Normal and Malignant Hematopoiesis Team, Aix Marseille University, CNRS, Inserm, Institut Paoli-Calmettes, CRCM, 27 Boulevard Lei Roure, 13273, Marseille Cedex 09, France.
2
Predictive Oncology Laboratory, CRCM, Inserm, U1068, CNRS UMR7258, Institut Paoli-Calmettes, Aix-Marseille University, Marseille, France.
3
Institut Pasteur, G5 Chromatin and Infection, Paris, France.
4
Aix-Marseille University, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Marseille Protéomique, Marseille, France.
5
Aix-Marseille University, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Centre d'Investigations Cliniques en Biothérapies, Marseille, France.
6
Service d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France Université Toulouse III Paul Sabatier, Cancer Research Center of Toulouse, UMR1037-INSERM, ERL5294 CNRS, Toulouse, France.
7
Aix-Marseille University, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Marseille, France.
8
Epigenetic Factors in Normal and Malignant Hematopoiesis Team, Aix Marseille University, CNRS, Inserm, Institut Paoli-Calmettes, CRCM, 27 Boulevard Lei Roure, 13273, Marseille Cedex 09, France. estelle.duprez@inserm.fr.

Abstract

BACKGROUND:

The epigenetic machinery is frequently altered in acute myeloid leukemia. Focusing on cytogenetically normal (CN) AML, we previously described an abnormal H3K27me3 enrichment covering 70 kb on the HIST1 cluster (6.p22) in CN-AML patient blasts. Here, we further investigate the molecular, functional, and prognosis significance of this epigenetic alteration named H3K27me3 HIST1 in NPM1-mutated (NPM1mut) CN-AML.

RESULTS:

We found that three quarter of the NPM1mut CN-AML patients were H3K27me3 HIST1high. H3K27me3 HIST1high group of patients was associated with a favorable outcome independently of known molecular risk factors. In gene expression profiling, the H3K27me3 HIST1high mark was associated with lower expression of the histone genes HIST1H1D, HIST1H2BG, HIST1H2AE, and HIST1H3F and an upregulation of genes involved in myelomonocytic differentiation. Mass spectrometry analyses confirmed that the linker histone protein H1d, but not the other histone H1 subtypes, was downregulated in the H3K27me3 HIST1high group of patients. H1d knockdown primed ATRA-mediated differentiation of OCI-AML3 and U937 AML cell lines, as assessed on CD11b/CD11c markers, morphological and gene expression analyses.

CONCLUSIONS:

Our data suggest that NPM1mut AML prognosis depends on the epigenetic silencing of the HIST1 cluster and that, among the H3K27me3 silenced histone genes, HIST1H1D plays a role in AML blast differentiation.

KEYWORDS:

Acute myeloid leukemia; Epigenetics; H3K27me3; HIST1; NPM1

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