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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 ( NPM1 mut) CN-AML.    Results  We found that three quarter of the  NPM1 mut CN-AML patients were H3K27me3  HIST1  high . H3K27me3  HIST1  high  group of patients was associated with a favorable outcome independently of known molecular risk factors. In gene expression profiling, the H3K27me3  HIST1  high  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  HIST1  high  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  NPM1 mut 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.    Graphical abstractElectronic supplementary material  The online version of this article (10.1186/s13148-019-0738-6) contains supplementary material, which is available to authorized users.

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