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

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.

Type: Other
Archiver: European Genome-Phenome Archive (EGA)

2 Datasets 1 Publication

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Dataset ID	Description	Technology	Samples
EGAD00001004436	Exome sequencing was performed on samples from patients 064, 105, and 8760, including the remission sample for 105. Exomes were captured using the Agilent SureSelect All Exon kit v5 kit and libraries sequenced on HiSeq 2000 or 2500 or 4000.	Illumina HiSeq 2000 Illumina HiSeq 2500 Illumina HiSeq 4000	6
EGAD00001004437	RNA-seq data from TEX cells transduced with HIST1H3H WT, HIST1H3H K27M, HIST1H3F WT, HIST1H3F K27I and Luc2 control in triplicate. In addition, RNA-Seq was performed on untransduced TEX cells. Libraries [rRNA-depleted stranded (HMR)] were sequenced on an Illumina Hiseq 4000 platform to generate 100 bp paired-end reads.	Illumina HiSeq 4000	18

Publications	Citations
Mutant H3 histones drive human pre-leukemic hematopoietic stem cell expansion and promote leukemic aggressiveness. Boileau M, Shirinian M, Gayden T, Harutyunyan AS, Chen CCL, Mikael LG, Duncan HM, Neumann AL, Arreba-Tutusaus P, De Jay N, Zeinieh M, Rossokhata K, Zhang Y, Nikbakht H, Mouawad C, Massoud R, Frey F, Nasr R, El Cheikh J, El Sabban M, Kleinman CL, Mahfouz R, Minden MD, Jabado N, Bazarbachi A, Eppert K. Nat Commun 10: 2019 2891	25

Publications

Citations

Mutant H3 histones drive human pre-leukemic hematopoietic stem cell expansion and promote leukemic aggressiveness.
Boileau M, Shirinian M, Gayden T, Harutyunyan AS, Chen CCL, Mikael LG, Duncan HM, Neumann AL, Arreba-Tutusaus P, De Jay N, Zeinieh M, Rossokhata K, Zhang Y, Nikbakht H, Mouawad C, Massoud R, Frey F, Nasr R, El Cheikh J, El Sabban M, Kleinman CL, Mahfouz R, Minden MD, Jabado N, Bazarbachi A, Eppert K. Nat Commun 10: 2019 2891