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Comparison of pre-leukemic and leukemic H9M AML clones from murine splenocytes

ABSTRACT: Comparison of pre-leukemic and leukemic H9M AML clones from murine splenocytes

PROVIDER: PRJNA814710 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR18293064_1.fastq.gz	Fastqsanger.gz
	SRR18293064_2.fastq.gz	Fastqsanger.gz
	SRR18293065_1.fastq.gz	Fastqsanger.gz
	SRR18293065_2.fastq.gz	Fastqsanger.gz
	SRR18293066_1.fastq.gz	Fastqsanger.gz

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Comparison of pre-leukemic and leukemic H9M AML clones from murine splenocytes

Project description:The tracking of leukemic clones in acute myeloid leukemic promisses deeper insights into disease development and therapeutic options. We therefore established a fluorescent genetic barcoding (FGB) labeling approach that allows for flow cytomtric tracking of color-coded clones in vitro and in vivo. In Hoxa9 and Meis1 (H9M) dependent murine AML, we tracked the growth behavior of 24 clones in parallel and enriched for pre-leukemic clones as well as their de novo expanded counterparts and stably expanded clones from leukemic mice by fluorescence-activated cell sorting. These samples were subjected toRNA sequencing for the assessment of transcriptional changes underlying clonal maintenance and expansion.

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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.

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