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Molecular and Functional Characterization of Disease-Propagating Stem Cells in Juvenile Myelomonocytic Leukemia [FACS sorted populations]

ABSTRACT: Molecular and Functional Characterization of Disease-Propagating Stem Cells in Juvenile Myelomonocytic Leukemia [FACS sorted populations]

PROVIDER: PRJNA437946 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR6826130.fastq.gz	Fastqsanger.gz
	SRR6826140.fastq.gz	Fastqsanger.gz
	SRR6826150.fastq.gz	Fastqsanger.gz
	SRR6826131.fastq.gz	Fastqsanger.gz
	SRR6826141.fastq.gz	Fastqsanger.gz

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Molecular and Functional Characterization of Disease-Propagating Stem Cells in Juvenile Myelomonocytic Leukemia

Project description:Molecular and Functional Characterization of Disease-Propagating Stem Cells in Juvenile Myelomonocytic Leukemia

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Molecular and Functional Characterization of Disease-Propagating Stem Cells in Juvenile Myelomonocytic Leukemia [FACS sorted populations]

Project description:We report on the characterization of JMML hematopoietic stem and progenitor cells (HSPCs). In order to molecularly characterize these populations we preformed bulk RNA-seq on purified cord blood and JMML HSCs, GMPs, and JMML double positives (+/+). We identified a conserved molecular hierarchy in JMML with high stem cell gene expression in HSCs, high progenitor and cell cycle gene expression in GMPs. We identified enriched gene sets in JMML HSCs vs CB HSCs, and find a number of potential therapeutic targets expressed in JMML.

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Project description:Juvenile myelomonocytic leukemia (JMML) is a poor-prognosis childhood leukemia usually caused by RAS-pathway mutations. The cellular hierarchy in JMML is poorly characterized, including the identity of leukemia stem cells (LSCs). FACS and single-cell RNA sequencing reveal marked heterogeneity of JMML hematopoietic stem/progenitor cells (HSPCs), including an aberrant Lin-CD34+CD38-CD90+CD45RA+ population. Single-cell HSPC index-sorting and clonogenic assays show that (1) all somatic mutations can be backtracked to the phenotypic HSC compartment, with RAS-pathway mutations as a "first hit," (2) mutations are acquired with both linear and branching patterns of clonal evolution, and (3) mutant HSPCs are present after allogeneic HSC transplant before molecular/clinical evidence of relapse. Stem cell assays reveal interpatient heterogeneity of JMML LSCs, which are present in, but not confined to, the phenotypic HSC compartment. RNA sequencing of JMML LSC reveals up-regulation of stem cell and fetal genes (HLF, MEIS1, CNN3, VNN2, and HMGA2) and candidate therapeutic targets/biomarkers (MTOR, SLC2A1, and CD96), paving the way for LSC-directed disease monitoring and therapy in this disease.

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