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Identifying DNA Mutations in Purified Hematopoietic Stem/Progenitor Cells
Published on: February 24, 2014
Epigenetic Profiling of PTPN11 Mutant JMML Hematopoietic Stem and Progenitor Cells Reveals an Aberrant Histone
Roshani Sinha1, Mai Dvorak2, Ananthakrishnan Ganesan2
1Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, School of Medicine, Stanford University, Stanford, CA 94305, USA.
Insights
Juvenile myelomonocytic leukemia (JMML) involves RAS pathway mutations. This study reveals unique histone modification changes in JMML stem cells, identifying new therapeutic targets for this pediatric leukemia.
Area of Science:
- Hematology
- Oncology
- Epigenetics
Background:
- Juvenile myelomonocytic leukemia (JMML) is a fatal pediatric leukemia.
- RAS pathway mutations, particularly in PTPN11, drive JMML pathogenesis.
- While DNA hypermethylation is linked to severe JMML phenotypes, epigenetic alterations in histone modifications and chromatin remain underexplored.
Purpose of the Study:
- To investigate the landscape of histone modifications and chromatin profiles in JMML patient hematopoietic stem and progenitor cells (HSPCs).
- To identify novel epigenetic abnormalities and potential therapeutic targets in JMML.
Main Methods:
- Utilized global mass cytometry (Epigenetic Time of Flight - EpiTOF) to analyze histone modifications in HSPCs from JMML patients with PTPN11 mutations.
- Performed assay for transposase-accessible chromatin with sequencing (ATAC-seq) to assess chromatin accessibility and profiles.
Main Results:
- Identified statistically significant, unique changes in histone methylation, phosphorylation, and acetylation marks in JMML HSPCs compared to healthy controls.
- ATAC-seq revealed significant alterations in chromatin profiles at loci encoding post-translational modification enzymes, indicating dysregulated expression.
Conclusions:
- This study uncovers histone modification pathways as a novel epigenetic abnormality in JMML patient HSPCs.
- These findings highlight a new family of potential druggable targets for JMML treatment.
Abstract:
Juvenile myelomonocytic leukemia (JMML) is a deadly pediatric leukemia driven by RAS pathway mutations, of which >35% are gain-of-function in PTPN11. Although DNA hypermethylation portends severe clinical phenotypes, the landscape of histone modifications and chromatin profiles in JMML patient cells have not been explored. Using global mass cytometry, Epigenetic Time of Flight (EpiTOF), we analyzed hematopoietic stem and progenitor cells (HSPCs) from five JMML patients with PTPN11 mutations. These data revealed statistically significant changes in histone methylation, phosphorylation, and acetylation marks that were unique to JMML HSPCs when compared with healthy controls. Consistent with these data, assay for transposase-accessible chromatin with sequencing (ATAC-seq) analysis revealed significant alterations in chromatin profiles at loci encoding post-translational modification enzymes, strongly suggesting their mis-regulated expression. Collectively, this study reveals histone modification pathways as an additional epigenetic abnormality in JMML patient HSPCs, thereby uncovering a new family of potential druggable targets for the treatment of JMML.
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