Epigenetic Profiling of PTPN11 Mutant JMML Hematopoietic Stem and Progenitor Cells Reveals an Aberrant Histone Landscape.
Roshani SinhaMai DvorakAnanthakrishnan GanesanLarry KalesinskasCharlotte M NiemeyerChristian FlothoKathleen M SakamotoNorman LacayoRachana Vinay PatilRhonda PerrimanAlma-Martina CepikaYunying Lucy LiuAlex KuoPaul J UtzPurvesh KhatriAlice BertainaPublished in: Cancers (2023)
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.
Keyphrases
- dna methylation
- genome wide
- single cell
- gene expression
- rna seq
- transcription factor
- high throughput
- dna damage
- case report
- acute myeloid leukemia
- bone marrow
- electronic health record
- big data
- single molecule
- machine learning
- poor prognosis
- wild type
- circulating tumor
- cell death
- oxidative stress
- deep learning
- risk assessment
- cell proliferation
- climate change
- protein kinase
- data analysis
- early onset
- young adults
- smoking cessation
- replacement therapy