Epigenetic Profiling of PTPN11 Mutant JMML Hematopoietic Stem and Progenitor Cells Reveals an Aberrant Histone Landscape.

Autor: Sinha, Roshani, Dvorak, Mai, Ganesan, Ananthakrishnan, Kalesinskas, Larry, Niemeyer, Charlotte M., Flotho, Christian, Sakamoto, Kathleen M., Lacayo, Norman, Patil, Rachana Vinay, Perriman, Rhonda, Cepika, Alma-Martina, Liu, Yunying Lucy, Kuo, Alex, Utz, Paul J., Khatri, Purvesh, Bertaina, Alice
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Zdroj: Cancers; Nov2023, Vol. 15 Issue 21, p5204, 16p
Abstrakt: Simple Summary: Juvenile myelomonocytic leukemia (JMML) is a deadly pediatric leukemia with limited treatment options and poor clinical outcomes. Effective targeted treatment strategies are an urgent unmet need. To improve outcomes for this pediatric patient population, we examined the structure of the DNA comprising the genomes of leukemic cells from five JMML patients and compared these to DNA structures from healthy controls. These data allowed us to identify structural features that were unique to the JMML patient DNA. Identification of these JMML-specific changes could guide development of targeted drugs to effectively treat this devastating malignancy. Our work provides a rich resource for additional investigations aimed at identifying and testing strategies designed to treat JMML. 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. [ABSTRACT FROM AUTHOR]
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