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

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2023 Nov 14

PMID 37958378

Authors

Roshani Sinha

Mai Dvorak

Ananthakrishnan Ganesan

Larry Kalesinskas

Charlotte M Niemeyer

Christian Flotho

Kathleen M Sakamoto

Norman Lacayo

Rachana Vinay Patil

Rhonda Perriman

Alma-Martina Cepika

Yunying Lucy Liu

Alex Kuo

Paul J Utz

Purvesh Khatri

Alice Bertaina

Affiliations

Soon will be listed here.

Abstract

Juvenile myelomonocytic leukemia (JMML) is a deadly pediatric leukemia driven by pathway mutations, of which >35% are gain-of-function in . 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 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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