Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

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

Roshani Sinha
ORCID logo ,
Mai Dvorak
,
Ananthakrishnan Ganesan
,
Larry Kalesinskas
,
Charlotte M. Niemeyer
ORCID logo ,
Christian Flotho
,
Kathleen M Sakamoto
,
Norman Lacayo
,
Rachana Vinay Patil
,
Rhonda Perriman
,
Alma-Martina Cepika
,
Y. Lucy Liu
,
Alex Kuo
,
Paul Utz
,
Purvesh Khatri
,
Alice Bertaina
*
Version 1 : Received: 6 October 2023 / Approved: 7 October 2023 / Online: 7 October 2023 (09:49:46 CEST)

A peer-reviewed article of this Preprint also exists.

Sinha, R.; Dvorak, M.; Ganesan, A.; Kalesinskas, L.; Niemeyer, C.M.; Flotho, C.; Sakamoto, K.M.; Lacayo, N.; Patil, R.V.; Perriman, R.; Cepika, A.-M.; Liu, Y.L.; Kuo, A.; Utz, P.J.; Khatri, P.; Bertaina, A. Epigenetic Profiling of PTPN11 Mutant JMML Hematopoietic Stem and Progenitor Cells Reveals an Aberrant Histone Landscape. Cancers 2023, 15, 5204. Sinha, R.; Dvorak, M.; Ganesan, A.; Kalesinskas, L.; Niemeyer, C.M.; Flotho, C.; Sakamoto, K.M.; Lacayo, N.; Patil, R.V.; Perriman, R.; Cepika, A.-M.; Liu, Y.L.; Kuo, A.; Utz, P.J.; Khatri, P.; Bertaina, A. Epigenetic Profiling of PTPN11 Mutant JMML Hematopoietic Stem and Progenitor Cells Reveals an Aberrant Histone Landscape. Cancers 2023, 15, 5204.

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 of 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.

Keywords

histone modifications; pediatric leukemia; chromatin acessibility; epigenetics; mass cytometry; JMML; novel targets

Subject

Biology and Life Sciences, Cell and Developmental Biology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Download PDF Download Supplementary

Comments (0)

We encourage comments and feedback from a broad range of readers. See criteria for comments and our Diversity statement.

Leave a public comment
Send a private comment to the author(s)
* All users must log in before leaving a comment
Views 0
Downloads 0
Comments 0
Get PDF Supplementary Files Cite Share 0
Bookmark BibSonomy Mendeley Reddit Delicious
×
Alerts
Notify me about updates to this article or when a peer-reviewed version is published.
We use cookies on our website to ensure you get the best experience.
Read more about our cookies here.