Pediatric glioma histone H3.3 K27M/G34R mutations drive abnormalities in PML nuclear bodies

Hsiao P.J. Voon; Linda Hii; Andrew Garvie; Maheshi Udugama; Brian Krug; Caterina Russo; Anderly C. Chüeh; Roger J. Daly; Alison Morey; Toby D.M. Bell; Stephen J. Turner; Joseph Rosenbluh; Paul Daniel; Ron Firestein; Jeffrey R. Mann; Philippe Collas; Nada Jabado; Lee H. Wong

doi:10.1186/s13059-023-03122-5

Pediatric glioma histone H3.3 K27M/G34R mutations drive abnormalities in PML nuclear bodies

Hsiao P.J. Voon, Linda Hii, Andrew Garvie, Maheshi Udugama, Brian Krug, Caterina Russo, Anderly C. Chüeh, Roger J. Daly, Alison Morey, Toby D.M. Bell, Stephen J. Turner, Joseph Rosenbluh, Paul Daniel, Ron Firestein, Jeffrey R. Mann, Philippe Collas, Nada Jabado, Lee H. Wong

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9 Citations (Scopus)

Abstract

Background: Point mutations in histone variant H3.3 (H3.3K27M, H3.3G34R) and the H3.3-specific ATRX/DAXX chaperone complex are frequent events in pediatric gliomas. These H3.3 point mutations affect many chromatin modifications but the exact oncogenic mechanisms are currently unclear. Histone H3.3 is known to localize to nuclear compartments known as promyelocytic leukemia (PML) nuclear bodies, which are frequently mutated and confirmed as oncogenic drivers in acute promyelocytic leukemia. Results: We find that the pediatric glioma-associated H3.3 point mutations disrupt the formation of PML nuclear bodies and this prevents differentiation down glial lineages. Similar to leukemias driven by PML mutations, H3.3-mutated glioma cells are sensitive to drugs that target PML bodies. We also find that point mutations in IDH1/2—which are common events in adult gliomas and myeloid leukemias—also disrupt the formation of PML bodies. Conclusions: We identify PML as a contributor to oncogenesis in a subset of gliomas and show that targeting PML bodies is effective in treating these H3.3-mutated pediatric gliomas.

Original language	English
Article number	284
Number of pages	27
Journal	Genome Biology
Volume	24
Issue number	1
DOIs	https://doi.org/10.1186/s13059-023-03122-5
Publication status	Published - Dec 2023

Keywords

Arsenic trioxide
Histone variant H3.3
Pediatric glioma
PML bodies

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Voon, H. P. J., Hii, L., Garvie, A., Udugama, M., Krug, B., Russo, C., Chüeh, A. C., Daly, R. J., Morey, A., Bell, T. D. M., Turner, S. J., Rosenbluh, J., Daniel, P., Firestein, R., Mann, J. R., Collas, P., Jabado, N., & Wong, L. H. (2023). Pediatric glioma histone H3.3 K27M/G34R mutations drive abnormalities in PML nuclear bodies. Genome Biology, 24(1), Article 284. https://doi.org/10.1186/s13059-023-03122-5

@article{6f9923add9af49868e94e1d46f75de14,

title = "Pediatric glioma histone H3.3 K27M/G34R mutations drive abnormalities in PML nuclear bodies",

abstract = "Background: Point mutations in histone variant H3.3 (H3.3K27M, H3.3G34R) and the H3.3-specific ATRX/DAXX chaperone complex are frequent events in pediatric gliomas. These H3.3 point mutations affect many chromatin modifications but the exact oncogenic mechanisms are currently unclear. Histone H3.3 is known to localize to nuclear compartments known as promyelocytic leukemia (PML) nuclear bodies, which are frequently mutated and confirmed as oncogenic drivers in acute promyelocytic leukemia. Results: We find that the pediatric glioma-associated H3.3 point mutations disrupt the formation of PML nuclear bodies and this prevents differentiation down glial lineages. Similar to leukemias driven by PML mutations, H3.3-mutated glioma cells are sensitive to drugs that target PML bodies. We also find that point mutations in IDH1/2—which are common events in adult gliomas and myeloid leukemias—also disrupt the formation of PML bodies. Conclusions: We identify PML as a contributor to oncogenesis in a subset of gliomas and show that targeting PML bodies is effective in treating these H3.3-mutated pediatric gliomas.",

keywords = "Arsenic trioxide, Histone variant H3.3, Pediatric glioma, PML bodies",

author = "Voon, {Hsiao P.J.} and Linda Hii and Andrew Garvie and Maheshi Udugama and Brian Krug and Caterina Russo and Ch{\"u}eh, {Anderly C.} and Daly, {Roger J.} and Alison Morey and Bell, {Toby D.M.} and Turner, {Stephen J.} and Joseph Rosenbluh and Paul Daniel and Ron Firestein and Mann, {Jeffrey R.} and Philippe Collas and Nada Jabado and Wong, {Lee H.}",

note = "Funding Information: High-throughput sequencing was performed at the MHTP Medical Genomics Facility. This research was supported by use of the Nectar Research Cloud, a collaborative Australian research platform supported by the NCRIS-funded Australian Research Data Commons (ARDC). Funding Information: This work was supported by Cure Brain Cancer Australia, American Brain Tumor Association, Worldwide Cancer Research Foundation and NHMRC Australia. Hsiao P. J Voon was supported by a mid-career fellowship from the Cure Brain Cancer Foundation. Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = dec,

doi = "10.1186/s13059-023-03122-5",

language = "English",

volume = "24",

journal = "Genome Biology",

issn = "1474-7596",

publisher = "BioMed Central",

number = "1",

}

Voon, HPJ, Hii, L, Garvie, A, Udugama, M, Krug, B, Russo, C, Chüeh, AC , Daly, RJ, Morey, A, Bell, TDM , Turner, SJ , Rosenbluh, J , Daniel, P , Firestein, R , Mann, JR, Collas, P, Jabado, N & Wong, LH 2023, 'Pediatric glioma histone H3.3 K27M/G34R mutations drive abnormalities in PML nuclear bodies', Genome Biology, vol. 24, no. 1, 284. https://doi.org/10.1186/s13059-023-03122-5

TY - JOUR

T1 - Pediatric glioma histone H3.3 K27M/G34R mutations drive abnormalities in PML nuclear bodies

AU - Voon, Hsiao P.J.

AU - Hii, Linda

AU - Garvie, Andrew

AU - Udugama, Maheshi

AU - Krug, Brian

AU - Russo, Caterina

AU - Chüeh, Anderly C.

AU - Daly, Roger J.

AU - Morey, Alison

AU - Bell, Toby D.M.

AU - Turner, Stephen J.

AU - Rosenbluh, Joseph

AU - Daniel, Paul

AU - Firestein, Ron

AU - Mann, Jeffrey R.

AU - Collas, Philippe

AU - Jabado, Nada

AU - Wong, Lee H.

N1 - Funding Information: High-throughput sequencing was performed at the MHTP Medical Genomics Facility. This research was supported by use of the Nectar Research Cloud, a collaborative Australian research platform supported by the NCRIS-funded Australian Research Data Commons (ARDC). Funding Information: This work was supported by Cure Brain Cancer Australia, American Brain Tumor Association, Worldwide Cancer Research Foundation and NHMRC Australia. Hsiao P. J Voon was supported by a mid-career fellowship from the Cure Brain Cancer Foundation. Publisher Copyright: © 2023, The Author(s).

PY - 2023/12

Y1 - 2023/12

N2 - Background: Point mutations in histone variant H3.3 (H3.3K27M, H3.3G34R) and the H3.3-specific ATRX/DAXX chaperone complex are frequent events in pediatric gliomas. These H3.3 point mutations affect many chromatin modifications but the exact oncogenic mechanisms are currently unclear. Histone H3.3 is known to localize to nuclear compartments known as promyelocytic leukemia (PML) nuclear bodies, which are frequently mutated and confirmed as oncogenic drivers in acute promyelocytic leukemia. Results: We find that the pediatric glioma-associated H3.3 point mutations disrupt the formation of PML nuclear bodies and this prevents differentiation down glial lineages. Similar to leukemias driven by PML mutations, H3.3-mutated glioma cells are sensitive to drugs that target PML bodies. We also find that point mutations in IDH1/2—which are common events in adult gliomas and myeloid leukemias—also disrupt the formation of PML bodies. Conclusions: We identify PML as a contributor to oncogenesis in a subset of gliomas and show that targeting PML bodies is effective in treating these H3.3-mutated pediatric gliomas.

AB - Background: Point mutations in histone variant H3.3 (H3.3K27M, H3.3G34R) and the H3.3-specific ATRX/DAXX chaperone complex are frequent events in pediatric gliomas. These H3.3 point mutations affect many chromatin modifications but the exact oncogenic mechanisms are currently unclear. Histone H3.3 is known to localize to nuclear compartments known as promyelocytic leukemia (PML) nuclear bodies, which are frequently mutated and confirmed as oncogenic drivers in acute promyelocytic leukemia. Results: We find that the pediatric glioma-associated H3.3 point mutations disrupt the formation of PML nuclear bodies and this prevents differentiation down glial lineages. Similar to leukemias driven by PML mutations, H3.3-mutated glioma cells are sensitive to drugs that target PML bodies. We also find that point mutations in IDH1/2—which are common events in adult gliomas and myeloid leukemias—also disrupt the formation of PML bodies. Conclusions: We identify PML as a contributor to oncogenesis in a subset of gliomas and show that targeting PML bodies is effective in treating these H3.3-mutated pediatric gliomas.

KW - Arsenic trioxide

KW - Histone variant H3.3

KW - Pediatric glioma

KW - PML bodies

UR - http://www.scopus.com/inward/record.url?scp=85179342177&partnerID=8YFLogxK

U2 - 10.1186/s13059-023-03122-5

DO - 10.1186/s13059-023-03122-5

M3 - Article

C2 - 38066546

AN - SCOPUS:85179342177

SN - 1474-7596

VL - 24

JO - Genome Biology

JF - Genome Biology

IS - 1

M1 - 284

ER -

Pediatric glioma histone H3.3 K27M/G34R mutations drive abnormalities in PML nuclear bodies

Abstract

Keywords

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