TY - JOUR
T1 - Multi-omics profiling reveals a distinctive epigenome signature for high-risk acute promyelocytic leukemia
AU - Singh, Abhishek A
AU - Petraglia, Francesca
AU - Nebbioso, Angela
AU - Yi, Guoqiang
AU - Conte, Mariarosaria
AU - Valente, Sergio
AU - Mandoli, Amit
AU - Scisciola, Lucia
AU - Lindeboom, Rik
AU - Kerstens, Hinri
AU - Janssen-Megens, Eva M
AU - Pourfarzad, Farzin
AU - Habibi, Ehsan
AU - Berentsen, Kim
AU - Kim, Bowon
AU - Logie, Colin
AU - Heath, Simon
AU - Wierenga, Albertus T J
AU - Clarke, Laura
AU - Flicek, Paul
AU - Jansen, Joop H
AU - Kuijpers, Taco
AU - Yaspo, Marie Laure
AU - Valle, Veronique Della
AU - Bernard, Olivier
AU - Gut, Ivo
AU - Vellenga, Edo
AU - Stunnenberg, Hendrik G
AU - Mai, Antonello
AU - Altucci, Lucia
AU - Martens, Joost H A
PY - 2018/5/22
Y1 - 2018/5/22
N2 - Epigenomic alterations have been associated with both pathogenesis and progression of cancer. Here, we analyzed the epigenome of two high-risk APL (hrAPL) patients and compared it to non-high-risk APL cases. Despite the lack of common genetic signatures, we found that human hrAPL blasts from patients with extremely poor prognosis display specific patterns of histone H3 acetylation, specifically hyperacetylation at a common set of enhancer regions. In addition, unique profiles of the repressive marks H3K27me3 and DNA methylation were exposed in high-risk APLs. Epigenetic comparison with low/intermediate-risk APLs and AMLs revealed hrAPL-specific patterns of histone acetylation and DNA methylation, suggesting these could be further developed into markers for clinical identification. The epigenetic drug MC2884, a newly generated general HAT/EZH2 inhibitor, induces apoptosis of high-risk APL blasts and reshapes their epigenomes by targeting both active and repressive marks. Together, our analysis uncovers distinctive epigenome signatures of hrAPL patients, and provides proof of concept for use of epigenome profiling coupled to epigenetic drugs to 'personalize' precision medicine.
AB - Epigenomic alterations have been associated with both pathogenesis and progression of cancer. Here, we analyzed the epigenome of two high-risk APL (hrAPL) patients and compared it to non-high-risk APL cases. Despite the lack of common genetic signatures, we found that human hrAPL blasts from patients with extremely poor prognosis display specific patterns of histone H3 acetylation, specifically hyperacetylation at a common set of enhancer regions. In addition, unique profiles of the repressive marks H3K27me3 and DNA methylation were exposed in high-risk APLs. Epigenetic comparison with low/intermediate-risk APLs and AMLs revealed hrAPL-specific patterns of histone acetylation and DNA methylation, suggesting these could be further developed into markers for clinical identification. The epigenetic drug MC2884, a newly generated general HAT/EZH2 inhibitor, induces apoptosis of high-risk APL blasts and reshapes their epigenomes by targeting both active and repressive marks. Together, our analysis uncovers distinctive epigenome signatures of hrAPL patients, and provides proof of concept for use of epigenome profiling coupled to epigenetic drugs to 'personalize' precision medicine.
U2 - 10.18632/oncotarget.25429
DO - 10.18632/oncotarget.25429
M3 - Article
C2 - 29876014
SN - 1949-2553
VL - 9
SP - 25647
EP - 25660
JO - Oncotarget
JF - Oncotarget
IS - 39
ER -