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Potent anti-tumor efficacy of palbociclib in H3K27M-mutant diffuse intrinsic pontine glioma

ABSTRACT: Diffuse intrinsic pontine glioma (DIPG) is a rare and fatal pediatric brain cancer without cure. DIPG has high percentage histone mutation at K27M on histone H3 locus, which is believed to be one of the drivers of the tumorigenesis. Dysregulation of G1/S cell cycle checkpoint is more enriched in the H3.3K27M mutant subgroup. In this study, we reported that palbociclib (PD0332991), a specific and cytostatic inhibitor of CDK4/6, effectively suppresses the growth of DIPG cells in vitro and in vivo. We established patient derived cell lines from treatment-naïve specimens, which all have H3.3K27M mutation. And our DIPG cell lines with H3.3K27M mutation have high CDK4/6 expression. Then, we showed that depletion of CDK4 or CDK6 inhibits DIPG cells growth and blocks G1/S transition. Furthermore, palbociclib effectively repressed all 8 cell lines self-renewal, proliferation and cell cycle progression from G1 to S phase in vitro. Transcriptome analysis showed that palbociclib not only blocks G1/S transition, it also blocks other oncogenic targets such as Myc. Finally, palbociclib activity was assayed in vivo against DIPG orthotropic xenografts to demonstrate the high efficiency of blocking tumor growth. Our findings revealed that palbociclib could be the therapy strategy for DIPG. Overall design: mRNA profiles of palbociclib or vehicle treated DIPG cells were generated by deep sequencing, in duplicate, using Illumina HiSeq X Ten.

INSTRUMENT(S): HiSeq X Ten (Homo sapiens)

ORGANISM(S): Homo Sapiens


PROVIDER: GSE115976 | GEO | 2019-06-20


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Potent anti-tumor efficacy of palbociclib in treatment-naïve H3.3K27M-mutant diffuse intrinsic pontine glioma.

Sun Yu Y   Sun Ye Y   Yan Kun K   Li Zhuxuan Z   Xu Cheng C   Geng Yibo Y   Pan Changcun C   Chen Xin X   Zhang Liwei L   Xi Qiaoran Q  

EBioMedicine 20190503

<h4>Background</h4>Diffuse intrinsic pontine glioma (DIPG) is a rare and fatal pediatric brain cancer without cure. Seeking therapeutic strategies is still a major challenge in DIPG research. Previous study has shown that dysregulation of G1/S cell cycle checkpoint was common in DIPG and this dysregulation is even more enriched in the H3.3K27 M mutant subgroup. Here we assess potential anti-tumor efficacy of palbociclib, a specific and cytostatic inhibitor of CDK4/6, on high grade H3.3-K27 M-mut  ...[more]

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