Histone lysine demethylase 4 family proteins maintain the transcriptional program and adrenergic cellular state of MYCN-amplified neuroblastoma

被引：1

作者：

Abu-Zaid, Ahmed ^{[1
,14
]}

Fang, Jie ^{[1
,6
]}

Jin, Hongjian ^{[2
]}

Singh, Shivendra ^{[1
]}

Pichavaram, Prahalathan ^{[1
]}

Wu, Qiong ^{[1
]}

Tillman, Heather ^{[3
]}

Janke, Laura ^{[3
]}

Rosikiewicz, Wojciech ^{[2
]}

Xu, Beisi ^{[2
]}

Van De Velde, Lee -Ann ^{[4
]}

Guo, Yian ^{[5
]}

Li, Yimei ^{[5
]}

Shendy, Noha A. M. ^{[6
]}

Delahunty, Ian M. ^{[6
]}

Rankovic, Zoran ^{[7
]}

Chen, Taosheng ^{[7
]}

Chen, Xiang ^{[8
]}

Freeman, Kevin W. ^{[9
]}

Hatley, Mark E. ^{[6
]}

Durbin, Adam D. ^{[6
]}

Murray, Peter J. ^{[10
]}

Murphy, Andrew J. ^{[1
,11
]}

Thomas, Paul G. ^{[4
]}

Davidoff, Andrew M. ^{[1
,11
,12
,13
]}

Yang, Jun ^{[1
,12
,13
,14
]}

机构：

[1] St Jude Childrens Res Hosp, Dept Surg, Memphis, TN 38105 USA

[2] St Jude Childrens Res Hosp, Ctr Appl Bioinformat, Memphis, TN 38105 USA

[3] St Jude Childrens Res Hosp, Dept Pathol, Memphis, TN 38105 USA

[4] St Jude Childrens Res Hosp, Dept Immunol, Memphis, TN 38105 USA

[5] St Jude Childrens Res Hosp, Dept Biostat, Memphis, TN 38105 USA

[6] St Jude Childrens Res Hosp, Dept Mol Oncol, Memphis, TN 38105 USA

[7] St Jude Childrens Res Hosp, Dept Chem Biol & Therapeut, Memphis, TN 38105 USA

[8] St Jude Childrens Res Hosp, Dept Computat Biol, Memphis, TN 38105 USA

[9] Univ Tennessee, Hlth Sci Ctr, Genet Genom & Informat, Memphis, TN 38103 USA

[10] Max Planck Inst Biochem, Klopferspitz 18, D-82152 Martinsried, Germany

[11] Univ Tennessee, Hlth Sci Ctr, Dept Surg, Div Pediat Surg, Memphis, TN 38105 USA

[12] St Jude Childrens Res Hosp, St Jude Grad Sch Biomed Sci, Memphis, TN 38105 USA

[13] Univ Tennessee, Coll Med, Dept Pathol & Lab Med, Hlth Sci Ctr, 930 Madison Ave,Suite 500, Memphis, TN 38163 USA

[14] Univ Tennessee, Hlth Sci Ctr, Coll Grad Hlth Sci, Memphis, TN 37996 USA

来源：

CELL REPORTS MEDICINE | 2024年 / 5卷 / 03期

关键词：

ACTIVATING MUTATIONS; INTERFERON-BETA; MURINE MODEL; ALK KINASE; EXPRESSION; DIFFERENTIATION; INHIBITION; BINDING; GROWTH; CELLS;

D O I：

10.1016/j.xcrm.2024.101468

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Neuroblastoma with MYCN amplification (MNA) is a high -risk disease that has a poor survival rate. Neuroblastoma displays cellular heterogeneity, including more differentiated (adrenergic) and more primitive (mesenchymal) cellular states. Here, we demonstrate that MYCN oncoprotein promotes a cellular state switch in mesenchymal cells to an adrenergic state, accompanied by induction of histone lysine demethylase 4 family members (KDM4A-C) that act in concert to control the expression of MYCN and adrenergic core regulatory circulatory (CRC) transcription factors. Pharmacologic inhibition of KDM4 blocks expression of MYCN and the adrenergic CRC transcriptome with genome-wide induction of transcriptionally repressive H3K9me3, resulting in potent anticancer activity against neuroblastomas with MNA by inducing neuroblastic differentiation and apoptosis. Furthermore, a short-term KDM4 inhibition in combination with conventional, cytotoxic chemotherapy results in complete tumor responses of xenografts with MNA. Thus, KDM4 blockade may serve as a transformative strategy to target the adrenergic CRC dependencies in MNA neuroblastomas.

引用

页数：30