KMT2D suppresses Sonic hedgehog-driven medulloblastoma progression and metastasis.
KMT2D suppresses Sonic hedgehog-driven medulloblastoma progression and metastasis.
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DOI：
10.1016/j.isci.2023.107831
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发表时间：
2023-10-20
期刊：
影响因子：
5.8
通讯作者：
Joyner, Alexandra L.
中科院分区：
文献类型：
--
作者：
Sanghrajka, Reeti Mayur;Koche, Richard;Medrano, Hector;El Nagar, Salsabiel;Stephen, Daniel N.;Lao, Zhimin;Bayin, N. Sumru;Ge, Kai;Joyner, Alexandra L.
髓母细胞瘤患者治疗失败和死亡的主要原因是颅内或沿着脊髓转移。然而，在Sonic hedgehog驱动的髓母细胞瘤（SHH-MB）患者中驱动肿瘤转移的分子机制在很大程度上仍然未知。在这项研究中，我们定义了KMT 2D（MLL 2）的肿瘤抑制作用，MLL 2是一种在大多数转移性β亚型中经常突变的基因。引人注目的是，SHH-MB的遗传小鼠模型表明，Kmt 2d的杂合丢失与SHH通路的激活一起导致高度渗透性疾病，存活率降低，后脑侵袭和脊髓转移增加。Kmt 2d的缺失减弱了神经分化，并使原发性和转移性肿瘤的转录/染色质景观朝着分化基因和肿瘤抑制因子减少以及与晚期癌症和转移有关的基因/途径（TGFβ、Notch、Atoh 1、Sox 2和Myc）增加的方向转变。因此，继发性杂合KMT 2D突变可能对鉴定易于发生转移的SHH-MB患者具有预后价值。Kmt 2d的杂合和纯合缺失降低SHH-MB中的存活率Kmt 2d突变增加SHH-MB的两种小鼠模型中的脊髓转移缺乏Kmt 2d的肿瘤降低神经分化基因的表达缺乏Kmt 2d的肿瘤上调干细胞维持和转移基因遗传学;癌症;模式生物
The major cause of treatment failure and mortality among medulloblastoma patients is metastasis intracranially or along the spinal cord. The molecular mechanisms driving tumor metastasis in Sonic hedgehog-driven medulloblastoma (SHH-MB) patients, however, remain largely unknown. In this study we define a tumor suppressive role of KMT2D (MLL2), a gene frequently mutated in the most metastatic β-subtype. Strikingly, genetic mouse models of SHH-MB demonstrate that heterozygous loss of Kmt2d in conjunction with activation of the SHH pathway causes highly penetrant disease with decreased survival, increased hindbrain invasion and spinal cord metastasis. Loss of Kmt2d attenuates neural differentiation and shifts the transcriptional/chromatin landscape of primary and metastatic tumors toward a decrease in differentiation genes and tumor suppressors and an increase in genes/pathways implicated in advanced stage cancer and metastasis (TGFβ, Notch, Atoh1, Sox2, and Myc). Thus, secondary heterozygous KMT2D mutations likely have prognostic value for identifying SHH-MB patients prone to develop metastasis. Heterozygous and homozygous loss of Kmt2d decreases survival in SHH-MB Kmt2d mutations increase spinal cord metastasis in two mouse models of SHH-MB Tumors lacking Kmt2d have decreased expression of neural differentiation genes Tumors lacking Kmt2d upregulate stem cell maintenance and metastasis genes Genetics; Cancer; Model organism
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
12.7
作者：
Wang X;Dubuc AM;Ramaswamy V;Mack S;Gendoo DM;Remke M;Wu X;Garzia L;Luu B;Cavalli F;Peacock J;López B;Skowron P;Zagzag D;Lyden D;Hoffman C;Cho YJ;Eberhart C;MacDonald T;Li XN;Van Meter T;Northcott PA;Haibe-Kains B;Hawkins C;Rutka JT;Bouffet E;Pfister SM;Korshunov A;Taylor MD
通讯作者：
Taylor MD
影响因子：
1.6
作者：
Miranda Kuzan-Fischer C;Juraschka K;Taylor MD
通讯作者：
Taylor MD
DOI：
10.1126/science.aaz2193
发表时间：
2020-07-17
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Chi Y;Remsik J;Kiseliovas V;Derderian C;Sener U;Alghader M;Saadeh F;Nikishina K;Bale T;Iacobuzio-Donahue C;Thomas T;Pe'er D;Mazutis L;Boire A
通讯作者：
Boire A
影响因子：
64.5
作者：
Guenther, Matthew G.;Levine, Stuart S.;Young, Richard A.
通讯作者：
Young, Richard A.