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DDX3X Suppresses the Susceptibility of Hindbrain Lineages to Medulloblastoma.

DDX3X 抑制后脑谱系对髓母细胞瘤的易感性。

  • 影响因子:6.41
  • DOI:10.1016/j.devcel.2020.05.027
  • 作者列表:"Patmore DM","Jassim A","Nathan E","Gilbertson RJ","Tahan D","Hoffmann N","Tong Y","Smith KS","Kanneganti TD","Suzuki H","Taylor MD","Northcott P","Gilbertson RJ
  • 发表时间:2020-06-09
Abstract

:DEAD-Box Helicase 3 X-Linked (DDX3X) is frequently mutated in the Wingless (WNT) and Sonic hedghog (SHH) subtypes of medulloblastoma-the commonest malignant childhood brain tumor, but whether DDX3X functions as a medulloblastoma oncogene or tumor suppressor gene is not known. Here, we show that Ddx3x regulates hindbrain patterning and development by controlling Hox gene expression and cell stress signaling. In mice predisposed to Wnt- or Shh medulloblastoma, Ddx3x sensed oncogenic stress and suppressed tumor formation. WNT and SHH medulloblastomas normally arise only in the lower and upper rhombic lips, respectively. Deletion of Ddx3x removed this lineage restriction, enabling both medulloblastoma subtypes to arise in either germinal zone. Thus, DDX3X is a medulloblastoma tumor suppressor that regulates hindbrain development and restricts the competence of cell lineages to form medulloblastoma subtypes.

摘要

: DEAD-Box 解旋酶 3 X 连锁 (DDX3X) 在髓母细胞瘤-最常见的恶性儿童脑肿瘤-的无翅 (WNT) 和 Sonic hedghog (SHH) 亚型中频繁突变,但 DDX3X 是否作为髓母细胞瘤癌基因或抑癌基因的功能尚不清楚。在此,我们发现 Ddx3x 通过控制 Hox 基因表达和细胞应激信号来调节后脑模式和发育。在易感 Wnt-或 Shh 髓母细胞瘤的小鼠中,Ddx3x 感知致癌应激并抑制肿瘤形成。WNT 和 SHH 髓母细胞瘤通常仅分别出现在菱形的下唇和上唇。Ddx3x 的缺失消除了这种谱系限制,使两个髓母细胞瘤亚型都能出现在任一生发区。因此,DDX3X 是一种髓母细胞瘤肿瘤抑制因子,调节后脑发育,限制细胞谱系形成髓母细胞瘤亚型的能力。

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DOI:10.1002/mrm.28183
作者列表:["Tiwari V","Mashimo T","An Z","Vemireddy V","Piccirillo S","Askari P","Hulsey KM","Zhang S","de Graaf RA","Patel TR","Pan E","Mickey BE","Maher EA","Bachoo RM","Choi C"]

METHODS:PURPOSE:To generate a preclinical model of isocitrate dehydrogenase (IDH) mutant gliomas from glioma patients and design a MRS method to test the compatibility of 2-hydroxyglutarate (2HG) production between the preclinical model and patients. METHODS:Five patient-derived xenograft (PDX) mice were generated from two glioma patients with IDH1 R132H mutation. A PRESS sequence was tailored at 9.4 T, with computer simulation and phantom analyses, for improving 2HG detection in mice. 2HG and other metabolites in the PDX mice were measured using the optimized MRS at 9.4 T and compared with 3 T MRS measurements of the metabolites in the parental-tumor patients. Spectral fitting was performed with LCModel using in-house basis spectra. Metabolite levels were quantified with reference to water. RESULTS:The PRESS TE was optimized to be 96 ms, at which the 2HG 2.25 ppm signal was narrow and inverted, thereby leading to unequivocal separation of the 2HG resonance from adjacent signals from other metabolites. The optimized MRS provided precise detection of 2HG in mice compared to short-TE MRS at 9.4 T. The 2HG estimates in PDX mice were in excellent agreement with the 2HG measurements in the patients. CONCLUSION:The similarity of 2HG production between PDX models and parental-tumor patients indicates that PDX tumors retain the parental IDH metabolic fingerprint and can serve as a preclinical model for improving our understanding of the IDH-mutation associated metabolic reprogramming.

影响因子:3.29
发表时间:2020-01-31
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DOI:10.1186/s12885-020-6536-x
作者列表:["Ang SYL","Lee L","See AAQ","Ang TY","Ang BT","King NKK"]

METHODS:BACKGROUND:Gliomas consist of a heterogeneous group of tumors. This study aimed to report the incidences of O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation, 1p19q co-deletion, isocitrate dehydrogenase (IDH) gene mutations, and inactivating mutations of alpha-thalassemia/mental retardation syndrome X-linked (ATRX) in high-grade gliomas in an ethnically diverse population. METHODS:Records of patients who underwent surgery for high-grade gliomas from January 2013 to March 2017 at our institution were obtained. The patients' age, gender, ethnicity, Karnofsky Performance Scale (KPS) score, ability to perform activities of daily living (ADLs), tumor location and biomarkers status were recorded. Data were analyzed using chi-square and Mann-Whitney U tests, Kaplan-Meier estimates and log-rank test. RESULTS:181 patients were selected (56 with grade III gliomas, 125 with grade IV gliomas). In the grade III group, 55% had MGMT promoter methylation, 41% had 1p19q co-deletion, 35% had IDH1 mutation and none had ATRX loss. In the grade IV group, 30% had MGMT promoter methylation, 2% had 1p19q co-deletion, 15% had IDH1 mutation and 8% had ATRX loss. After adjusting for effects of age, surgery and pre-operative ADL statuses, only MGMT promoter methylation was found to be significantly associated with longer overall survival time in grade III (p = 0.024) and IV patients (p = 0.006). CONCLUSIONS:The incidences of MGMT promoter methylation and IDH1 mutation were found to be comparable to globally reported rates, but those of 1p19q co-deletion and ATRX loss seemed to be lower in our cohort. MGMT promoter methylation was associated with increased overall survival in our cohort and might serve as favorable prognostic factor.

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影响因子:5.34
发表时间:2020-01-31
DOI:10.1186/s13046-020-1534-z
作者列表:["Abbruzzese C","Matteoni S","Persico M","Villani V","Paggi MG"]

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