DDX3X suppresses the susceptibility of hindbrain lineages to medulloblastoma

Deanna M. Patmore; Amir  Jassim; Erica Nathan; Reuben J. Gilbertson; Daniel Tahan; Nadin Hoffmann; Yiai  Tong; Kyle S. Smith; Thirumala-Devi Kanneganti; Hiromichi Suzuki; Michael D. Taylor; Paul Northcott; Richard J. Gilbertson

doi:10.1016/j.devcel.2020.05.027

DDX3X suppresses the susceptibility of hindbrain lineages to medulloblastoma

Deanna M. Patmore, Amir Jassim, Erica Nathan, Reuben J. Gilbertson, Daniel Tahan, Nadin Hoffmann, Yiai Tong, Kyle S. Smith, Thirumala-Devi Kanneganti, Hiromichi Suzuki, Michael D. Taylor , Paul Northcott, Richard J. Gilbertson

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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.

Original language	English
Pages (from-to)	455-470.e5
Journal	Developmental Cell
Volume	54
Issue number	4
Early online date	17 Jun 2020
DOIs	https://doi.org/10.1016/j.devcel.2020.05.027
Publication status	Published - 24 Aug 2020
Externally published	Yes

Keywords

DDX3X
HOX genes
inflammasome
medulloblastoma
stress granule
tumor suppressor gene

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Accepted_ManuscriptAccepted author manuscript, 385 KBLicence: CC BY-NC-ND

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title = "DDX3X suppresses the susceptibility of hindbrain lineages to medulloblastoma",

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.",

keywords = "DDX3X, HOX genes, inflammasome, medulloblastoma, stress granule, tumor suppressor gene",

author = "Patmore, {Deanna M.} and Amir Jassim and Erica Nathan and Gilbertson, {Reuben J.} and Daniel Tahan and Nadin Hoffmann and Yiai Tong and Smith, {Kyle S.} and Thirumala-Devi Kanneganti and Hiromichi Suzuki and Taylor, {Michael D.} and Paul Northcott and Gilbertson, {Richard J.}",

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doi = "10.1016/j.devcel.2020.05.027",

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T1 - DDX3X suppresses the susceptibility of hindbrain lineages to medulloblastoma

AU - Patmore, Deanna M.

AU - Jassim, Amir

AU - Nathan, Erica

AU - Gilbertson, Reuben J.

AU - Tahan, Daniel

AU - Hoffmann, Nadin

AU - Tong, Yiai

AU - Smith, Kyle S.

AU - Kanneganti, Thirumala-Devi

AU - Suzuki, Hiromichi

AU - Taylor , Michael D.

AU - Northcott, Paul

AU - Gilbertson, Richard J.

PY - 2020/8/24

Y1 - 2020/8/24

N2 - 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.

AB - 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.

KW - DDX3X

KW - HOX genes

KW - inflammasome

KW - medulloblastoma

KW - stress granule

KW - tumor suppressor gene

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DO - 10.1016/j.devcel.2020.05.027

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SP - 455-470.e5

JO - Developmental Cell

JF - Developmental Cell

IS - 4

ER -

DDX3X suppresses the susceptibility of hindbrain lineages to medulloblastoma

Abstract

Keywords

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