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 languageEnglish
Pages (from-to)455-470.e5
JournalDevelopmental Cell
Volume54
Issue number4
Early online date17 Jun 2020
DOIs
Publication statusPublished - 24 Aug 2020
Externally publishedYes

Keywords

  • DDX3X
  • HOX genes
  • inflammasome
  • medulloblastoma
  • stress granule
  • tumor suppressor gene

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