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Published on: October 3, 2010
DDX3X Suppresses the Susceptibility of Hindbrain Lineages to Medulloblastoma
Deanna M Patmore1, Amir Jassim1, Erica Nathan1
1CRUK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
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.
Insights
DEAD-Box Helicase 3 X-Linked (DDX3X) acts as a tumor suppressor in medulloblastoma, a common childhood brain tumor. It regulates hindbrain development and prevents specific tumor subtypes from forming in restricted cell lineages.
Area of Science:
- Neuro-oncology
- Developmental Neuroscience
- Molecular Biology
Background:
- Medulloblastoma is the most common malignant childhood brain tumor.
- DDX3X mutations are frequent in WNT and SHH medulloblastoma subtypes.
- The precise role of DDX3X in medulloblastoma and hindbrain development remains unclear.
Purpose of the Study:
- To investigate the function of DDX3X in hindbrain development and medulloblastoma.
- To determine whether DDX3X acts as an oncogene or tumor suppressor in medulloblastoma.
Main Methods:
- Utilized mouse models of WNT- and SHH-driven medulloblastoma.
- Analyzed Ddx3x's role in regulating Hox gene expression and cell stress signaling.
- Examined the impact of Ddx3x deletion on medulloblastoma lineage restriction.
Main Results:
- Ddx3x regulates hindbrain patterning and development by controlling Hox gene expression and cell stress signaling.
- Ddx3x functions as a tumor suppressor, sensing oncogenic stress and inhibiting medulloblastoma formation in mice.
- Deletion of Ddx3x removes lineage restriction, allowing both WNT and SHH medulloblastoma subtypes to arise in either germinal zone.
Conclusions:
- DDX3X is a critical tumor suppressor gene in medulloblastoma.
- DDX3X plays a vital role in hindbrain development and restricts cell lineage competence for medulloblastoma formation.
