DDX3X Suppresses the Susceptibility of Hindbrain Lineages to Medulloblastoma

Abstract

DDX3X is frequently mutated in the WNT and SHH subtypes of medulloblastomathe 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 Shhmedulloblastoma, Ddx3x sensed oncogenic stress and suppressed tumor formation. WNT and SHHmedulloblastomas 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.

Developmental and behavioral phenotypes in a new mouse model of DDX3X syndrome

“…We sought to generate a novel mouse line with construct validity for loss-of-function mutations clinically associated with DDX3X syndrome. Two Ddx3x knockout (KO) lines have been published (17, 18, 31), but the female heterozygous progeny have not been examined. Also, one of these lines (18, 31) is a brain-specific conditional and thus has limited construct validity.…”

“…The developmental mechanisms underlying DDX3X syndrome are just beginning to emerge. Evidence from mouse studies indicate that Ddx3x is required for embryogenesis (17), hindbrain development (18), corticogenesis (3), and synaptogenesis (10). Ddx3x germline knockout in the mouse results in placentation defects, followed by early lethality at embryonic day E6.5 (17).…”

“…Ddx3x heterozygous females were described as grossly normal, but were not characterized from developmental or behavioral perspectives (17). Mice with a Ddx3x conditional deletion in neural stem cells at E9.5 survive but show altered brain growth, especially at the expense of the cerebellum, accompanied by severe ataxia and seizures (18). In addition, Ddx3x regulates cortical neurogenesis: knockdown of ~25% Ddx3x in cortical neuronal progenitors at E14.5 impacts their differentiation into neurons (3).…”

“…While Ddx3x has been found to regulate brain development (3, 18), its role in postnatal and adult behavior is unknown. Also, while studies have showed that Ddx3x is needed for corticogenesis (3) and synaptogenesis (10), the lack of analyses in an animal model has limited our ability to relate these cellular functions to behavior.…”

Mutational analysis of extranodal marginal zone lymphoma using next generation sequencing

“…Dysregulation of DDX3X has been associated with tumorigenesis caused by loss of function ( 75 ). Furthermore, DDX3X has been identified as a mutational cancer driver in medulloblastoma, cutaneous melanoma and chronic lymphocytic leukemia by PAN-cancer analysis ( 76 – 78 ). However, to the best of our knowledge, the role of DDX3X in MALT lymphoma has not been elucidated and the relationship between DDX3X mutations and disease occurrence has not been clarified.…”