Data from The X-Linked Helicase DDX3X Is Required for Lymphoid Differentiation and MYC-Driven Lymphomagenesis

Abstract

<div>Abstract<p>The X-linked gene <i>DDX3X</i> encodes an RNA helicase that is mutated at high frequencies in several types of human B-cell lymphoma. Females have two active <i>DDX3X</i> alleles and males carry a <i>DDX3Y</i> homolog on the Y chromosome. We show here that pan-hematopoietic, homozygous deletion of <i>Ddx3x</i> in female mice perturbs erythropoiesis, causing early developmental arrest. However, both hemizygous male and heterozygous female embryos develop normally, suggesting that one <i>Ddx3x</i> allele is sufficient for fetal hematopoietic development in females and that the <i>Ddx3y</i> allele can compensate for the loss of <i>Ddx3x</i> in males. In adult mice, DDX3X deficiency altered hematopoietic progenitors, early lymphoid development, marginal zone and germinal center B cells, and lymphomagenesis in a sex-dependent manner. Loss of both <i>Ddx3x</i> alleles abrogated MYC-driven lymphomagenesis in females, whereas <i>Ddx3x</i> deletion in males did not affect the formation of B-cell lymphoma in both mouse models. Moreover, tumors that appeared in male mice lacking DDX3X showed upregulated expression of DDX3Y, indicating a critical requirement for DDX3 activity for lymphomagenesis. These data reveal sex-specific roles of DDX3X in erythro- and lymphopoiesis as well as in MYC-driven lymphomagenesis.</p>Significance:<p>The sex-dependent effects of DDX3X deficiency in malignant transformation of B cells and the compensatory role of DDX3Y support inhibition of DDX3 as a treatment strategy for MYC-driven B-cell lymphoma.</p></div>