The X-linked gene for the helicase DDX3X is required for lymphoid differentiation and MYC-driven lymphomagenesis

Abstract

Abstract The X-linked gene DDX3X encodes an RNA helicase and is mutated at high frequencies in several types of human B-cell lymphoma. Females have two active DDX3X alleles and males carry a DDX3Y homolog on the Y chromosome. We show here that pan-hematopoietic, homozygous deletion of Ddx3x in female mice perturbs erythropoiesis causing early developmental arrest. However, both hemizygous male and heterozygous female embryos develop normally, suggesting that one Ddx3x allele is sufficient for fetal hematopoietic development in females and that the Ddx3y allele can compensate for the loss of Ddx3x in males. In adult mice, loss of DDX3X affects hematopoietic progenitors, early lymphoid development, marginal zone and germinal center B-cells and lymphomagenesis driven by an Em-Myc transgene in a sex-dependent manner. Loss of one Ddx3x allele slightly accelerated MYC-driven lymphomagenesis in female mice, while male Em-Myc mice lacking Ddx3x remained almost lymphoma-free. However, the few tumors that appeared in male mice showed upregulated expression of DDX3Y indicating a minimal requirement for DDX3 activity for lymphomagenesis. Our data reveal sex specific roles of DDX3X in erythro- and lymphopoiesis as well as in MYC-driven lymphomagenesis, which are important when considering inhibition of DDX3 as a treatment of B-cell lymphoma. Tarik Möröy holds a Canada Research Chair (Tier 1), a Foundation grant from the CIHR (FDN-148372) and support from the Cancer Research Society (CRS). Marion Lacroix is supported by fellowships from the Cole Foundation and the IRCM.