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

B lymphocytes are cells that are one of the major pillars of our immune response since they generate antibodies to protect us against bacteria, viruses or parasites. A subset of these cells remain active for long periods of time and provide us with a lasting immunity against recurring infections. Like all blood and immune cells, B cells are generated by hematopoietic stem cells via their progeny, the common lymphoid progenitors (CLPs), that reside in the bone marrow. CLPs differentiate into immature B cells which leave the bone marrow and settle in the spleen and lymph nodes where they become part of the so called germinal center (GC), a defined region where follicular dendritic cells present antigen to B cells and stimulate them to produce very specific antibodies. This process called affinity maturation provides an efficient immune response, but at the same time is very risky since it involves mutations and rearrangements of parts of the genome that can in rare cases lead to the activation of oncogenes and to the development of malignancies called B cell lymphoma. These types of cancers are deadly if not treated and are characterized by specific mutations. A combination of those mutations has recently raised much interest in the research community, because they arise together in a subset of GC B cell derived malignant lymphomas it involves the activation and mutation of the c-MYC and DDX3X genes.

The c-MYC gene encodes a transcription factor that regulates a myriad of genes and when expressed at high levels can lead to uncontrolled proliferation of cells and is therefore classified as an oncogene. The DDX3X gene encodes an RNA helicase with many functions in RNA metabolism including mRNA translation, alternative pre-mRNA splicing and mRNA stability. However, in contrast to the well-known functions of c-MYC, the role of DDX3X in B cells and B cell lymphomas had not been unveiled. What is known is that in humans and mice the DDX3X gene is located on the X-chromosome and females therefore have two active copies whereas males only have one. The case of the DDX3X gene is a particular one, since it escapes a process called X-Inactivation, which represses the expression of one copy of genes on the X-chromosome in females. The Y chromosome contains a male DDX3 homologue, called DDX3Y, which is almost identical to DDX3X, but its expressed in humans is very restricted.

In a new study published in the peer-reviewed journal Cancer Research, Professor Tarik Moroy and colleagues from Institut de recherches cliniques de Montreal (Montreal Clinical Research Institute, IRCM) describe how their findings with gene deficient and transgenic mice has shed new light on the interplay between c-MYC and DDX3X in B cell lymphoma. The Canadian researchers have created mice that are conditionally deficient for Ddx3x to mimic loss of function mutations in the human DDX3X gene that occur in those GC derived B cell lymphoma that also have a c-MYC activation. They confirmed with their mouse model that DDX3X plays a crucial, sex-dependent function in various stages of erythropoiesis and in lymphoid development. Most importantly, their experiments demonstrated differential effects of the loss of DDX3X for MYC-driven lymphomagenesis between male and female mice. Their findings indicate that DDX3X is most likely necessary to maintain proliferative growth of GC cells. Additionally, the authors’ study offers first answers to the question whether the male homologue of DDX3, DDX3Y, is expressed during the creation of blood cells and whether it can perform the same function as DDX3X. It would be consistent with the idea that DDX3Y can replace DDX3X loss, at least in foetal erythropoiesis, if male mice lacking Ddx3x but retaining Ddx3y were generated at a mendelian ratio but live-born female mice lacking both Ddx3x alleles were never acquired. Their major finding however suggests that female animals with an activated c-MYC gene, which normaly develop lymphomas rapidly, remain healthy when they are lack DDX3X in their B cells. In male mice with an activated c-MYC gene, lymphomas develop in absence of DDX3X, but only when the expression of the DDX3Y paralog is upregulated, suggesting strongly that DDX3 helicase activity is strictly necessary for lymphomagenesis, at least in this mouse model. Studies done by other groups on human B cell lymphoma with heterozygous loss of function mutations of the DDX3X gene support this hypothesis, because the lymphoma cells either contain a second functional DDX3X allele in females or upregulate expression of the DDX3Y in males.

In a nutshell,  Professor Tarik Moroy  and the research team showed that DDX3X plays sex-specific roles in lymphogenesis, erythropoiesis, and MYC-driven lymphomagenesis. The authors proposed DDX3 suppression as a therapeutic target for MYC-driven B-cell lymphoma which is supported by the sex-dependent effects of DDX3X loss on the malignant transformation of B cells and the compensatory involvement of DDX3Y.