Parnad Basu, Amity University Kolkata
Lymphoma is a type of cancer that occurs in the human lymphatic system- the network that fights the body’s diseases. It includes the lymph nodes, bone marrow, spleen, and the thymus gland. There are mainly two major subtypes of lymphoma, Hodgkin’s lymphoma and non-Hodgkin’s lymphoma (NHL). Hodgkin’s lymphoma has Reed-Sternberg (RS) cells which are found to be absent in NHL. NHL can be further divided into B-cell lymphoma, T-cell lymphoma, Burkitt’s lymphoma, etc. And Hodgkin’s lymphoma can be divided into Lymphocyte-depleted Hodgkin’s disease, Lymphocyte-rich Hodgkin’s disease, etc.
Recently, a study conducted on a type of NHL known as Burkitt’s lymphoma (BL), was published in the journal Molecular Cell. In previous studies, it was seen that DDX3X (ubiquitously expressed RNA helicase) mutates frequently in BL. BL appears from the GC (germinal center) stage of B-cell development. Here B-cells go through somatic hypermutation for which an oncoprotein MYC is required. However, the expression of MYC is transient and is limited to a small portion of GC B-cells.
The Study
In this particular study, scientists investigated the role of DDX3X mutations in BL and MYC-driven DLBCL (diffuse large B cell lymphoma). Researchers have disclosed that the early stages of MYC-driven lymphomagenesis are facilitated by the loss-of-function mutations of DDX3X. The ectopic expression of DDX3Y helps the lymphoma cells restore full translation. This results in the loss of DDX3X and gain of DDX3Y. This helps the cells to adopt the level of protein synthesis needed for tumor development.
Results of the study
DDX3X is preferentially mutated in MYC-driven lymphomagenesis (the growth and development of lymphoma). In this study, targeted sequencing was applied to 39 BL cases. Despite being one of the most frequently mutated genes, the role of DDX3X is not very well known. Out of those 39 cases, 12 have shown the mutation of DDX3X. However, when applied to 928 DLBCL only 5.2% showed DDX3X mutation. Scientists have also suggested that the functional effect of DDX3X mutations can be different between cancer types. It was suggested that nonsense and frameshift mutations were frequently found in lymphoma.
DDX3X mutation cooperates with MYC in ex vivo cultured human GC B-cells: In this study, the scientists used a strategy to transduce and culture primary human GC B cells in a co-culture system. It was designed to mimic the GC microenvironment. Genetic manipulation was done to recreate the early stages of human GC lymphomagenesis. By doing so a competitive advantage was observed. It was observed with both the dominant-negative DDX3X mutant and MYC. Even though this competitive advantage was not observed in cells cotransduced with DDX3Y. In addition to that, in mutant DDX3X transduced cells no competitive advantage was detected.
Protein and mRNA interactomes implicate DDX3X in the regulation of mRNA translation in lymphocytes: Identifying DDX3X-interacting proteins is necessary to understand their role in human lymphoid cells. Immunoprecipitation (IP) and mass spectrometry (MS) were performed on endogenous DDX3X. This resulted in the expression of WT and R475S helicase mutant DDX3X.
Conclusion and limitations
This study revealed the requirement of a complex stage-specific DDX3X helicase activity. The findings also tell us about the therapeutic strategies for MYC-driven lymphoma. Where drugs disrupting the delicate balance of proteotoxic stress and translation can be a huge breakthrough. However, path-breaking has some limitations. Such as, ddx3x mutation has not been observed in murine models of BL. Further studies on this matter can help us to understand and administer drugs for MYC-driven lymphoma.
Also read: Use of Nanoclusters in protecting precious Metals
Reference:
- Gong, C., Krupka, J. A., Gao, J., Grigoropoulos, N. F., Giotopoulos, G., Asby, R., Screen, M., Usheva, Z., Cucco, F., Barrans, S., Painter, D., Zaini, N. B. M., Haupl, B., Bornelöv, S., Ruiz De Los Mozos, I., Meng, W., Zhou, P., Blain, A. E., Forde, S., Hodson, D. J. (2021). Sequential inverse dysregulation of the RNA helicases DDX3X and DDX3Y facilitates MYC-driven lymphomagenesis. Molecular Cell, S1097276521006250. https://doi.org/10.1016/j.molcel.2021.07.041
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