The role of the RNA helicase DDX3 in B cell differentiation and malignant transformation

• Applicant: Dr. Eva-Maria Piskor
• Subject Area: Hematology, Oncology ; Immunology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 559980616

Lymphomas are cancers originating in the hematopoetic system, characterized by uncontrolled growth of transformed lymphocytes. Burkitt’s lymphoma (BL), are highly aggressive and primarily affect children and young adults, with five-year survival rates varying significantly between 90.4% in children and 28.9% in older patients. The molecular cause of BL are genetic abnormalities involving the MYC oncogene, where chromosomal translocations position MYC under the control a constitutively active promoter in B cells and leads to their malignant cell growth. This translocation results from off-target effects of 'Activation induced cytidine deaminase' (AICD or AID) in B cells. AID mediates antibody affinity maturation and class-switch recombination by inducing DNA lesions in the Immunoglobulin (Ig) locus. The basis of AID recognition of target sites within the switch regions (Sμ) of the Ig locus are so called R-loops, consisting of three stranded DNA:RNA hybrids, serving as substrates of AID. Other genomic loci, like the MYC locus, also show R-loop formation for transcriptional regulation. Resolution of R-loops by topoisomerases and helicases is critical to prevent mis-regulation of the DNA damage response, and to preserve genomic integrity. However, if not resolved, persisting R-loop formation within Ig and other gene loci render cells susceptible to unintended chromosomal translocations as seen in BL. The RNA helicase DDX3 unwinds RNA-RNA and RNA-DNA strands, remodels RNA-protein complexes and contributes to prevents genomic instability. The protein has two variants, DDX3X and DDX3Y on the X- and Y-chromosome respectively. DDX3X function is crucial for germinal center B cell expansion and immunocompetence, as DDX3X-deficiency abrogates GC B development, subsequent antibody production and increases the susceptibility to infection. Additionally, Loss of function (LOF) mutations in DDX3X are found in over 30% of BL cases, predominantly in males and correlates with highly aggressive and chemoresistance. Male patients with DDX3X LOF mutations often upregulate DDX3Y, suggesting a compensatory mechanism for loss of DDX3X. Furthermore, current standard treatments for BL involve intensive chemotherapy regimens. However, pediatric Burkitt’s lymphoma patients often suffer from secondary malignancies, likely caused by chemotherapy, highlighting the need to identify new treatment approaches with less side effects. However, the mechanism of action of both, DDX3X and Y, in B cell function and lymphomagenesis remains unresolved. The project aims to unravel the physiological role of DDX3X or Y for normal B cell function and GC development and if the proteins act as "onco-requisite factors" that are necessary for the malignant transformation of B cells in Burkitt’s lymphoma. The results of this project will identify the molecular role of DDX3 in lymphomagenesis and thereby open new potential treatment strategies against B cell lymphoma.

• DFG Programme: WBP Fellowship
• International Connection: Canada
• Host: Professor Dr. Tarik Möröy