Lymphoma is the sixth most common form of cancer, with 90% of cases belonging to a heterogeneous group of lymphomas called Non-Hodgkin Lymphoma (NHL). One of the most common types of NHL, Diffuse Large B Cell Lymphoma (DLBCL), is characterized into two subtypes on the basis of differential gene expression: Activated B Cell (ABC) and Germinal Centre (GC), of these ABC is the most aggressive and least curable form. Recurrent somatic mutations in MYD88 were initially identified in ABC-DLBCL patients. MYD88 is an adaptor protein that transmits innate immune signalling from Toll-like receptor (TLR) and interleukin-1 (IL-1) receptor to the nuclear factor-kappa B (NF-kB) pathway, for immune and inflammatory responses. The most frequent MYD88 mutation in lymphoma is a single amino acid variant L265P, identified in approximately 30% of ABC-DLBCL and 90% of Waldenström Macroglobulinemia (WM) patients. Apart from the L265P mutation, additional mutations in MYD88 have been reported in lymphoma. Moreover, genome-wide analysis of ABC-DLBCL and WM indicates that MYD88 L265P is preferentially found in combination with mutations in the B-cell antigen component CD79B and chemokine receptor CXCR4, which result in further induction of NF-κB pathway.
We are currently investigating the role of MYD88 in both normal development and immune cell function. For this purpose, we have developed Drosophila melanogaster and mouse model systems. In the fly model, we are investigating potential effects of Myd88 knockdown and CRISPR-generated Myd88 I335P substitutions (designed to mimic oncogenic MYD88 L265P) on hematopoietic development and immunity. In the mouse model, compound mutations (MYD88 loss-of-function together with MYD88 L265P) are being examined to determine potential of MYD88 L265P as a therapeutic target. Further to this, we are testing the combined effect of the MYD88 L265P mutation and CD79B mutations in our B cell lymphoma mouse models.