Universität Tübingen
MyD88 mutations in B cell tumors: constitutive signaling by TIR domain oligomerization
Abstract
Myeloid differentiation primary response 88 (MyD88) is the key adaptor protein that mediates signals upon activation of Toll-like receptors (TLR) and the IL-1 receptor (IL-1R). MyD88 consists of a Toll/IL-1R (TIR) domain that interacts with TIR domains of receptors or other adaptor proteins, whereas the death domain (DD) recruits downstream IL-1R-associated kinases (IRAKs) to form the so-called Myddosome signaling complex. A leucine to proline substitution of the amino acid residue 265 (L265P) within the TIR domain of MyD88 has recently been described as a very frequent somatic mutation in several types of B cell non-Hodgkin lymphomas, all of which are associated with considerable mortality; i.e. diffuse large B cell lymphoma (DLBCL), Waldenström’s macroglobulinemia (WM), mucosa-associated lymphoid tissue lymphoma (MALT) and chronic lymphocytic leukemia (CLL). Recent reports revealed MyD88 L265P strongly increases binding and activation of IRAK1 as well as Bruton’s tyrosine kinase (BTK), thus these interactions are suggested to sustain cancer cell survival by constitutive activation of the transcription factor NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells). However, the precise molecular events leading to NF-κB hyperactivation and whether other B cell-intrinsic pathways are affected still remains unknown. In an effort to address these questions we found that the hyperactive phenotype of MyD88 L265P is caused by increased oligomerization propensity of the mutated TIR domain. L265P TIR domains in contrast to WT TIRs were alone able to trigger cell activation by strongly interacting with and therefore utilizing WT MyD88, possibly explaining why heterozygous mutation could be sufficient to trigger tumorigenesis. Confocal microscopy revealed cytosolic aggregation of TIR-mutants. MyD88 L265P colocalized with IRAKs indicating that L265P mutant assembly of oligomeric Myddosome post-receptor complexes leads to cell activation. Furthermore, cell lysates of L265P-mutated lymphoma cell lines contained complexes of high molecular weight including MyD88 and IRAK1, indicative for Myddosomes and confirming the aggregation phenotype of the mutant. Consequently blocking MyD88 oligomerization induced death of L265P-mutated but not WT DLBCL cells. Preliminary data indicate that L265P alters binding of MyD88 to several proteins which are important for regulatory circuits in B cell carcinogenesis. We plan to corroborate these findings in primary tumor cells and in vitro murine models, and propose to evaluate and utilize novel insights of how L265P may modulate tumor cell persistence by using small molecule inhibitors targeting the newly discovered interaction partners.
Author and committee
dc:creator, dc:contributor.*- Author
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- Wolz, Olaf-Oliver
Identifiers
dc:identifier.*- Identifier
- hdl:10900/69312