Therapeutic targeting of the B-cell lymphoma associated mutation MYD88-L265P

University Of Maryland Baltimore, Baltimore MD

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Abstract

? DESCRIPTION (provided by applicant): The myeloid differentiation factor 88 (MYD88) acts as a central signaling adapter for mediating innate and cytokine driven inflammation for the Interleukin-1 (IL-1R) and Toll- like receptors (TLRs). A recurring single amino acid somatic mutation associated with nearly 1/3 of human diffuse large B cell lymphomas (DLBCLs), over 90% of Waldenstrom macroglobulinemia (WM) and 54% of immunoglobulin M monoclonal gammopathy, has been identified within MYD88. This gain of function single amino acid mutation correlates with tumor cell proliferation and survival involving chronic activation of MYD88-dependent NF-kB and Janus Kinase (JAK) signaling pathways. We hypothesize that in normal healthy cells, MYD88 is held in an auto-inhibitory state with its own death and TIR domains fused together in negative self-regulation until activated by appropriate receptor-ligand engagement, involving Toll-like or Interleukin-1 ligands. We propose the oncogenic mutation, MYD88L265P located within the TIR domain of MYD88 results in discrete structural changes within its TIR domain architecture, which releases binding and auto-inhibition. Defining the molecular mechanism of this recurring MYD88L265P mutation associated with human patient tumor isolates will rationally inform and propel development of novel therapeutics to counteract both inflammation as well as tumor cell formation. In this proposal we will: (1) Elucidate the molecular effects that MYD88L265P has on auto-inhibition and recruitment of death domain signaling by using biophysical, biochemical and functional characterization and protein engineering methods; (2) Characterize existing microbial derived peptides for the ability to block chronic and spontaneous signaling associated with the MYD88L265P mutation in both transfected HEK293T and tumor cell lines. Using a structure-based drug design approach, our long-term goal is development of novel small molecule therapeutics that inhibit acute and chronic inflammation.