Mouse model of MYD88L265P-dependent DLBCL.

The frequent detection of a highly recurrent, oncogenic, gain-of-function mutation that substitutes a leucine (L) residue at position 265 of the adapter protein myeloid differentiation primary response gene 88 (MYD88) with a proline (P) residue has implicated the mutant MYD88 allele in the natural history and clinical outcome of an important subset of diffuse DLBCL. However, a genetically engineered mouse model (GEMM) for indepth mechanistic studies on the role of MYD88 in the biology and genetics of DLBCL has been lacking. In their article, Knittel and his associates remedy this shortcoming by recapitulating the MYD88 mutation in B lymphocytes of transgenic mice that go on to develop DLBCL-like neoplasms. DLBCL, the most common non-Hodgkin lymphoma in the United States, has 2 major subtypes, as defined by distinct gene expression programs that correspond to different putative cells of origin: a germinal center B cell in the case of GCB-DLBCL and a plasmablast (activated B cell) in the case of ABC-DLBCL. Combination chemotherapy results in ;80% 3-year survival for patients with GCB-DLBCL but achieves only 45% survival for patients with ABC-DLBCL. Thus, ABC-DLBCL patients have an unmet medical need that warrants additional research efforts and new therapeutic options. A well-established hallmark of ABCDLBCL is the constitutive activation of the classicalNF-kBpathway. In;40%of patients, this is accomplished by somatic (acquired) mutations in MYD88, an adaptor protein of crucial importance for cellular signal transduction pathways that govern pattern recognition, inflammation, innate and adaptive immune responses and, importantly,malignant cell transformation. MYD88 links upstream members of the Toll-like receptor and interleukin-1 receptor superfamily (see figure) with downstream effector hubs that regulate, in addition to NF-kB, Janus kinase signal transducer and activator of transcription (JAK-STAT), mitogen-activated protein kinases (MAPKs), and type-I interferon (IFN) binding to the IFN-a/b receptor signaling in ABC-DLBCL and other cells. Evidence indicates that the L265P substitution is the most common and most oncogenic representative of a variety of mutations that occur inMYD88 in ABCDLBCL. Moreover, the L265P exchange is of predictive value for these patients because it is associated with extranodal tumor dissemination and poor clinical outcome. Subsequent to its discovery in ABC-DLBCL, the MYD88 mutation has also been found in the great majority of patients with Waldenström macroglobulinemia (nearly 100%) and a fraction of patients with primary central nervous system lymphoma (;35%), splenic marginal zone lymphoma (;15%), gastric mucosa-associated lymphoid tissue lymphoma (;9%), and chronic lymphocytic leukemia (;3%). These findings demonstrated that MYD88 is by no means specific for ABC-DLBCL; instead, it is broadly involved in the natural history of a large subset of mature B-lineage neoplasms. Fully appreciating that lymphoma modeling in transgenic mice enables fundamental and translational studies that are difficult to pursue in humans, Knittel et al used an elegant genetic engineering tool to express the orthologous mouse allele of human MYD88,Myd88, in laboratory mice. This was accomplished by Cre recombinaseinduced activation of anMYD88 knockin gene inserted into the germline Myd88 locus using homologous recombination (gene targeting) in embryonic stem cells. The investigators took advantage of three different Cre drivers (AID,CD19, andCD22) to express MYD88 in different B-cell populations. Regardless, transgenic mice from all experimental groups developed lymphoma that shared important features with human ABCDLBCL. Practical limitations relating to tumor incidence (low) and tumor onset (long) were readily overcome by co-expression of theMyc oncogene. Thus, Knittel et al achieved, for the first time, a GEMM of MYD88-driven ABC-DLBCL. Another advance reported by Knittel et al concerns the collaboration of MYD88 and deregulated expression of B-cell leukemia TRAF6