Sha C, et al. - Diffuse large B-cell lymphoma (DLBCL) display biologic heterogeneity, and there is a subgroup with poor prognosis with phenotypic closeness to Burkitt lymphoma, so researchers sought to define a molecular high-grade (MHG) group by applying a gene expression–based classifier to 928 patients with DLBCL from a clinical trial that investigated the addition of bortezomib to standard rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy. Eighty-three patients (9%) were there in the MHG group, with 75 in the cell-of-origin germinal center B-cell-like group. In MHG, strong over-representation of MYC rearranged and double-hit groups was evident, but these contained only one half of the total. A proliferative phenotype with a relationship to centroblasts was identified in the gene expression analysis. The MHG group had progression-free survival rate of 37% at 36 months after R-CHOP compared with 72% for others. They thus suggest MHG defines a biologically coherent high-grade B-cell lymphoma group with separate molecular features and clinical outcomes that effectively doubles the size of the poor-prognosis, double-hit group. Intensified chemotherapy or novel targeted therapies may benefit patients with MHG.