Transformation of FL into DLBCL with a PMBL gene expression signature.

We investigated the clinicopathologic features of 5 follicular lymphomas (FLs) that transformed (tFL) morphologically to diffuse large B-cell lymphomas (DLBCLs) and had a primary mediastinal large B-cell lymphoma (PMBL)-like gene expression profile (tFL-PMBLsig-pos). None of the tFL-PMBLsig-pos cases arose in the mediastinum, all cases tested had a germinal center B-cell phenotype, 20% were CD30+, 60% CD23+, 80% MAL+, 20% CD200+, and 0% CD273/PDL2+. Whole-exome sequencing detected alterations in genes associated with both FL/DLBCL (CREBBP, KMT2C, KMT2D, ARID1A, HIST1 members, and TNFRSF14) and PMBL (JAK-STAT pathway genes, B2M, and CD58). Copy number (CN) analysis detected gains/amplification of REL and STAT6 in 60%, gains of SOCS1 in 40%, and gains of chromosome 16, including IL4R, in 40% of the cases. CN gains/amplification of BCL6 and MYC and loss of TNFRSF14 and TNFAIP3 were identified in 20% of the cases. Three of 5 cases lacked a BCL2 rearrangement. Despite having some features that are less common in DLBCL (MAL and CD23 expression and JAK-STAT activation), these tFL-PMBLsig-pos cases lack the most characteristic CN alteration seen in PMBL (9p24.1 gain/amplification). This cohort expands the biologic heterogeneity of tFL, illustrating a subset with gene expression and some genetic features reminiscent of PMBL, with potential treatment implications that include the use of novel targeted therapies.

Incorporation of Digital Gene Expression Profiling for Cell-of-Origin Determination (Lymph2Cx Testing) into the Routine Work-Up of Diffuse Large B-Cell Lymphoma.

Diffuse large B-cell lymphomas (DLBCL) represent a clinically heterogeneous group of lymphomas that are classified together based on similarities in morphology and immunophenotype. Gene expression profiling further classifies DLBCL into distinct molecular subgroups based on cell-of-origin (COO), including Germinal Center B-cell type, Activated B-cell type, and Unclassified type. COO assignment of DLBCL has important biological and prognostic significance, as well as emerging therapeutic implications. Herein, we describe the first clinical validation of a digital gene expression profiling assay (Lymph2Cx) to perform COO assignment in the routine work-up of DLBCL using formalin-fixed paraffin-embedded (FFPE) tissue sections and describe the results of 90 consecutive DLBCL cases analyzed prospectively by a College of American Pathologists/Clinical Laboratory Improvement Amendments (CAP/CLIA)-certified clinical molecular diagnostics laboratory.

Roles of genes 38, 39, and 40 in shutoff of host biosyntheses during infection of Bacillus subtilis by bacteriophage SPO1.

A nonsense mutation in SPO1 gene 40 prevented normal shutoff of both host DNA and host RNA synthesis, showing that gp40 is required for the normal occurrence of both shutoffs. A gene 39 nonsense mutation caused accelerated shutoff of both host DNA and host RNA synthesis (aided by a gene 38 nonsense mutation), showing that gp39 (aided by gp38) limits the rate at which both shutoffs occur. The 40(-) mutation suppressed the accelerative effects of the 39(-) and 38(-) mutations, showing that gp40 also plays an essential role in the accelerated shutoffs. To the best of our knowledge, proteins with the particular activities implied for gp39 and gp40 have not been identified in any other bacteriophage. SPO1 has at least three different mechanisms that have the effect of delaying the shutoff of host DNA and RNA synthesis.