No abstract

Diffuse large B-cell lymphoma (DLBCL) is a biologically and clinically heterogenous disease. Transcriptomic and genetic characterization of DLBCL have increased the understanding of its intrinsic pathogenesis and provided potential therapeutic targets. However, the role of the microenvironment in DLBCL biology remains less understood. Here, we performed a transcriptomic analysis of the microenvironment of 4,655 DLBCLs from multiple independent cohorts and described four major lymphoma microenvironment categories that associate with distinct biological aberrations and clinical behavior. We also found evidence of genetic and epigenetic mechanisms deployed by cancer cells to evade microenvironmental constrains of lymphoma growth; supporting the rationale for implementing DNA hypomethylating agents in selected DLBCL patients. In addition, our work uncovered new therapeutic vulnerabilities in the biochemical composition of the extracellular matrix that were exploited to decrease DLBCL proliferation in pre-clinical models. This novel classification provides a roadmap for the biological characterization and therapeutic exploitation of the DLBCL microenvironment.

Most familial early-onset Alzheimer's disease cases are caused by mutations in the presenilin 1 (PS1) gene. Subcellular localization of the endogenous PS1 is essential for understanding its function, interactions with proteins, and role in Alzheimer's disease. Although numerous studies revealed predominant localization of PS1 to endoplasmic reticulum and Golgi, there are conf licting reports on the localization of PS1 to the cell surface. We found that endogenous PS1 is highly expressed in T lymphocytes (Jurkat cells). Using a variety of methods, we present evidence that endogenous PS1 is localized to the cell surface in addition to intracellular membrane compartments. Moreover, PS1 appeared in high levels on the surface of lamellipodia upon adhesion of the cells to a collagen matrix. The redistribution of PS1 in adhered cells was strikingly similar to that of the well characterized adhesion protein CD44. Cell surface PS1 formed complexes in vivo with actin-binding protein filamin (ABP-280), which is known to form bridges between cell surface receptors and cytoskeleton and mediate cell adhesion and cell motility. Taken together, our results suggest a role of PS1 in cell adhesion and͞or cell-matrix interaction.The presenilin (PS1 and PS2) genes have been identified as major causal genes for early-onset familial Alzheimer's disease (FAD) (1-3). However, the biological functions of presenilins are unknown.The presenilins are integral membrane proteins with a proposed structure of seven to eight hydrophobic transmembrane domains and a hydrophilic loop located between transmembrane domains 6 and 7 (1). More than 60% of amino acid residues in the sequence of PS1 and PS2 are conserved (1, 3). FAD mutations are found throughout the entire molecule of PS1 (4-6).Northern blot analysis and in situ hybridization studies of PS1 and PS2 mRNAs demonstrate a widespread, uniform expression of RNAs both in the brain and peripheral tissues of humans and rodents (1, 7-9). A high level of expression of endogenous presenilins was detected only in neurons (8, 9).Light and electron microscopy studies revealed predominant localization of PS1 and PS2 to endoplasmic reticulum-Golgi compartments and to coated transport vesicles in neurons and in various cell types transfected by PS1 or PS2 cDNAs (9-12). In addition, immunocytochemical studies of transfected cells have identified PS-1 in the nuclear membrane, interphase kinetochores, and centrosomes (13). Conflicting results were reported for localization of PS1 to the plasma membrane (10,(14)(15)(16).PS1 reveals approximately 50% homology with Caenorhabditis elegans protein sel-12 (17), which facilitates signaling mediated by the Notch͞lin-12 family receptors. Notch receptors are cell surface proteins that regulate cell-cell interactions and cell fate choices during T cell and neural development (18,19). The expression of Notch 1 mRNA is decreased significantly in the presomitic mesoderm of PS1 null mice characterized by massive neuronal loss in specific subregions of the mutant br...