title: Elucidation and Pharmacological Targeting of Novel Molecular Drivers of Follicular Lymphoma Progression.
abstract: Follicular lymphoma, the most common indolent subtype of non-Hodgkin lymphoma, is associated with a relatively long overall survival rate ranging from 6 to 10 years from the time of diagnosis. However, in 20% to 60% of follicular lymphoma patients, transformation to aggressive diffuse large B-cell lymphoma (DLBCL) reduces median survival to only 1.2 years. The specific functional and genetic determinants of follicular lymphoma transformation remain elusive, and genomic alterations underlying disease advancement have only been identified for a subset of cases. Therefore, to identify candidate drivers of follicular lymphoma transformation, we performed systematic analysis of a B-cell-specific regulatory model exhibiting follicular lymphoma transformation signatures using the Master Regulator Inference algorithm (MARINa). This analysis revealed FOXM1, TFDP1, ATF5, HMGA1, and NFYB to be candidate master regulators (MR) contributing to disease progression. Accordingly, validation was achieved through synthetic lethality assays in which RNAi-mediated silencing of MRs individually or in combination reduced the viability of (14;18)-positive DLBCL (t-DLBCL) cells. Furthermore, specific combinations of small-molecule compounds targeting synergistic MR pairs induced loss of viability in t-DLBCL cells. Collectively, our findings indicate that MR analysis is a valuable method for identifying bona fide contributors to follicular lymphoma transformation and may therefore guide the selection of compounds to be used in combinatorial treatment strategies.
authors.affiliation: Department of Systems Biology, Columbia University, New York, New York.
authors.forename: Brygida
authors.initials: B
authors.lastname: Bisikirska
authors.affiliation: Department of Systems Biology, Columbia University, New York, New York.
authors.forename: Mukesh
authors.initials: M
authors.lastname: Bansal
authors.affiliation: Department of Systems Biology, Columbia University, New York, New York.
authors.forename: Yao
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York. Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Julie
authors.initials: J
authors.lastname: Teruya-Feldstein
authors.affiliation: Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Raju
authors.initials: R
authors.lastname: Chaganti
authors.affiliation: Department of Systems Biology, Columbia University, New York, New York. ac2248@cumc.columbia.edu.
authors.forename: Andrea
authors.initials: A
authors.lastname: Califano
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D018450:Disease Progression; D006801:Humans; D008224:Lymphoma, Follicular / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D058990:Molecular Targeted Therapy / Q000379:methods