Elucidation and pharmacological targeting of novel molecular drivers of follicular lymphoma progression Journal Article

Authors: Bisikirska, B.; Bansal, M.; Shen, Y.; Teruya-Feldstein, J.; Chaganti, R.; Califano, A.
Article 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 smallmolecule compounds targeting synergistic MR pairs induced loss of viability in t-DLBCLcells. 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. © 2015 American Association for Cancer Research.
Keywords: human tissue; human cell; cancer growth; drug potentiation; drug targeting; cytarabine; molecular genetics; cell viability; gene; gene targeting; rna interference; b lymphocyte; gene silencing; large cell lymphoma; malignant transformation; follicular lymphoma; prostaglandin e1; lethality; genetic algorithm; transcription factor dp1; econazole; troglitazone; promazine; human; priority journal; article; clemastine; atf5 gene; foxm1 gene; hmga1 gene; nfyb gene; tfdp1 gene
Journal Title: Cancer Research
Volume: 76
Issue: 3
ISSN: 0008-5472
Publisher: American Association for Cancer Research  
Date Published: 2016-02-01
Start Page: 664
End Page: 674
Language: English
DOI: 10.1158/0008-5472.can-15-0828
PROVIDER: scopus
PMCID: PMC4738055
PUBMED: 26589882
Notes: Article -- Export Date: 3 March 2016 -- Source: Scopus
Citation Impact
MSK Authors
  1. Julie T Feldstein
    290 Feldstein
  2. Raju S K Chaganti
    353 Chaganti