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Cancer Res. 2016 Feb 1;76(3):664-74. doi: 10.1158/0008-5472.CAN-15-0828. Epub 2015 Nov 20.

Elucidation and Pharmacological Targeting of Novel Molecular Drivers of Follicular Lymphoma Progression.

Author information

1
Department of Systems Biology, Columbia University, New York, New York.
2
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.
3
Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York.
4
Department of Systems Biology, Columbia University, New York, New York. ac2248@cumc.columbia.edu.

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.

PMID:
26589882
PMCID:
PMC4738055
DOI:
10.1158/0008-5472.CAN-15-0828
[Indexed for MEDLINE]
Free PMC Article

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