title: Identification of potential glucocorticoid receptor therapeutic targets in multiple myeloma.
abstract: Glucocorticoids (GC) are a cornerstone of combination therapies for multiple myeloma. However, patients ultimately develop resistance to GCs frequently based on decreased glucocorticoid receptor (GR) expression. An understanding of the direct targets of GC actions, which induce cell death, is expected to culminate in potential therapeutic strategies for inducing cell death by regulating downstream targets in the absence of a functional GR. The specific goal of our research is to identify primary GR targets that contribute to GC-induced cell death, with the ultimate goal of developing novel therapeutics around these targets that can be used to overcome resistance to GCs in the absence of GR. Using the MM.1S glucocorticoid-sensitive human myeloma cell line, we began with the broad platform of gene expression profiling to identify glucocorticoid-regulated genes further refined by combination treatment with phosphatidylinositol-3'-kinase inhibition (PI3Ki). To further refine the search to distinguish direct and indirect targets of GR that respond to the combination GC and PI3Ki treatment of MM.1S cells, we integrated 1) gene expression profiles of combination GC treatment with PI3Ki, which induces synergistic cell death; 2) negative correlation between genes inhibited by combination treatment in MM.1S cells and genes over-expressed in myeloma patients to establish clinical relevance and 3) GR chromatin immunoprecipitation with massively parallel sequencing (ChIP-Seq) in myeloma cells to identify global chromatin binding for the glucocorticoid receptor (GR). Using established bioinformatics platforms, we have integrated these data sets to identify a subset of candidate genes that may form the basis for a comprehensive picture of glucocorticoid actions in multiple myeloma. As a proof of principle, we have verified two targets, namely RRM2 and BCL2L1, as primary functional targets of GR involved in GC-induced cell death.
authors.affiliation: Northwestern University, Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois (ALT, JQ, NLK, STR); Baylor College of Medicine, Department of Molecular and Human Genetics, Houston, Texas (CC, JJW, KR); University of Houston, Department of Biology and Biochemistry, Houston, Texas (JJW, PHG) and Feinberg School of Medicine, Northwestern University, Department of Medicine, Chicago, Illinois (STR).
authors.forename: Alexandra L
authors.initials: AL
authors.lastname: Thomas
authors.affiliation: Northwestern University, Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois (ALT, JQ, NLK, STR); Baylor College of Medicine, Department of Molecular and Human Genetics, Houston, Texas (CC, JJW, KR); University of Houston, Department of Biology and Biochemistry, Houston, Texas (JJW, PHG) and Feinberg School of Medicine, Northwestern University, Department of Medicine, Chicago, Illinois (STR).
authors.forename: Cristian
authors.initials: C
authors.lastname: Coarfa
authors.affiliation: Northwestern University, Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois (ALT, JQ, NLK, STR); Baylor College of Medicine, Department of Molecular and Human Genetics, Houston, Texas (CC, JJW, KR); University of Houston, Department of Biology and Biochemistry, Houston, Texas (JJW, PHG) and Feinberg School of Medicine, Northwestern University, Department of Medicine, Chicago, Illinois (STR).
authors.forename: Jun
authors.initials: J
authors.lastname: Qian
authors.affiliation: Northwestern University, Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois (ALT, JQ, NLK, STR); Baylor College of Medicine, Department of Molecular and Human Genetics, Houston, Texas (CC, JJW, KR); University of Houston, Department of Biology and Biochemistry, Houston, Texas (JJW, PHG) and Feinberg School of Medicine, Northwestern University, Department of Medicine, Chicago, Illinois (STR).
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Wilkerson
authors.affiliation: Northwestern University, Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois (ALT, JQ, NLK, STR); Baylor College of Medicine, Department of Molecular and Human Genetics, Houston, Texas (CC, JJW, KR); University of Houston, Department of Biology and Biochemistry, Houston, Texas (JJW, PHG) and Feinberg School of Medicine, Northwestern University, Department of Medicine, Chicago, Illinois (STR).
authors.forename: Kimal
authors.initials: K
authors.lastname: Rajapakshe
authors.affiliation: Northwestern University, Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois (ALT, JQ, NLK, STR); Baylor College of Medicine, Department of Molecular and Human Genetics, Houston, Texas (CC, JJW, KR); University of Houston, Department of Biology and Biochemistry, Houston, Texas (JJW, PHG) and Feinberg School of Medicine, Northwestern University, Department of Medicine, Chicago, Illinois (STR).
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Krett
authors.affiliation: Northwestern University, Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois (ALT, JQ, NLK, STR); Baylor College of Medicine, Department of Molecular and Human Genetics, Houston, Texas (CC, JJW, KR); University of Houston, Department of Biology and Biochemistry, Houston, Texas (JJW, PHG) and Feinberg School of Medicine, Northwestern University, Department of Medicine, Chicago, Illinois (STR).
authors.forename: Preethi H
authors.initials: PH
authors.lastname: Gunaratne
authors.affiliation: Northwestern University, Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois (ALT, JQ, NLK, STR); Baylor College of Medicine, Department of Molecular and Human Genetics, Houston, Texas (CC, JJW, KR); University of Houston, Department of Biology and Biochemistry, Houston, Texas (JJW, PHG) and Feinberg School of Medicine, Northwestern University, Department of Medicine, Chicago, Illinois (STR).
authors.forename: Steven T
authors.initials: ST
authors.lastname: Rosen
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D023281:Genomics; D006801:Humans; D058990:Molecular Targeted Therapy; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009711:Nucleotides / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D012262:Ribonucleoside Diphosphate Reductase / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D009711:Nucleotides; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011965:Receptors, Glucocorticoid; D051020:bcl-X Protein; D003907:Dexamethasone; C093713:ribonucleotide reductase M2; D012262:Ribonucleoside Diphosphate Reductase
keywords: BCL2L1; ChIP-Seq; RRM2; glucocorticoid receptor; multiple myeloma