NDLI: Pharmacogenomics of bortezomib test-dosing identifies hyperexpression of proteasome genes, especially PSMD4, as novel high-risk feature in myeloma treated with Total Therapy 3

Content Provider	PubMed Central
Author	Shaughnessy, John D. Qu, Pingping Usmani, Saad Heuck, Christoph J. Zhang, Qing Zhou, Yiming Tian, Erming Hanamura, Ichiro Rhee, Frits Van Elias, Anaissie Epstein, Joshua Nair, Bijay Stephens, Owen Williams, Ryan Waheed, Sarah Alsayed, Yazan Crowley, John Bart, Barlogie
Copyright Year	2011
Abstract	Gene expression profiling (GEP) of purified plasma cells 48 hours after thalidomide and dexamethasone test doses showed these agents' mechanisms of action and provided prognostic information for untreated myeloma patients on Total Therapy 2 (TT2). Bortezomib was added in Total Therapy 3 (TT3), and 48 hours after bortezomib GEP analysis identified 80 highly survival-discriminatory genes in a training set of 142 TT3A patients that were validated in 128 patients receiving TT3B. The 80-gene GEP model (GEP80) also distinguished outcomes when applied at baseline in both TT3 and TT2 protocols. In context of our validated 70-gene model (GEP70), the GEP80 model identified 9% of patients with a grave prognosis among those with GEP70-defined low-risk disease and 41% of patients with favorable prognosis among those with GEP70-defined high-risk disease. PMSD4 was 1 of 3 genes common to both models. Residing on chromosome 1q21, PSMD4 expression is highly sensitive to copy number. Both higher PSMD4 expression levels and higher 1q21 copy numbers affected clinical outcome adversely. GEP80 baseline-defined high risk, high lactate dehydrogenase, and low albumin were the only independent adverse variables surviving multivariate survival model. We are investigating whether second-generation proteasome inhibitors (eg, carfilzomib) can overcome resistance associated with high PSMD4 levels.
Related Links	http://dx.doi.org/10.1182/blood-2010-12-328252
Ending Page	3524
Page Count	13
Starting Page	3512
File Format	PDF
ISSN	00064971
e-ISSN	15280020
Journal	Blood
Issue Number	13
Volume Number	118
Language	English
Publisher	American Society of Hematology
Publisher Date	2011-09-29
Access Restriction	Open
Rights Holder	American Society of Hematology
Subject Keyword	Immunology Cell Biology Biochemistry Hematology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cell Biology Hematology Biochemistry Immunology

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