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Series GSE98206 Query DataSets for GSE98206
Status Public on Apr 03, 2018
Title MALT1 Inhibition Is Efficacious in Both Naïve and Ibrutinib-Resistant Chronic Lymphocytic Leukemia.
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary The clinical efficacy displayed by ibrutinib in chronic lymphocytic leukemia (CLL) has been challenged by the frequent emergence of resistant clones. The ibrutinib target, Bruton's tyrosine kinase (BTK), is essential for B-cell receptor signaling, and most resistant cases carry mutations in BTK or PLCG2, a downstream effector target of BTK. Recent findings show that MI-2, a small molecule inhibitor of the para-caspase MALT1, is effective in preclinical models of another type of BCR pathway-dependent lymphoma. We therefore studied the activity of MI-2 against CLL and ibrutinib-resistant CLL. Treatment of CLL cells in vitro with MI-2 inhibited MALT1 proteolytic activity reduced BCR and NF-κB signaling, inhibited nuclear translocation of RelB and p50, and decreased Bcl-xL levels. MI-2 selectively induced dose and time-dependent apoptosis in CLL cells, sparing normal B lymphocytes. Furthermore, MI-2 abrogated survival signals provided by stromal cells and BCR cross-linking and was effective against CLL cells harboring features associated with poor outcomes, including 17p deletion and unmutated IGHV Notably, MI-2 was effective against CLL cells collected from patients harboring mutations conferring resistance to ibrutinib. Overall, our findings provide a preclinical rationale for the clinical development of MALT1 inhibitors in CLL, in particular for ibrutinib-resistant forms of this disease. Cancer Res; 77(24); 7038-48. ©2017 AACR.
 
Overall design To investigate the effect targeting MALT1 with MI-2 on tumor biology, 1 μg of total RNA from purified CLL cells treated for 8h with 2 µM MI-2 in vitro (N=3) was subject to RNA sequencing (by next-generation sequencing) and compared to untreated controls (N=3).
Web link http://cancerres.aacrjournals.org/content/77/24/7038.long
 
Contributor(s) Saba NS, Wong D, Tanios G, Iyer J, Lobelle-Rich P, Dadashian E, Liu D, Fontan L, Flemington EK, Nichols C, Underbayev C, Safah H, Melnick A, Wiestner A, Herman SE
Citation(s) 28993409
Submission date Apr 25, 2017
Last update date Jul 25, 2021
Contact name Nakhle Saba
E-mail(s) nsaba@tulane.edu
Phone 504-988-6234
Organization name Tulane University
Department Internal Medicine/Hematology
Lab Saba
Street address 1415 Tulane Ave, Room 118
City New Orleans
State/province LA
ZIP/Postal code 70056
Country USA
 
Platforms (1)
GPL20301 Illumina HiSeq 4000 (Homo sapiens)
Samples (6)
GSM2589284 CLL-11_1064_Control
GSM2589285 CLL-07_1074_Control
GSM2589286 CLL-03_1088_Control
Relations
BioProject PRJNA384250
SRA SRP105222

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE98206_CLL-1064_TreatedvsControl.results.txt.gz 969.8 Kb (ftp)(http) TXT
GSE98206_CLL-1074_TreatedvsControl.results.txt.gz 1.0 Mb (ftp)(http) TXT
GSE98206_CLL-1088_TreatedvsControl.results.txt.gz 1022.7 Kb (ftp)(http) TXT
GSE98206_RAW.tar 8.5 Mb (http)(custom) TAR (of TXT)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file
Processed data are available on Series record

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