|
|
GEO help: Mouse over screen elements for information. |
|
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)
|
|
Relations |
BioProject |
PRJNA384250 |
SRA |
SRP105222 |
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 Selector |
Raw data are available in SRA |
Processed data provided as supplementary file |
Processed data are available on Series record |
|
|
|
|
|