E-GEOD-53684 - A mechanistic rationale for targeting the unfolded protein response in pre-B acute lymphoblastic leukemia [array]

Status
Released on 24 April 2014, last updated on 13 May 2014
Organism
Mus musculus
Samples (6)
Array (1)
Protocols (5)
Description
The plasma cell transcription factor XBP1 is critical for terminal differentiation of B cells into plasma cells but has no known role at earlier stages of B-cell development. Here we show that XBP1 is not only important during early B-cell development and for survival of pre-B cells but also protects pre-B ALL cells. Among pre-B ALL subset, XBP1 was hypomethylated and highest expressed in the Ph+ ALL subset. Cre-mediated deletion of XBP1 in a mouse model of Ph+ ALL compromised proliferation and viability and prolonged survival of leukemia-bearing mice. Interestingly, XBP1 expression levels were positively transcriptionally regulated by STAT5 and negatively by BACH2 and BCL6. High XBP1 expression in high risk ALL patients at the time of diagnosis predicted poor outcome in two clinical trials. Clinically, small-molecule inhibition of IRE1-dependent XBP1-activation caused cell death of patient-derived pre-B ALL cells and affected leukemia-initiation in transplant recipient mice. Collectively, these studies identify XBP1 as an important survival factor and as a potential therapeutic target to overcome drug-resistance in pre-B ALL. Genome-wide profiling of mRNA levels in BCR-ABL1 transduced murine Grp78 fl/fl pre-B cells with an empty vector (Grp78 wild type, MIG-1,2,3) and Cre  (Grp78 deletion, CRE-1,2,3).
Experiment type
transcription profiling by array 
Contacts
Huimin Geng <huimin.geng@ucsf.edu>, Behzad K Masouleh, Markus Muschen, Misook Chang
MIAME
PlatformsProtocolsVariablesProcessedRaw
Files
Investigation descriptionE-GEOD-53684.idf.txt
Sample and data relationshipE-GEOD-53684.sdrf.txt
Raw data (1)E-GEOD-53684.raw.1.zip
Processed data (1)E-GEOD-53684.processed.1.zip
Array designA-AFFY-36.adf.txt
Links