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GEO help: Mouse over screen elements for information. |
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Status |
Public on Feb 14, 2018 |
Title |
Modulation of Navitoclax Sensitivity by Dihydroarteminisin-Mediated MCL-1 Repression |
Organism |
Mus musculus |
Experiment type |
Expression profiling by array
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Summary |
Poor prognosis BCR-ABL+ B-ALL leukemic cells are highly dependent on the expression of endogenous anti-apoptotic MCL-1. However, the survival of most normal blood cells (e.g. progenitors, lymphocytes, and granulocytes) and other normal cell types (e.g. cardiomyocytes and neurons) are also exquisitely dependent on Mcl-1 gene expression, suggesting that effective therapeutic inhibition of MCL-1 could be acutely toxic, especially when combined with standard chemotherapy. Therefore, as an alternative to MCL-1 inhibition, we have identified dihydroarteminisin (DHA), a water-soluble metabolite of the anti-malarial arteminisin, which induces the down-modulation of MCL-1 protein expression by triggering an endoplasmic reticulum stress response. The DHA induced repression of MCL-1 expression renders leukemic cells highly sensitive to synergistic cell death induced by BH3-mimetic agents such as navitoclax (ABT-263) in a mouse model of BCR-ABL+ B-ALL. Furthermore, DHA also synergizes with navitoclax in human Ph+ ALL cell lines, and primary patient derived xenografts of Ph+ ALL. These data demonstrate that combining DHA with BH3-mimetic agents can improve therapeutic response in poor prognosis leukemia.
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Overall design |
We used microarrays to compare the DHA treatement to controls in mice.
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Contributor(s) |
Budhraja A, Tunis M, Churchman ML, Kothari AR, Yang X, Xu H, Kaminska E, Panetta JC, Finkelstein D, Opferman JT |
Citation(s) |
28974549 |
Submission date |
Mar 08, 2017 |
Last update date |
Feb 21, 2018 |
Contact name |
David Finkelstein |
E-mail(s) |
david.finkelstein@stjude.org
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Phone |
9014953931
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Organization name |
St Jude Children's Research Hospital
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Department |
Computational Biology
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Street address |
332 N. Lauderdale St.
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City |
Memphis |
State/province |
TN |
ZIP/Postal code |
38105 |
Country |
USA |
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Platforms (1) |
GPL16570 |
[MoGene-2_0-st] Affymetrix Mouse Gene 2.0 ST Array [transcript (gene) version] |
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Samples (6)
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Relations |
BioProject |
PRJNA378488 |
Supplementary file |
Size |
Download |
File type/resource |
GSE95809_RAW.tar |
55.2 Mb |
(http)(custom) |
TAR (of CEL) |
Processed data included within Sample table |
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